gave a crude reaction mixture (58% conv) that contained
4-Formylbenzonitrile 1e. Elemental fluorine (33 mmol) and
4-formylbenzonitrile 1e (1.5 g, 11 mmol) in acetonitrile (150
3
2
-fluoro-4-methylbenzaldehyde 2e, δ
F
-126.9 (t, JHF ) 6.77),
3
and 3-fluoro-4-methylbenzaldehyde 2f, δ
F
-116.5 (qt, JHF
)
mL) gave a crude reaction mixture (44% conv) that contained
5
3
1
0.16, JHF ) 2.07), in the ratio 1:7.3.
The reaction mixture was poured into water, extracted by
) and evaporated
3-fluoro-4-formylbenzonitrile 2k, δ
F
-119.6 (dd, JHF ) 9.48,
3
JHF ) 7.81), and 4-cyanobenzoyl fluoride 2l, δ
F
20.3 (s), in
dichloromethane (3 × 100 mL), dried (MgSO
4
the ratio 1:4.
to give a dark crude product. Purification by column chroma-
After reaction with 3,5-dinitrophenylmethanol and pyridine
(1 mL), purification by column chromatography gave 3-fluoro-
tography gave 3-fluoro-4-methylbenzaldehyde 2f (0.73 g, 73%)
28
as a bright yellow liquid; (found C 69.3; H, 5.4. C
8
5
H
7
FO
-116.5 (qt, JHF ) 10.16, JHF
2.23 (3H, d, JHF ) 1.90, CH ), 7.21 (1H, m, H-5),
.36 (1H, m, H-2), 7.45 (1H, m, H-6), 9.87 (1H, br s, CHO);
4-formylbenzonitrile 2l (0.09 g, 12%) as a pale yellow solid;
3
3
4
requires C, 69.5; H, 5.1); δ
F
)
mp 71–72 °C; δ
F
H
-119.6 (dd, JHF ) 9.5, JHF ) 7.8); δ 7.45
4
(
1H, m, H-2), 7.51 (1H, m, H-6), 7.92 (1H, m, H-5), 10.33
2
.07); δ
H
3
4
3
(1H, s, CHO); δ
c
115.5 (d, JCF ) 2.7, CN), 118.6 (d, JCF )
7
2
2
3
2
9.9, C-1), 119.7 (d, J ) 24.3, C-2), 127.1 (d, J ) 33.7,
C-4), 127.4 (d, J ) 4.2, C-6), 128.9 (d, J ) 2.6, C-5),
162.5 (d, J ) 241.3, C-F), 182.5 (m, CHO); m/z (EI ) 150
([M] , 36%), 130 (100), 102 (58) and 4-cyano-3,5-dinitroben-
δ
(
c
14.5 (d, JCF ) 3.52, CH
3
), 122.5 (d, JCF ) 22.9, C-2), 126.1
CF
CF
4
3
d, 4JCF ) 3.0, C-6), 132.3 (d, JCF ) 4.78, C-5), 132.2 (d, JCF
3
2
CF
CF
1
+
3
1
)
18.8, C-4), 136.2 (d, JCF ) 5.21, C-1), 160.6 (d, JCF
)
CF
+
4
+
+
246.3, C-F), 191.0 (d, JCF ) 2.03, CHO); m/z (EI ) 138 ([M] ,
zyl-benzoate 3d (0.85 g, 54%) as a white solid; mp 199.9–201.6
100%), 137 (88), 113 (98).
