B. Shen et al. / Journal of Fluorine Chemistry 128 (2007) 1461–1468
1465
Germany). For the MPLC system (Bu¨chi, Switzerland) silica
gel 60 (0.040–0.063 mm; Merck) was used, eluents were
mixtures of petrolether (60/90) and ethylacetate. Precursors and
reference standards were characterized by their melting point
(Gallenkamp MPG 350, Germany), IR (Spectrum One FT-
ATR-IR, Perkin–Elmer, Boston, USA), MS (Finnigan MAT
TSQ 70, Bremen, Germany) and NMR (Bruker Avance 400,
Rheinstetten, Germany). For NMR measurements, as internal
standards the deuterated solvents were used (DMSO-d6:
d = 2.49 in H and d = 39.5 in 13C; CDCl3: d = 7.25 in H
and d = 77.0 in 13C). The chemical shift d in ppm was referred to
the internal standard. All radiochemical yields given in this
work represent an average of three to five experiments.
IR (n¯, cmꢁ1): 3104 (85%), 3066 (82%), 2945 (84%), 2841
(85%), 1679 (56%), 1600 (59%), 1564 (77%), 1524 (41%),
1500 (56%), 1458 (74%), 1435 (70%), 1403 (79%), 1353
(52%), 1320 (60%), 1282 (54%), 1241 (38%), 1200 (65%),
1184 (52%), 1140 (59%), 1067 (48%), 1025 (44%), 963 (78%),
910 (56%), 897 (47%), 825 (29%), 775 (57%), 758 (54%), 698
(76%), 675 (73%), 655 (62%).
MS-EI (70 eV): m/z: 181 ([M]ꢂ+, C8H7NO4, 4%); 151
([M ꢁ NO]+, C8H7O3, 100%); 134 ([M ꢁ NO ꢁ OH]+,
C8H6O2, 21%); 119 (4%); 108 (18%); 106 (26%); 95 (22%);
92 (12%); 77 ([C6H5]+, 8%); 63 ([C5H3]+, 23%); 50 (3%).
HRMS (EI): m/z measured: 181.03411 ([M]ꢂ+, C8H7NO4);
m/z calculated: 181.037486.
1
1
4.2. Precursors and reference standards
4.2.2. 5-Methoxy-2-nitrobenzaldehyde (3c)
To a stirred suspension of 5-hydroxy-2-nitrobenzaldehyde
(3.99 g, 24 mmol) and K2CO3 (3.18 g, 24 mmol) in DMF
(40 mL), methyliodide (1.49 mL, 24 mmol) was added drop-
wise at 0 8C. After the addition, the suspension was stirred at
room temperature. The reaction was monitored by TLC. After
3 h, the starting material was completely reacted. The reaction
mixture was poured into water and extracted with 3ꢃ 50 mL of
diethylether. The combined organic layers were washed with
100 mL of water and dried over Na2SO4. After evaporation of
the solvent, the residue was purified by MPLC using
petrolether:ethylacetate (1:1) to yield 3.77 g 3c as yellow
crystals (87%).
As precursors and reference standards, the following
compounds of the highest purity available were from either
Sigma–Aldrich, Fluka, ABCR, Alfa Aesar, AVOCADO or
Fluorochem and were used as received (authenticity of the
fluoro compounds used as standards was confirmed by NMR
and MS): 2-fluorobenzaldehyde (1a; purity 97%), 4-fluoro-
benzaldehyde (2a; >98%), 2-nitrobenzaldehyde (1b; 98%), 4-
nitrobenzaldehyde (2b; 98%), 2-chlorobenzaldehyde (1c;
99%), 4-chlorobenzaldehyde (2c; 97%), 2-bromobenzaldehyde
(1d; >98%), 4-bromobenzaldehyde (2d; >97%), 3-methoxy-2-
nitrobenzaldehyde (3a; >97%), 4-nitro-2-methoxybenzalde-
hyde (4b; 97%), 2-fluoro-3-methoxybenzaldehyde (97%), 2-
fluoro-4-methoxybenzaldehyde (98%), 2-fluoro-5-methoxybe-
nzaldehyde (98%), 2-fluoro-6-methoxybenzaldehyde (98%), 4-
fluoro-3-methoxybenzaldehyde (98%), 4-fluoro-2-methoxy-
benzaldehyde (98%), 2-bromobenzoic acid (98%), 2-nitroben-
zoic acid (98%) and 4-nitrobenzoic acid (>98%).
mp: 81–82 8C (83 8C [21]).
