Organic Syntheses, Vol. 79, pp. 196-204
Checked by Hui Li and Marvin J. Miller.
1. Procedure
2. Notes
2. The salts can also be dissolved at room temperature. Warming to
ca. 40°C facilitates dissolution. Note that complete dissolution and observance
of precise concentration of the solution are essential for the success of the procedure.
3. The quality of the commercially available (colorless)
2-fluoroaminobenzene (1) is sufficient
(Fluka Chemical Company). Older or colored material
requires distillation prior to use (bp 171°C, d = 1.15).
4. Dissolution of aniline
1 is exothermic and it should therefore
be added in small portions. Complete dissolution is essential in order to avoid the
formation of dark tar-like by-products.
5. The longer the solution boils the more tar-like by-product is
formed. One to two min of boiling are necessary and sufficient for complete conversion
of the reactants.
6. The reaction mixture must not be cooled to 0°C as this leads
to the precipitation of inorganic salts.
7. The long period is necessary to obtain maximum yield.
8. Spectral characteristics are as follows: IR (KBr) cm
−1 : 3390 m (O-H), 1660
s (C=O), 1618 s (C=N), 1546, 1486,
1460 s (C=C), 1260 s (C-F)], 1021 m [ν(N-O)],
756 s [ν(C-H)
arom];
1H NMR (CD
3OD, 500.13 MHz)
δ: 7.09 (m, 3 H, H-3, H-4, H-5), 7.53 (s, 1 H, HC=NOH),
7.94 (m, 1 H, H-6);
13C NMR (CD
3OD,75.47 MHz) δ: 116.33
(d,
2J
F,3 = 19.8, C-3), 124.76 (C-5), 125.47
(d,
3J
F,6 = 4.0, C-6), 126.53 (d,
2J
F,1
= 11.3, C-1), 126.99 (d,
3J
F,4 = 7.9, C-4),
144.01 (HC=NOH), 155.42 (d,
1J
F,2
= 245.3, C-2), 162.88 (C=O).
9. Anilide
2 has to be completely dry. Residual water reacts
violently with the acid with heat generation causing decomposition.
10. By-products form if the temperature is too high. Anilide
2
does not dissolve completely if the temperature is below 50°C and then the reaction
does not go to completion.
11. The progress of the reaction can be monitored by hydrolysis of
a sample, extraction with
ethyl acetate,
and TLC [
silica gel Macherey, Nagel & Co.
"Polygram Sil G/UV 254",
petroleum ether/ethyl
acetate/acetic acid 99:50:1, UV visualization,
R
f (
2) = 0.40, R
f (
3) = 0.31 (yellow spot)].
12. If the temperature is too high, tar-like by-products form. If
the solution is cooled to 0°C, hydrolysis does not take place because the
sulfuric acid does not mix with the
hydrolysis solution and mainly oxime
5 is obtained.
13. The presence of
ethyl acetate
is essential as otherwise the yellow oxime
5 (
mp
233-235°C) is formed in yields of
20-30%.
Ethyl acetate is added in
order to extract the isatin
3 from the aqueous phase immediately upon formation.
Oxime
5 is probably formed by reaction of isatin
3 with
hydroxylamine
generated by decomposition of unreacted anilide
2.
2
Spectral characteristics of
7-fluoroisatin
3-oxime (5) are as follows:
TLC:
silica gel Macherey, Nagel & Co.
"Polygram Sil G/UV 254",
petroleum ether/ethyl
acetate PE/EE 2:1 elution,
2 drops
of glacial acetic acid, UV visualization, R
f
= 0.19; IR (KBr) cm
−1: ≈3500
m, br (OH), 1723 s (C=O), 1640 s (C=N),
1596, 1494, 1445 m (C=C), 1208
m (C-F), 942 m (N-O), 794 w νC-H
arom);
1H NMR (acetone-d
6,
500.13 MHz) δ: 7.06 (ddd, 1 H,
4J
5,F + 4.6,
3J
4,5
= 7.5,
3J
5,6 = 8.5, H-5), 7.20 (ddd, 1 H,
4J
4,6
=1.1,
3J
5,6 = 8.5,
3J
6,F = 10.1, H-6),
7,83 (dd, 1 H,
4J
4,6 = 1,0,
3J
4,5
= 7.0, H-4), 10.14 (bs, 1 H, N-H), 12.75 (bs, 1H,
N-OH);
13C
NMR (acetone-d
6, 125.76 MHz) δ: 115.75 (d,
3J
F,3
= 4.2, C-3a), 115.96 (C-6), 120.33 (C-5), 120.43
(C-4), 126.40 (d,
2J
F,8 = 13.4, C-7a), 140.65
(d,
4J
F,2 = 4.1, C-3), 143.85 (d,
1J
F,7
= 243,2, C-7), 161.71 (C-2); HR-MS (EI, direct insert): m/z 180.03322 (M
+
exact mass calcd for C
8H
5O
2N
2F: 180.0335),
163.0070 (M
+ - OH), 152.0365 (M
+ -
CO), 135.0359 (M
+ - CO
2H), 108.0271
(M
+ - CO - OH - HCN). Anal. Calcd for C
8H
5FN
2O
2:
C, 53.43; H, 2.80; N, 15.55. Found: C, 53.34; H, 3.08; N, 15.28.
