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× 3.5 um); the column oven was maintained 40 °C. A reaction
sample (5 μL) was injected, and the progress of reaction was
monitored at 220 nm. The gradient program used was as
follows: 40% B at 0.0 min, 95% B at 8.0 min, 95% B up to 12.0
min, 40% B at 12.1 min. The post-run column equilibrium time
was 3 min. Reaction sample preparation for HPLC analysis
proceeded as follows: ∼0.1 mL of reaction sample was diluted
to 10 mL with 10% aqueous methanol, and the sample was
analysed. Spectroscopic data and HPLC chromatograms are
given in the Supporting Information.
Experimental Procedure (Method A) for 3a−10a. The
alcohol or thiol (6.29 mmol) was dissolved in toluene (10 mL)
and the contents cooled to 0−5 °C. To this reaction mixture
the base was slowly added (6.60 mmol) at 0−5 °C, and the
reaction mixture was stirred for 15 min. The 2,4-difluoro-1-
nitrobenzene (6.29 mmol) was slowly added to the above
mixture at 0−5 °C. The reaction progress was monitored by
HPLC. After completion of reaction, the reaction mass was
quenched with water (10 mL), the organic layer separated, and
sample concentrated to get the desired product.
General Experimental Procedure (Method B) for 3a−
10a. To the solution of 2,4-difluoro-1-nitrobenzene (6.29
mmol) in toluene (10 mL), alcohol or thiol (6.29 mmol) was
added at 0−5 °C. The base (6.60 mmol) was slowly added to
the above reaction contents at 0−5 °C. The reaction progress
was monitored by HPLC. After completion of the reaction, the
reaction mass was quenched with water (10 mL), the organic
layer separated, and sample concentrated to get the desired
product.
Product 3b [(4-Benzyloxy-2-fluoro-1-nitrobenzene)
(O-Bn FNB Isomer)]. H NMR (400 MHz, CDCl3): δ =
1
7.99−8.03 (m, 1H), 7.28−7.37 (m, 5H), 6.71−6.77 (m, 2H),
5.07 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 164.3 (d, J =
11 Hz, C4, C4 carbon coupled with C2−F), 157.5 (d, J = 264
Hz, C2, C2 carbon coupled with F), 134.9 (C), 130.9 (d, J = 6
Hz, C1, C1 carbon coupled with C2−F), 128.9 (2CH), 128.7
(CH), 127.9 (CH, C5, no coupling due to long space i.e. para
fluoro), 127.5 (2CH), 111.1 (d, J = 3 Hz, CH, C6 carbon
coupled with C2−F), 104.1 (d, J = 24 Hz, CH, C3 carbon
coupled with C2−F), 71.1 (CH2-O-Ph). HRMS calcd for
[C13H10FNO3·NH4]+: 265.0988, found 265.0980.
Product 3c [(2,4-Dibenzyloxy-1-nitrobenzene) (O-Bn
1
Disubstituted)]. H NMR (400 MHz, CDCl3): δ = 7.92 (d, J
= 9.2 Hz, 1H), 7.24−7.40 (m, 10H), 6.58 (d, J = 2 Hz, 1H),
6.51 (dd, J = 9.2 Hz, 2 Hz, 1H), 5.11 (s, 2H), 5.02 (s, 2H); 13
C
NMR (100 MHz, CDCl3): δ = 163.6 (C4), 154.5 (C2), 135.5
(C, 2C), 135.4 (C1), 128.8 (2CH), 128.7 (2CH), 128.5 (CH),
128.4 (CH), 128.2 (CH, C6), 127.5 (2CH), 126.9 (2CH),
106.1 (CH, C5), 102.0 (CH, C3), 71.5 (CH2-O-Ph), 70.7 (CH2-
O-Ph). HRMS calcd for [C20H17NO4·H]+: 336.1230, found
336.1233.
