PAPER
Regioexhaustive Functionalization of Difluorophenols and Trifluorophenols
1613
1H NMR: d = 6.58 (dd, J = 8.9, 2.2 Hz, 2 H), 6.46 (tt, J = 9.0, 2.3
amine (diisopropylamine or 2,2,6,6-tetramethylpiperi-
dine) catalyzes the equilibration2 between a more basic
and a less basic organometallic intermediate.
Hz, 1 H), 5.14 (s, 2 H), 3.47 (s, 3 H).
13C NMR: d = 163.5 (dd, J = 246, 16 Hz, 2 C), 159.1 (t, J = 14 Hz),
99.9 (d, J = 29 Hz), 97.3 (t, J = 26 Hz, 2 C), 94.5 (s), 56.1 (s).
MS (c.i.): m/z (%) = 192 (0, [M+ + NH4]), 175 (12, [M+ + 1]), 174
Details concerning standard operations and abbreviations can be
found in previous publications from this laboratory.9,10 1H and (1H-
decoupled) 13C NMR spectra were recorded at 400 and 101 MHz,
respectively, samples having been dissolved in CDCl3 or, if marked
by an asterisk (*), in acetone-d6. Mass spectra were obtained at 70
eV ionization potential while a source temperature of 200 °C was
maintained. Whenever no molecular peak was observed under such
conditions, chemical ionization (c.i.) in an ammonia atmosphere at
100 °C source temperature was applied. To avoid redundancy, only
the [35Cl] fragments, and not the [37Cl] isotopomers, are listed in all
cases.
(100, [M+]), 143 (28), 113 (36).
1,2-Difluoro-4-(methoxymethoxy)benzene (23)
Prepared, analogously as compound 19, from 3,4-difluorophenol
(13 g, 0.10 mol); colorless liquid; bp 65–66 °C/10 Torr;
nD20 1.4566; yield: 14.3 g (82%).
1H NMR: d = 7.06 (symm. m, 1 H), 6.89 (ddd, J = 11.8, 6.7, 3.0 Hz,
1 H), 6.7 (symm. m, 1 H), 5.12 (s, 2 H), 3.47 (s, 3 H).
13C NMR: d = 153.5 (dd, J = 8, 2 Hz), 150.3 (dd, J = 247, 14 Hz),
145.7 (dd, J = 241, 13 Hz), 117.1 (dd, J = 18, 2 Hz), 111.8 (dd,
J = 6, 3.5 Hz), 106.0 (d, J = 20 Hz), 94.9, 55.9.
Starting Materials
MS (c.i.): m/z (%) = 192 (0, [M+ + NH4]), 175 (70, [M+ + 1]), 174
(100, [M+]), 144 (28), 129 (14), 101 (20).
1,3-Difluoro-4-(methoxymethoxy)benzene (19); Typical Proce-
dure
Chloromethyl methyl ether11 (9.1 mL, 9.7 g, 0.12 mol) was added to
a solution of 2,4-difluorophenol (13 g, 0.10 mol) and N-ethyldiiso-
propylamine (18 mL, 16 g, 0.12 mol) in CH2Cl2 (80 mL) kept at
0 °C. After standing for 2 h at 25 °C, the mixture was poured into a
3.0 M aq solution of NaOH (0.20 L). Extraction with Et2O (2 × 100
mL) and distillation gave a colorless liquid; bp 68–70 °C/4 Torr;
nD20 1.4594; yield: 14.4 g (83%).
1H NMR: d = 7.14 (td, J = 9.1, 5.5 Hz, 1 H), 6.86 (td, J = 11.2, 1.6
Hz, 1 H), 6.78 (tm, J = 9.1 Hz, 1 H), 5.15 (s, 2 H), 3.52 (s, 3 H).
13C NMR: d = 157.9 (dd, J = 242, 10 Hz), 153.6 (dd, J = 256, 22
Hz), 141.8 (dd, J = 11, 4 Hz), 119.6 (dd, J = 9, 3 Hz), 110.0 (dd,
J = 22, 4 Hz), 105.2 (dd, J = 27, 22 Hz), 95.8 (s), 56.7 (s).
1,2,4-Trifluoro-5-(methoxymethoxy)benzene (24)
Prepared, analogously as compound 19, from 2,4,5-trifluorophenol
(7.4 g, 50 mmol); colorless liquid; bp 61–62 °C/8 Torr; nD20 1.4407;
yield: 7.58 g (79%).
1H NMR: d = 7.09 (ddd, J = 11.3, 7.7, 7.7 Hz, 1 H), 6.98 (ddd,
J = 10.2, 10.2, 7.4 Hz, 1 H), 5.15 (s, 2 H), 3.52 (s, 3 H).
13C NMR: d = 148.6 (ddd, J = 245, 9, 3 Hz), 146.3 (ddd, J = 244,
13, 4 Hz), 144.7 (ddd, J = 245, 14, 10 Hz), 141.2 (ddd, J = 12, 8, 4
Hz), 107.5 (dd, J = 22, 2 Hz), 106.0 (ddd, J = 24, 22, 2 Hz), 96.4,
56.5.
MS (c.i.): m/z (%) = 210 (0, [M+ + NH4]), 193 (25, [M+ + 1]), 192
(45, [M+]), 161 (52), 147 (34), 119 (100).
