176
X. Zou, Z. Qiu / Journal of Fluorine Chemistry 116 (2002) 173±179
Compound (5): 51.5 g (yield 99.4%); mp: 118±20 8C (lit.
115±116 8C); IR(KBr): n 3347 and 1567 (NH2), 1515 and
round-bottomed ¯ask was heated to 80 8C. After added a
little AIBN, 1.1 ml (0.02 mol) of bromide was added drop-
wise in 5 h. After removal of the carbon tetrachloride, 4.1 g
of slight yellow solid was obtained, and the puri®cation was
1378 (NO2), and 1566, 1461 and 864 cmÀ1 (Ph); H NMR
1
(60 MHz, CCl4): d 2.21 (s, 3H, CH3), 5.81 (s, br, 2H,
3
NH2), 6.59 (d, 1H, JH;H 7:9 Hz, ArH-6), 7.10 (d, 1H,
not required. MS (EI, 70 eV), (m/e, %): 232 [M] (5.9), 234
3JH;H 7:9 Hz, ArH-5), 7.83 (s, 1H, ArH-3).
3.4. Preparation of 4-bromo-3-nitrotoluene (6)
[M 2] (5.9), 153 [M À Br] (100), 136 [M À Br±OH]
(5.9), 125 [M À 107] (27.9), 108 [M À Br±COOH] (17.6),
107 [M À 125] (20.0).
The reaction was carried out as described in [10]. 4-
Methyl-2-nitroaniline (36.4 g, 0.24 mol) was used to give a
yellow liquid (6): 26.8 g (yield 51.8%); bp: 84±100 8C/0.2±
0.3 mmHg (lit. 151.5±152.5 8C/14 mmHg); IR(®lm): n
3.9. Preparation of 2-fluoro-4-methoxymethylbenzonic
acid (11)
To a solution of 4.1 g of crude 4-bromomethyl-2-¯uor-
obenzonic acid in 10 ml methanol, 30 ml of sodium meth-
oxide solution which was prepared from 1.5 g (0.065 mol) of
sodium and 30 ml methanol was added dropwise. After the
addition, the mixture was heated to re¯ux for 2 h. After
cooled to room temperature, 50 ml of water was added.
After removal of the methanol, the mixture was acidi®ed by
concentrated hydrochloride acid, and a lot of white solid was
precipitated. After ®ltered and dried, 2.9 g of white solid was
obtained, and the puri®cation was also not required. MS (EI,
1535 and 1354 (NO2), and 1475 and 821 cmÀ1 (Ph); H
1
NMR(60 MHz, CCl 4): d 2.36 (s, 3H, CH3), 7.20±7.66 (m,
3H, ArH).
3.5. Preparation of 2-bromo-5-methylaniline (7)
The reaction was carried out as described in [11]. 4-
Bromo-3-nitrotoluene (40 g, 0.185 mol) was used to give a
colorless liquid (7): 29.35 g (yield 84.9%); bp: 72±80 8C/
0.22±0.25 mmHg (lit. 129±130 8C/16 mmHg); IR(®lm): n
3471, 3381 and 1614 (NH2), 1486 and, 858 cmÀ1 (Ph); 1H
70 eV), (m/e, %): 184 [M] (32.4), 183 [M À 1] (29.4), 169
[M À Me] (48.5), 167 [M À OH] (11.8), 153 [M À OMe]
NMR(60 MHz, CCl ): d 2.17 (s, 3H, CH3), 3.80 (s, br,
(55.9), 151 [M À Me±H2O] (61.8), 139 [M À COOH]
4
2H, NH2), 6.26 (d, 1H, 3JH;H 7:9 Hz, ArH-4), 6.43 (s, 1H,
(72.1), 125 [M À OMe±CO] (43.5), 107 [M À OMe±CO±
3
ArH-6), 7.18 (d, 1H, JH;H 7:9 Hz, ArH-3).
H2O] (37.6), 45 [M À C6H3FCOOH] (100).
3.6. Preparation of 4-bromo-3-fluorotoluene (8)
3.10. Preparation of 2-fluoro-4-methoxymethylbenzyl
alcohol (12)
The reaction was carried out as described in [12]. 2-
Bromo-5-methylaniline (29 g, 0.156 mol) was used to give a
colorless liquid (8): 17 g (yield 57.7%); bp: 84±86 8C/
30 mmHg (lit. 95 8C/50 mmHg); IR(®lm): n 1582,
A solution of 2 g (0.048 mol) of lithium aluminum
hydride in 20 ml THF was added in a 100 ml three-necked
¯ask equipped with re¯ux condenser, dropping funnel and
mechanical stirrer, and protected from moisture by calcium
chloride tube attached to the openings. Through the drop-
ping funnel, a solution of 2.9 g of crude 2-¯uoro-4-methox-
ymethylbenzonic acid in 15 ml THF was added at a rate such
as to produce gentle re¯ux. After the addition, water was
added cautiously to decompose excess hydride. Then 50 ml
of 10% sulfuric acid was added. After removal of the THF,
the mixture was extracted with ether, and the ether layer was
washed by saturated sodium hydrogen carbonate and dried.
After removal of the ether, 2.3 g of liquid was obtained. The
liquid was puri®ed by column chromatography on silica gel.
The eluate cyclohexane-ethyl acetate (4:1 v/v) was evapo-
rated in vacuum to give a colorless liquid (12): 0.9 g (yield
26.3% based on 2-¯uoro-4-methylbenzonic acid); IR(®lm):
n 3409 and 1509 (alcohol), 1581, 871 and 829 (Ph), 1194
(C±F), and 1096 cmÀ1 (C±O±C); 1H NMR(400 MHz,
CDCl3): d 1.756 (s, 1H, OH), 3.388 (s, 3H, CH3),
4.441 (s, 2H, ROCH2ph), 4.743 (s, 2H, phCH2OH), 7.052
(d, 1H, 3JF;H 10:4 Hz, ArH-3), 7.100 (d, 1H,
1486, 861 and 808 (Ph), and 1158 cmÀ1 (C±F); H NMR
1
(60 MHz, CCl4): d 2.33 (s, 3H, CH3), 6.89±7.69 (m, 3H,
ArH).
3.7. Preparation of 2-fluro-4-methylbenzonic acid (9)
The reaction was carried out as described in [13]. Com-
pound (8) (6.3 g, 0.058 mol) was used to give a white solid
(9): 3.1 g (yield 34.9%); mp: 183±186 8C (lit. 181±182 8C);
IR(KBr): n 3000±2500, 1689 and 1439 (COOH), 1574,
839, and 774 (Ph), and 1161 cmÀ1 (C±F); 1H NMR
(400 MHz, DMSO-d6): d 2.363 (s, 3H, CH3), 7.095±
3
7.132 (m, 2H, ArH-3, -5), 7.752 (t, 1H, JH;H 8 Hz,
4JF;H 8 Hz, ArH-6); 12.9 (s, br, 1H, COOH). MS (EI,
70 eV), (m/e, %): 154 [M] (60.9), 137 [M À OH] (100),
109 [M À COOH] (48.7).
3.8. Preparation of 4-bromomethyl-2-fluorobenzonic acid
(10)
3
3JH;H 7:6 Hz, ArH-5) 7.387 (t, 1H, JH;H 7:6 Hz,
4JF;H 7:6 Hz, ArH-6); 19F NMR(284 MHz, CDCl ): d
A solution of 2-¯uoro-4-methylbenzonic acid (3.1 g,
0.02 mol) of in 70 ml of carbon tetrachloride in a 100 ml
3
À120.5 (s, 1F, ArF). MS (EI, 70 eV), (m/e, 100%): 170