B. Jagadish et al.
spectrometer. NMR spectra were referenced to TMS (0.00 ppm) or CDCl3
(7.26 ppm, 77.0 ppm). Mass spectrometry was conducted using gas
chromatography (GC)/MS (EI, Shimadzu QP 2010 Ultra instrument) on
a DB-5 column with a flow rate of 1 mL/min. High resolution mass
spectrometry was conducted on an AB Sciex TripleTOF 5600 mass
spectrometer (AB SCIEX 500 Old Connecticut Path Framingham, MA
01701 USA) using positive mode electrospray ionization according to
methods described in reference 2.
we attempted its dinitration with in situ generated acetyl nitrate.
Thus, a solution of anisole (10 mmol) in CCl4 was added dropwise
to an ice-cold mixture of acetic anhydride (53 mmol) and
100% nitric acid (47 mmol). After stirring overnight at room
temperature, the reaction mixture was diluted with CH2Cl2 and
washed several times with water. The organic layer was dried
and concentrated under reduced pressure, and the resulting oil
was subjected to flash silica gel column chromatography using
5% ethyl acetate/hexanes and 20% ethyl acetate/hexanes as
elutants. DNAN (1) was obtained as a light yellow solid in 85%
yield. 13C-labeled 2 was similarly prepared from [13C6]-anisole
(ring-13C6, Sigma Aldrich) in 83% yield, along with [13C6]-4-
nitroanisole (5, 15% yield), as depicted in Scheme 1 and
described in the Experimental section. While this work was in
progress, Smith, et al. reported the synthesis of 1 from anisole
by treatment with propanoyl nitrate generated in situ over
zeolite Hβ catalyst in 97% yield.16
[
13C6]-2,4-Dinitroanisole (2)
Nitric acid (100%, 2.96 g, 47 mmol, 2 mL) was added dropwise to acetic
anhydride (5 mL, 5.4 g, 53 mmol) at 0 °C with stirring. After 10 min, a
solution of 4 (1.14 g, 10 mmol, Sigma-Aldrich) in CCl4 (3 mL) was added
dropwise and the mixture allowed to come to room temperature. After
stirring overnight, the reaction mixture was diluted with CH2Cl2
(200 mL) and washed with water (4 × 150 mL), brine (100 mL), and dried
(MgSO4). Volatiles were removed under reduced pressure and the
residual oil loaded onto a flash silica gel column (100 g). Elution with
5% EtOAc/hexanes gave 5 (0.24 g, 1.50 mmol, 15%) as a light yellow solid.
Further elution with 25% EtOAc/hexanes gave 2 (1.70 g, 8.33 mmol) as an
off-white crystalline solid in 83% yield. Recrystallization of 2 from 20%
EtOAc/hexanes afforded colorless needles that melted at 86–87 °C. 1H
NMR (500 MHz, CDCl3) δ 4.10 (3H, d, J = 4 Hz), 7.23 (1H, merged dd,
J = 167 Hz), 8.44 (1H, merged dd, J = 172 Hz), 8.72 (1H, apparent d,
J = 173 Hz); 13C NMR (125 MHz, CDCl3) δ 57.4 (s), 113.6 (t, J = 62 Hz),
121.8 (t, J = 70 Hz), 129.1 (merged t, J = 63 Hz), 138.7 (t, J = 74 Hz), 140.0
(t, J = 69 Hz), 157.2 (merged dt, J = 72 Hz); GC/MS (EI, M+) 204, tr = 12.4
min; HRMS (ESI+) calculated m/z for (M + H)+ 205.0551, observed
205.0586; calculated m/z for (M + Na)+ 227.0370, observed 227.0372.
With 13C-labeled DNAN (2) in hand, we set about preparing
15N-labeled 3 from anisole. [15N]-labeled nitric acid is available
commercially as a 10 N solution in water. Therefore, we
investigated the synthesis of 1 from anisole using a 10 N solution
of nitric acid in water. To account for the presence of water,
excess acetic anhydride was used. Thus, a solution of anisole
(10 mmol) in CCl4 was added dropwise to an ice-cold mixture
of acetic anhydride (212 mmol) and 10 N nitric acid (40 mmol).