MS (c.i.): m/z (%) = 192 (0, [M+ + NH4]), 174 (67, [M+]), 143 (100),
129 (76).
1,2,3-Trifluoro-4-(methoxymethoxy)benzene (25)
Prepared, analogously as compound 19, from 2,3,4-trifluorophenol
(14.8 g, 0.10 mol); mp 24 – 26 °C; yield: 15.5 g (81%).
1H NMR: d = 6.9 (m, 2 H), 5.18 (s, 2 H), 3.54 (s, 3 H).
13C NMR: d = 146.9 (ddm, J = 239, 10 Hz), 143.6 (ddd, J = 236, 11,
4 Hz), 142.9 (dd, J = 9, 4 Hz), 142.2 (ddd, J = 251, 16, 13 Hz),
112.2 (dd, J = 7, 4 Hz), 110.9 (dd, J = 18, 4 Hz), 96.8 (s), 56.8 (s).
1,4-Difluoro-2-(methoxymethoxy)benzene (20)
Prepared, analogously as compound 19, from 2,5-difluorophenol
(13 g, 0.10 mol); colorless liquid; bp 46–47 °C/3 Torr; nD20 1.4649;
yield: 15.8 g (91%).
1H NMR: d = 7.05 (ddd, J = 10.5, 9.1, 5.3 Hz, 1 H), 6.96 (ddd,
J = 12.1, 8.4, 5.4 Hz, 1 H), 6.7 (m, 1 H), 5.19 (s, 2 H), 3.51 (s, 3 H).
13C NMR: d = 158.6 (dd, J = 242, 2 Hz), 149.4 (dd, J = 241, 3 Hz),
145.6 (dd, J = 12, 4 Hz), 116.4 (dd, J = 21, 10 Hz), 108.2 (dd,
J = 23, 6 Hz), 105.6 (d, J = 27 Hz), 95.6 (s), 56.4 (s).
MS (c.i.): m/z (%) = 210 (3, [M+ + NH4]), 192 (3, [M+]), 154 (9),
130 (100).
(3,4-Difluorophenoxy)triisopropylsilane (26)
MS (c.i.): m/z (%) = 192 (0, [M+ + NH4]), 174 (65, [M+]), 144 (27),
143 (33), 84 (100).
3,4-Difluorophenol (6.5 g, 50 mmol), chlorotriisopropylsilane (11
mL, 10 g, 50 mmol) and imidazole (3.4 g, 50 mmol) were dissolved
in DMF (25 mL). After 20 h at 25 °C, the mixture was poured into
H2O (50 mL) and extracted with CH2Cl2 (3 × 25 mL). Distillaton
under reduced pressure gave a colorless liquid; bp 186–188 °C/9
Torr; nD20 1.4759; yield: 11.2 g (78%).
1H NMR: d = 6.98 (q, J = 9.2 Hz, 1 H), 6.68 (ddd, J = 11.9, 6.7, 3.0
Hz, 1 H), 6.6 (symm. m, 1 H), 1.2 (m, 3 H), 1.09 (d, J = 7.2 Hz, 18
H).
13C NMR: d = 152.3 (dd, J = 9, 3 Hz), 150.2 (dd, J = 248, 14 Hz),
145.3 (dd, J = 240, 13 Hz), 116.9 (dd, J = 18, 2 Hz), 115.1 (dd,
J = 6, 3 Hz), 109.1 (d, J = 18 Hz), 17.8 (6 C), 12.5 (3 C).
MS (c.i.): m/z (%) = 304 (0, [M+ + NH4]), 286 (21, [M+]), 243 (86),
215 (22), 187 (100), 173 (62), 157 (53).
1,2-Difluoro-3-(methoxymethoxy)benzene (21)
Prepared, analogously as compound 19, from 2,3-difluorophenol
(13 g, 0.10 mol); colorless liquid; bp 68–70 °C/9 Torr; nD20 1.4669;
yield: 14.3 g (82%).
1H NMR: d = 7.0 (m, 2 H), 6.8 (m, 1 H), 5.22 (s, 2 H), 3.53 (s, 3 H).
13C NMR: d = 151.5 (dd, J = 247, 11 Hz), 146.7 (dd, J = 8, 3 Hz),
142.1 (dd, J = 248, 14 Hz), 123.3 (dd, J = 8, 5 Hz), 112.8 (d, J = 3
Hz), 110.4 (d, J = 17.5 Hz), 95.9, 56.5.
MS (c.i.): m/z (%) = 192 (0, [M+ + NH4]), 175 (57, [M+ + 1]), 174
(79, [M+]), 144 (71), 113 (35), 101 (100).
1,3-Difluoro-5-(methoxymethoxy)benzene (22)
Prepared, analogously as compound 19, from 3,5-difluorophenol
(13 g, 0.10 mol); colorless liquid; bp 40–42 °C/3 Torr; nD20 1.4684;
yield: 14.1 g (81%).
(2,3-Difluorophenoxy)triisopropylsilane (27)
Prepared, analogously as compound 26, from 2,3-difluorophenol
(6.5 g, 50 mmol); colorless liquid; bp 124–126 °C/8 Torr;
nD20 1.4782; yield: 13.4 g (94%).
Synthesis 2004, No. 10, 1609–1618 © Thieme Stuttgart · New York