1H NMR (CDCl3, 250 MHz): d = 10.46 (s, 1H, –CHO), 8.13
(d, 1H, J = 9.1 Hz, Harom), 7.30 (s, 1H, Harom), 7.13 (d, 1H,
J = 9.1 Hz, Harom), 3.94 (s, 3H, –OCH3). 13C NMR (CDCl3,
60 MHz): d = 55.7, 113.5, 118.9, 127.6, 134.6, 142.6, 164.3,
188.8.
All other precursors in Table 2 were synthesized as follows.
IR (n¯, cmꢁ1): 3102 (81%), 2982 (82%), 2946 (79%), 2845
(82%), 2666 (83%), 2166 (87%), 1922 (87%), 1689 (37%),
1609 (77%), 1580 (29%), 1499 (31%), 1479 (47%), 1459
(61%), 1442 (47%), 1419 (51%), 1390 (45%), 1326 (24%),
1286 (25%), 1233 (29%), 1187 (41%), 1159 (33%), 1079
(39%), 1024 (38%), 1001 (48%), 963 (66%), 929 (27%), 892
(28%), 847 (31%), 834 (22%), 771 (52%), 741 (23%), 688
(42%), 667 (45%).
4.2.1. 4-Methoxy-2-nitrobenzaldehyde (3b)
4-Bromo-3-nitroanisole (1.75 g, 7.5 mmol) was dissolved
in anhydrous THF (80 mL) under argon. The solution was
cooled to ꢁ78 8C, and phenyl lithium (4 mL, 7.5 mmol) was
added dropwise. The temperature was kept between ꢁ70 and
ꢁ90 8C for 2 h. Then, DMF (1.5 mL, 20 mmol) was added
dropwise and the reaction solution was stirred between ꢁ70
and ꢁ90 8C for an additional hour. After warming to 0 8C
within 1 h the solution was quenched by adding acetic acid
(100%; 5 mL). The resulting mixture was partitioned between
100 mL of diethylether and 50 mL of water. The organic layer
was washed with 50 mL of saturated NaHCO3 solution, 50 mL
of water and 50 mL of brine, dried over Na2SO4 and
concentrated to afford a crude product, which was purified
by MPLC (petrolether:ethylacetate, 9:1) to yield 0.9 g 3b as
yellow crystals (65%).
MS-EI (70 eV): m/z: 181 ([M]ꢂ+, C8H7NO4, 10%); 180
([M ꢁ H]+, C8H6NO4, 29%); 163 ([M ꢁ H2O]ꢂ+, C8H5NO3,
5%); 151 ([M ꢁ NO]+, C8H7O3, 41%); 133 ([M ꢁ H2O
ꢁ NO]ꢂ+, C8H5O2, 21%); 123 (32%); 108 (65%); 95 (54%);
77 ([C6H5]+, 24%); 64 (37%); 63 ([C5H3]+, 100%); 52
([C4H4]ꢂ+, 21%); 49 (14%).
HRMS (EI): m/z measured: 181.03488 ([M]ꢂ+, C8H7NO4);
m/z calculated: 181.037486.
4.2.3. 2-Methoxy-6-nitrobenzaldehyde (3d)
mp: 95–96 8C (96–97 8C [20]).
To a stirred solution of hexamethylenetetramine (3.63 g,
25.92 mmol) in trifluoro acetic acid (35 mL) 3-nitrophenol
(3 g, 21.6 mmol) was added. The solution was refluxed at
130 8C under Ar. After 27 h, TLC showed complete conversion
of the starting material. The reaction solution was cooled down
and quenched by adding 6N HCl (120 mL). After 20 min of
1H NMR (CDCl3, 400 MHz): d = 10.28 (s, 1H, –CHO), 7.96
(d, 1H, J = 8.5 Hz, Harom), 7.50 (d, 1H, J = 2.6 Hz, Harom), 7.22
(d, 1H, J = 8.8 Hz, Harom), 3.95 (s, 3H, –OCH3). 13C NMR
(CDCl3, 100 MHz): d = 56.3, 109.6, 119.1, 123.4, 131.5, 151.6,
163.7, 187.0.