°
C; (found C, 54.9; H, 2.7; N, 12.9. C15
H
9
N
3
O
6
requires C,
), 7.60 (2H, AX,
HH ) 8.05, H-3), 8.15 (1H, AX, JHH ) 7.21, H-2), 8.50
2H, m, H-2′), 9.02 (1H, m, H-4′); δ 69.2 (s, CH ), 116.2 (s,
4-Methoxy-benzaldehyde 1c. Elemental fluorine (44 mmol)
5
5.0; H, 2.7; N, 12.8); δ 5.51 (2H, s, CH
H
2
and 4-methoxy-benzaldehyde 1c (2.0 g, 14.7 mmol) in aceto-
nitrile (150 mL) gave a crude reaction mixture (66% conv) that
3
3
J
(
c
2
contained 3-fluoro-4-methoxybenzaldehyde 2g, δ
and 3,5-difluoro-4-methoxy-benzaldehyde 2 h, δ
F
-133.8 (m),
F
126.9 (m),
CN), 116.7 (s, C-4), 117.4 (s, C-4′), 128.3 (s, C-2′), 130.0 (s,
C-2), 131.4 (s, C-3), 134.7 (s, C-1), 142.3 (s, C-1′), 148.8
in the ratio 5:1.
+
+
(
9
s, C-3′), 168.7 (s, C)O); m/z (EI ) 327 ([M] , 11%) 131 (100),
2 (59).
Fluorination of meta-Substituted Benzaldehydes 4. 3-Ni-
Purification by column chromatography gave 3-fluoro-4-
methoxybenzaldehyde 2g (1.18 g. 79%) as a yellow liquid; δ
133.9 (m); δ 3.89 (3H, br s, OCH ), 7.01 (1H, m, H-5), 7.51
2H, m, H-2,6), 9.77 (1H, br s, CHO); δ 56.5 (s, OCH ), 118.6
F
-
H
3
trobenzaldehyde 4a. Elemental fluorine (45 mmol) and 3-ni-
trobenzaldehyde 4a (2.5 g, 15 mmol) in acetonitrile (150 mL)
(
c
3
3
2
4
(d, JCF ) 9.9, C-5), 115.7 (d, JCF ) 24.3, C-2), 128.3 (d, JCF
3
1
gave a crude reaction mixture (39% conv) that contained
)
3.37, C-6), 130.3 (d, JCF ) 4.8, C-1), 152.6 (d, JCF ) 248.3,
3
2
4
3-fluoro-5-nitrobenzaldehyde 5a, δ
3-nitrobenzoyl fluoride 5b, δ
After reaction with 3,5-dinitrophenylmethanol and pyridine
1 mL), purification by column chromatography gave 3-fluoro-
-nitrobenzaldehyde 5a (0.15 g, 15%) as an orange solid; mp
7–49 °C; (found C, 49.2; H, 2.4; N, 8.1. C FNO requires
-103.2 (t, JHF ) 7.8); δ 7.95
1H, m, H-2), 8.15 (1H, m, H-4), 8.47 (1H, m, H-6), 10.03
F
-103.2 (t, JHF ) 7.8), and
C-F), 153.3 (d, JCF ) 11.01, C-4), 190.0 (d, JCF ) 2.13, CHO);
+
F
20.3 (s), in the ratio 1:4.1.
m/z (EI ) 156 (2), 154 (88), 153 (98) and 3,5-difluoro-4-
27
methoxy-benzaldehyde 2h (0.18 g, 12%) as a yellow liquid;
4.07 (3H, br s, OCH ), 7.39 (2H, m, H-2), 9.76 (1H, br s,
CHO); δ 60.7 (s, OCH ), 112.1 (m, C-2), 129.1 (m, C-1), 141.5
t, JCF ) 13.5, C-4), 156.2 (dd, JCF ) 252.1, JCF ) 5.96,
(
5
δ
H
3
c
3
4
7 4
H
3
2
1
3
(
3
C, 49.2; H, 2.3; N, 8.2); δ
F
H
+
+
C-3), 188.2 (s, C)O); m/z (EI ) 172 ([M] , 2%) 172 (84), 171
100).