2,4-Difluoro-1-nitrobenzene 1 (DFN Benzene). 1H
NMR (400 MHz, CDCl3): δ 8.07−8.13 (m, 1H), 6.94−7.00
(m, 2H); 13C NMR (100 MHz, CDCl3): δ = 164.7 (dd, J = 255
Hz, 11 Hz, C4 carbon coupled with F and C2−F), 155.9 (dd, J
= 266 Hz, 13 Hz, C2 carbon coupled with F and C4−F), 133.1
(C1 carbon), 127.2 (dd, J = 11, 2 Hz, CH, C6 carbon coupled
with C2−F and C4−F), 111.2 (dd J = 23 Hz, 4 Hz, CH, C5
carbon coupled with C4−F and C2−F), 105.8 (dd, J = 26 Hz,
24 Hz CH, C3 carbon coupled with C2−F and C4−F).
Product 4a [(4-Fluoro-2-methoxy-1-nitrobenzene) (O-
1
Me FNB)]. H NMR (400 MHz, CDCl3): δ = 7.87−7.91 (m,
1H), 6.71−6.74 (m, 1H), 6.64−6.68 (m, 1H), 3.89 (s, 3H); 13
C
NMR (100 MHz, CDCl3): δ = 165.8 (d, J = 255 Hz, C4, C4
carbon coupled with F), 155.3 (d, J = 11 Hz, C2, C2 carbon
coupled with C4−F), 135.9 (C1 carbon), 128.2 (d, J = 11 Hz,
CH, C6 carbon coupled with C4−F), 107.3 (d, J = 23 Hz, CH,
C5 carbon coupled with C4−F), 101.4 (d, J = 27 Hz, CH, C3
carbon coupled with C4−F), 56.8 (CH3-O). HRMS calcd for
[C7H6FNO3·H]+: 172.0404, found 172.0368.
Product 3a [(2-Benzyloxy-4-fluoro-1-nitrobenzene)
(O-Bn FNB)]. H NMR (400 MHz, CDCl3): δ = 7.86−7.88
1
(m, 1H), 7.25−7.39 (m, 5H), 6.73−6.76 (m, 1H), 6.62−6.67
(m, 1H), 5.13 (s, 2H); 13C NMR (100 MHz, CDCl3): δ =
165.6 (d, J = 255 Hz, C4 carbon coupled with F), 154.2 (d, J =
11 Hz, C, C2 carbon coupled C4−F), 136.4 (C1 carbon), 134.8
(C), 128.8 (2CH), 128.5 (CH), 128.1 (d, J = 11 Hz, C6 carbon
coupled with C4−F), 126.9 (2CH), 107.7 (d, J = 23 Hz, CH,
C5 carbon coupled C4−F), 102.9 (d, J = 26 Hz, CH, C3
coupled with C4−F), 71.5 (CH2-O-Ph); HRMS calcd for
[C13H10FNO3·Na]+: 270.0537, found 270.0537.
Product 5a [(2-Ethoxy-4-fluoro-1-nitrobenzene) (O-Et
FNB)]. H NMR (400 MHz, CDCl3): δ = 7.83−7.87 (m, 1H),
1
6.67−6.70 (m, 1H), 6.61−6.65 (m, 1H), 4.09 (q, J = 6.8, 2H),
1.41 (t, J = 6.8, 3H); 13C NMR (100 MHz, CDCl3): δ = 165.7
(d, J = 254 Hz, C4, C4 carbon coupled with F), 154.6 (d, J = 11
Hz, C2, C2 carbon coupled with C4−F), 136.2 (C1 carbon),
127.9 (d, J = 12 Hz, CH, C6 carbon coupled with C4−F), 107.1
(d, J = 24 Hz, CH, C5 carbon coupled with C4−F), 102.1 (d, J
= 26 Hz, CH, C3 carbon coupled with C4−F), 65.8 (CH2-O),
14.3 (CH3). HRMS calcd for [C8H8FNO3·Na]+: 208.0380,
found 208.0380.
915
dx.doi.org/10.1021/op500120z | Org. Process Res. Dev. 2014, 18, 912−918