The Journal of Organic Chemistry
Article
CDCl3): δ 8.35 (d, J = 9.1 Hz, 2H), 8.29 (d, J = 9.2 Hz, 2H). Spectral
data are in agreement with the literature.37
4-Benzonitrotrifluoride (2h). 4-(trifluoromethyl)phenylboronic
acid (124 mg, 0.65 mmol) was employed to afford product as an
off-white solid (98 mg, 0.51 mmol, 79%). 1H NMR (400 MHz,
CDCl3): δ 8.46−8.19 (m, 2H), 7.94−7.68 (m, 2H). Spectral data are
in agreement with the literature.38
4H), 7.54−42 (m, 4H). Spectral data are in agreement with the
literature.33
4-((4-Nitrophenyl)sulfonyl)morpholine (2s). (4-
(Morpholinosulfonyl)phenyl)boronic acid (128 mg, 0.65 mmol)
was employed to afford product as an off-white solid (85 mg, 0.31
1
mmol, 48%). H NMR (400 MHz, CDCl3): δ 8.43 (d, J = 8.8 Hz,
2H), 7.97 (d, J = 8.8 Hz, 2H), 4.12−3.59 (m, 4H), 3.32−2.85 (m,
4H). Spectral data are in agreement with the literature.47
N,N-Dimethyl-4-nitrobenzamide (2i). (4-(Dimethylcarbamoyl)-
phenyl)boronic acid (125 mg, 0.65 mmol) was employed. Flash
chromatography (eluent: 5−50% EtOAc/heptanes) was conducted,
and the appropriate fractions were concentrated in vacuo to afford
5-Chloro-2-fluoro-1-methyl-3-nitrobenzene (3). 5-Chloro-2-fluo-
ro-3-methylphenylboronic acid (500 mg, 2.7 mmol), ammonium
nitrate (3 equiv, 640 mg, 8.0 mmol) were loaded into a pressure
release vial (20 mL) and 1,2-dichloroethane (10 mL) added followed
by H2O (60 μL, 1.2 equiv, 3.2 mmol). The reaction mixture was
heated to 70 °C for 16 h on a heating mantle before being allowed to
cool to RT. The organic phase was diluted with 1,2-dichloroethane
(10 mL) and washed with NaOH (1 M, 10 mL) and water (10 mL)
and concentrated in vacuo to afford crude oil. Crude product was
purified by flash chromatography (eluent: 100% heptanes) to afford
1
product as a yellow solid (89 mg, 0.46 mmol, 71%). H NMR (400
MHz, CDCl3): δ 8.29 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H),
3.17 (d, J = 11.6 Hz, 6H), 2.99 (d, J = 6.6 Hz, 6H). Spectral data are
in agreement with the literature.39
1,2-Chloro-4-nitrobenzene (2j). 3,4-Dichlorophenylboronic acid
(123 mg, 0.65 mmol) was employed to afford product as light yellow
oil (117 mg, 0.61 mmol, 94%). 1H NMR (400 MHz, CDCl3): δ 8.37
(d, J = 2.6 Hz, 1H), 8.11 (dd, J = 8.8, 2.6 Hz, 1H), 7.66 (d, J = 8.8 Hz,
1H). Spectral data are in agreement with the literature.40
1
product as a light yellow solid (90 mg, 18%). H NMR (400 MHz,
CDCl3): δ 7.87 (ddd, J = 6.0, 2.7, 0.8 Hz, 1H), 7.49 (ddd, J = 6.0, 2.7,
0.8 Hz, 1H). 19F NMR (376 MHz, CDCl3): δ −128.82. 13C{1H}
NMR (101 MHz, CDCl3): δ 152.9, 150.3, 135.3 (d, J = 5.3 Hz),
129.2 (d, J = 18.2 Hz), 127.9 (d, J = 4.7 Hz), 122.3 (d, J = 2.8 Hz),
13.7 (d, J = 4.0 Hz). HRMS (m/z + ES): Found 188.9996 (M+
C7H5ClFNO2 Requires: 188.9992).