14. If the aqueous phase is extracted more than twice, the yield
may rise, but the oxime
5 and other by-products are extracted as well.
15. Spectral characteristics are as follows: IR (KBr) cm
−1: 3446 w (NH-CO), 1737
s (C3=O), 1637 s (C2=O), 1602, 1495,
1452 m (C=C), 1209 m (C-F), 780 w (C-H)
arom;
1H NMR (acetone-d
6,
500.13 MHz) δ: 7.14 (ddd, 1 H,
4J
5,F = 4.2,
3J
4,5
= 7.7,
3J
5,6 = 8.3, H-5), 7.39 (dd, 1 H,
4J
4,6
= 1.1,
3J
4,5 = 7.4, H-4), 7.48 (ddd, 1 H,
4J
4,6
= 1.0,
3J
4,5 = 8.4,
3J
6,F = 10.2, H-6),
10.45 (bs, 1 H, N-H);
13C NMR (acetone-d
6, 125.76 MHz) δ:
119.15 (d,
3J
F,3 = 3.4, C-3a), 119.26 (d,
4J
F,4 = 3.5, C-4), 122.52 (d,
3J
F,5
= 5.3, C-5), 123.57 (d,
2J
F,6 = 17.6, C-6),
136.20 (d,
2J
F,8 = 13.9, C-7a), 146.38 (d,
1J
F,7 = 246.8, C-7), 157.29 (C-2), 181.70
(d,
4J
F,2 = 4.5, C-3).
16. Previously
3 3 N or 10 N NaOH was used. The submitters found that
this reaction also proceeds to completion at room temperature in 1 N NaOH solution.
17. Monitoring was carried out by extracting acidified samples with
ethyl acetate and TLC [
silica gel Macherey, Nagel & Co. "Polygram
Sil G/UV 254",
petroleum ether/ethyl
acetate/acetic acid 99:50:1, visualization
of spots by UV R
f = 0.37 (spot shows strong blue fluorescence)].
18. Spectral characteristics of
4 are as follows: IR (KBr) cm
−1: 3500-3391 m (NH
2),
3085 m, br (CO
2-H), 1678 s (C=O), 1630
w (C-NH
2)], 1590, 1562, 1476 m (C=C)],
780 w (C-H
arom);
1H NMR (acetone-d
6, 500.13 MHz) δ:
6.58 (ddd, 1 H,
4J
5,F = 4.9,
3J
5,6
= 7.9,
3J
4,5 = 8.0, H-5), 6.84 (bs, 1 H),
7.19 (ddd, 1 H,
4J
4,6 = 1.3,
3J
4,5
= 8.0,
3J
4,F = 11.6, H-4), 7.31 (bdd, 1 H),
7.63 (bd, 1 H), 7.67 (ddd, 1 H,
3J
6,F = 1.3,
4J
4,6 = 1.3,
3J
5,6 = 7.9, H-6);
13C NMR (acetone-d
6,
125.76 MHz) δ: 108.71 (d,
3J
F,1 = 4.5, C-1),
110.30 (d,
3J
F,5 = 7.0, C-5), 114.51 (d,
2J
F,4 = 18.5, C-4), 122.97 (d,
4J
F,6
= 3.0, C-6), 136.35 (d,
2J
F,2 = 14.0, C-2),
147.55 (d,
1J
F,3 = 237.4, C-3), 165.27 (d,
4J
F,7 = 3.4, C-7).
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
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