-Trifluoromethyl-benzaldehyde 1d. Elemental fluorine
24mmol) and 4-trifluoromethyl-benzaldehyde 1d (1.4 g, 8
mmol) in acetonitrile (150 mL) gave a crude reaction mixture
35% conv) that contained 2-fluoro-4-trifluoromethyl-benzal-
(
(
2
2
(1H, s, CHO); δ
c
116.9 (d, JCF ) 25.3, C-4), 120.7 (d, JCF
)
4
2
3
3
.37, C-6), 121.5 (d, JCF ) 22.4, C-2), 139.1 (d, JCF ) 6.1,
(
3
1
C-1), 149.9 (d, JCF ) 8.14, C-5), 164.1 (d, JCF ) 254.3, C-F),
4
+
+
1
88.8 (d, JCF ) 1.9, CHO); m/z (EI ) 170 ([M] , 18%), 140
100), 96 (48) and 3-nitro-3,5-dinitrobenzyl-benzoate 6a (1.45
g, 64%) as an orange solid; mp 135.4–137.1 °C; (found C, 48.3;
H, 2.5; N, 12.3. C14 requires C, 48.4; H, 2.6; N, 12.1);
5.79 (2H, m, CH ), 7.89 (1H, m, H-5), 8.51 (1H, m, H-4),
.54 (1H, m, H-6), 8.82 (1H, t, JHH ) 1.64, H-2), 8.88 (2H,
m, H-2′), 8.95 (1H, m, H-4′); δ 65.0 (s, CH ), 118.2 (s, C-4′),
24.3 (s, C-2′), 128.1 (s, C-2), 128.9 (s, C-4), 130.7 (s, C-5),
31.2 (s, C-1), 135.6 (s, C-6), 140.6 (s, C-3), 148.6 (s, C-1′),
(
(
3
3
dehyde 2i, δ
F
-115.6 (dd, JFF ) 10.48, JHF ) 9.83) and
-trifluoromethyl-benzoyl fluoride 2j, δ 21.3 (s), in the ratio
:2.
After reaction with 3,5-dinitrophenylmethanol and pyridine
1 mL), purification by column chromatography gave 4-triflu-
4
1
F
9 3 8
H N O
δ
8
H
2
3
(
c
2
oromethyl-(3,5-dinitrobenzyl)-benzoate 3c (0.63 g, 61%) as a
white solid; mp 149–151 °C; (found C, 48.7; H, 2.4; N, 7.6.
1
1
1
C
CH
15
H
9
F
3
N
2
O
6
requires C, 48.6; H, 2.4; N, 7.6); δ
H
5.75 (2H, s,
+
+
48.9 (s, C-3′), 164.2 (s, C)O); m/z (EI ) 347 ([M] , 5%) 330
3
3
2
), 7.89 (2H, AX, JHH ) 8.85, H-3), 8.31 (2H, AX, JHH )
(24), 180 (100), 150 (42).
7
.75, H-2), 8.86 (2H, m, H-2′), 8.92 (1H, m, H-4′); δ
c
65.2 (s,
3-Formylbenzonitrile 4b. Elemental fluorine (57 mmol) and
1
CH
2 3
), 118.2 (q, JCF ) 245.2, CF ) 118.7 (s, C-4′), 125.3 (q,
3-formylbenzonitrile 4b (2.5 g, 19 mmol) in acetonitrile (150
3
J
CF ) 3.75, C-3), 128.3 (s, C-2′), 130.4 (s, C-2), 130.7 (s, C-1),
mL) gave a crude reaction mixture (34% conv) that contained
2
1
1
1
35.3 (q, JCF ) 32.5, C-4), 140.6 (s, C-1′), 148.8 (s, C-3′),
64.7 (s, C)O), m/z (EI ) 370 ([M] , 8%) 330 (24), 180 (100),
50 (42).
3
3
-fluoro-5-formyl benzonitrile 5c, δ
F
-107.2 (t, JHF ) 7.2),
+
+
and 3-cyanobenzoyl fluoride 5d, δ 17.3 (s), in the ratio 1:3.2.
F
(
28) Solms, S. J. D.; Ciccarone, T. M.; MacTough, S. C. J. Med. Chem.
(
27) Sander; W. Exner, M. J. Chem. Soc., Perkin Trans. 1 1999, 2295.
2003, 46, 2973.
Vol. 12, No. 2, 2008 / Organic Process Research & Development
•
343