4-Bromo-2-methoxy-1-nitrobenzene (2k). 4-Bromo-2-methoxy-
phenylboronic acid (231 mg, 0.65 mmol) was employed to afford
1
product as an off-white solid (130 mg, 0.56 mmol, 87%). H NMR
(400 MHz, CDCl3): δ 7.77 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.6 Hz,
1H), 7.20 (dd, J = 8.6, 1.9 Hz, 1H), 3.99 (s, 3H). Spectral data are in
agreement with the literature.41
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
1-Methoxy-2,4-dinitrobenzene (2l). 4-Methoxyl-3-nitrophenylbor-
onic acid (128 mg, 0.65 mmol) was employed. Flash chromatography
(eluent: 5−25% EtOAc/heptanes) was conducted, and the appro-
priate fractions were concentrated in vacuo to afford product as an off-
white solid (93 mg, 0.47 mmol, 72%). 1H NMR (400 MHz, CDCl3):
δ 8.76 (d, J = 2.8 Hz, 1H), 8.47 (dd, J = 9.3, 2.8 Hz, 1H), 7.25 (d, J =
9.3 Hz, 1H), 4.12 (s, 3H). Spectral data are in agreement with the
literature.35
■
sı
Full details of CryoFree NMR spectroscopy experiments
including all raw data used in kinetic analysis and
variable time normalization (PDF)
1-Bromo-3-methyl-5-nitrobenzene (2m). 3-Bromo-5-methylphe-
nylboronic acid (100 mg, 0.44 mmol) was employed to afford product
as white solid (95 mg, 0.44 mmol, 99%). 1H NMR (400 MHz,
CDCl3): δ 8.19 (br s, 1H), 7.99 (br s, 1H), 7.67 (br s, 1H), 2.47 (s,
3H). Spectral data are in agreement with the literature.42
1,4-Dinitrobenzene (2n). 1,4-benzenedibronic acid (100 mg, 0.58
mmol) was employed with HNO3 (2.6 equiv) to afford product as
Protocol for scale up of HNO3-mediated nitration
process including description of HNO3 titration (PDF)
AUTHOR INFORMATION
Corresponding Author
■
James I. Murray − Pivotal and Commercial Synthetics, Drug
Substance Technologies, Process Development, Amgen Inc.,
Thousand Oaks, California 91320, United States;
1
pale yellow solid (92 mg, 0.55 mmol, 95%). H NMR (400 MHz,
CDCl3): δ 8.44 (s, 4H). Spectral data are in agreement with the
literature.43
4-Fluoronitrobenzene (2o). 4-Fluorophenylboronic acid (90 mg,
0.65 mmol), 4-fluorophenylboronic acid pinacol ester (145 mg, 0.65
mmol), or potassium 4-fluorophenltricluoroborate (130 mg, 0.65
mmol) was employed to afford product as a colorless oil in 96−97%
yield. 1H NMR (400 MHz, CDCl3): δ 8.28 (dd, J = 9.2, 4.7 Hz, 2H),
7.23 (dd, J = 9.3, 7.7 Hz, 2H). Spectral data are in agreement with the
literature.44
Authors
Maria V. Silva Elipe − Attribute Sciences, Amgen Inc.,
Kyle D. Baucom − Pivotal and Commercial Synthetics, Drug
Substance Technologies, Process Development, Amgen Inc.,
Thousand Oaks, California 91320, United States
Derek B. Brown − Pivotal and Commercial Synthetics, Drug
Substance Technologies, Process Development, Amgen Inc.,
Thousand Oaks, California 91320, United States;
Kyle Quasdorf − Pivotal and Commercial Synthetics, Drug
Substance Technologies, Process Development, Amgen Inc.,
Thousand Oaks, California 91320, United States
Seb Caille − Pivotal and Commercial Synthetics, Drug
Substance Technologies, Process Development, Amgen Inc.,
Thousand Oaks, California 91320, United States;
(4-Nitrophenyl)methanol (2p). (4-(Hydroxymethyl)phenyl)-
boronic acid (99 mg, 0.65 mmol) was employed. Flash chromatog-
raphy (eluent: 5−50% EtOAc/heptanes) was conducted, and the
appropriate fractions were concentrated in vacuo to afford product as
1
an off-white solid (20 mg, 0.013 mmol, 20%). H NMR (400 MHz,
CDCl3): δ 8.23 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 4.89 (s,
2H). Spectral data are in agreement with the literature.45
4-Nitrobenzonitrile (2q). 4-Cyanophenylboronic acid (105 mg,
0.68 mmol) was employed to provide the product as white solid (25
1
mg, 0.17 mmol, 25%). H NMR (400 MHz, CDCl3): δ 8.37 (dt, J =
9.0 Hz, 2H), 7.90 (dt, J = 9.0 Hz, 2H). Spectral data are in agreement
with the literature.46
Chloro-4-(2-nitrovinyl)benzene (2r). (4-Chlorostyryl)boronic acid
(176 mg, 0.65 mmol) was employed. Flash chromatography (eluent:
5−50% EtOAc/heptanes) was conducted, and the appropriate
fractions were concentrated in vacuo to afford product as a yellow
1
Complete contact information is available at:
solid (45 mg, 0.025 mmol, 38%). H NMR (400 MHz, CDCl3): δ
7.98 (d, J = 13.7 Hz, 1H), 7.58 (d, J = 13.7 Hz, 1H), 4.12−3.59 (m,
G
J. Org. Chem. XXXX, XXX, XXX−XXX