After 24 h of stirring at room temperature, TLC analysis of the
reaction mixture indicated that 2-nitroanisole was the major
product, with 1 and 4-nitroanisole as minor products. The
reaction mixture was diluted with CH2Cl2 and washed several
times with water. The organic layer was dried and concentrated
under reduced pressure, and the residue was subjected to a
second treatment with acetic anhydride (212 mmol) and 10 N
nitric acid (40 mmol) as previously described. TLC analysis
indicated the presence of much more 1 after the second
exposure to acetyl nitrate. After workup as previously described,
the resulting oil was subjected to flash silica gel column
chromatography using 5% ethyl acetate/hexanes and 20% ethyl
acetate/hexanes as elutants. DNAN (1) was obtained in 43%
yield, along with 2-nitroanisole (7, 31% yield) and 4-nitroanisole
(8, 12% yield). 15N-Labeled 3 was similarly prepared in 44%
yield from anisole and [15N]-acetyl nitrate generated in situ,
[
15N2]-2,4-Dinitroanisole (3)
[
15N]-Nitric acid (10 N, 4 mL, 40 mmol, Sigma-Aldrich) was added
dropwise to acetic anhydride (21.64 g, 212 mmol, 20 mL) at 0 °C with
stirring. After 10 min, a solution of anisole (6, 1.08 g, 10 mmol) in CCl4
(3 mL) was added dropwise and the mixture allowed to come to room
temperature. After stirring for 24 h, the reaction mixture was diluted
with CH2Cl2 (200 mL), washed with water (4 × 150 mL), brine (10 mL),
and dried (MgSO4). Volatiles were removed under reduced pressure
and the residue subjected to a second nitration as just described.
After the second workup, the residual oil was loaded onto a flash
silica gel column (150 g). Elution with 5% EtOAc/hexanes gave 8
(0.19 g, 1.2 mmol, 12%) as a colorless solid. Further elution with 10%
EtOAc/hexanes gave 7 (0.56 g, 3.6 mmol, 36%) as a yellow oil. Finally,
elution with 25% EtOAc/hexanes gave 3 (0.88 g, 4.4 mmol, 44%)
as an off-white crystalline solid. Recrystallization of 3 from 20%
EtOAc/hexanes produced colorless crystals that melted at 86–87 °C.
1H NMR (500 MHz, CDCl3) δ 4.10 (3H, s), 7.24 (1H, merged dd),
8.43–8.46 (1H, m), 8.72–8.75 (1H, m); 13C NMR (125 MHz, CDCl3) δ
57.4 (s), 113.6 (s), 121.8 (s), 129.1 (s), 138.8 (d, J = 16 Hz), 140.1
(d, J = 17 Hz), 157.2 (s); GC/MS (EI, M+) 200, tr = 12.4 min; HRMS (ESI+)
calculated m/z for (M+ H)+ 201.0290, observed 201.0291; calculated m/z
for (M + Na)+ 223.0110, observed 223.0116.
Scheme 1. Synthesis of [13C6]-2,4-dinitroanisole (2).
Results and discussion
Prior to attempts at syntheses of 2 and 3, we performed the
claycop nitration of anisole according to the published
procedure,12 which involved addition of a solution of anisole
(10 mmol) in CCl4 (30 mL) to a mixture of claycop (4.8 g, Sigma-
Aldrich) and acetic anhydride (15 mL, 16 mmol). As described,
~6 equivalents of nitric acid were required to complete the
nitration process. Acetic anhydride and nitric acid mixtures
generate acetyl nitrate13 in situ, and many examples of aromatic
nitration with acetyl nitrate have been reported.14,15 In order to
check whether claycop was required for dinitration of anisole,
Scheme 2. Synthesis of [15N2]-2,4-dinitroanisole (3).
J. Label Compd. Radiopharm 2014, 57 434–436
Copyright © 2014 John Wiley & Sons, Ltd.