The Journal of Organic Chemistry
Note
171.9, 170.0, 144.3, 144.0, 139.0, 136.5, 131.9, 130.1, 129.8, 129.2,
127.8, 125.9, 119.8, 57.4. UPLC-DAD-QTOF, HRMS (ESI) m/z: [M
+ H]+ calcd for C21H17N3O3, 360.1270; found, 360.1372.
N-(2,4-Dinitrophenyl)-2-((diphenylmethylene)amino)acetamide
16.
mmol, 1 equiv) was added. The resulting solution was refluxed
overnight (caution: HBr evolution), cooled, and concentrated in
vacuo. The residue was purified through silica gel chromatography
(eluting with hexane/EtOAc 70:30), affording the desired product as
a yellow oil in 94% yield (2.27 g, 9.7 mmol). The spectroscopic data
were coincident with those described in the literature.45 1H NMR
(300 MHz, CHCl3), major rotamer: δ 8.05 (dd, J = 8.1, 1.5 Hz, 1H),
7.74 (dd, J = 7.7, 1.6 Hz, 1H), 7.62 (td, J = 7.9, 1.5 Hz, 1H), 7.53 (dd,
J = 7.8, 1.4 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.52 (d, J = 10.8 Hz,
1H), 3.23 (s, 3H); minor rotamer δ 7.99 (dd, J = 8.2, 1.4 Hz, 1H),
7.71−7.64 (m, 1H), 7.48 (td, J = 8.1, 1.4 Hz, 1H), 7.34 (dd, J = 7.9,
1.3 Hz, 1H), 3.98 (s, 2H), 3.50 (s, 3H).
equiv) was dissolved in dry DMF (14 mL), and DIPEA (5.2 mL, 30
mmol, 6 equiv) was added at room temperature. Then, 2,4-
ninitroaniline (920 mg, 5 mmol, 1 equiv) was added, followed by
HATU (2.09 g, 5.5 mmol, 1.1 equiv). The mixture was stirred at room
temperature for 16 h. Then, a solution of EtOAc/H2O (1:1) was
added to the reaction mixture, and it was extracted with EtOAc (3 ×
50 mL), washed with brine (5 × 30 mL), dried over MgSO4,
evaporated under reduced pressure, and purified by flash column
chromatography on silica gel (hexane/EtOAc, 90:10) to afford the
pure product as a yellow solid. Yield: 77% (1.31 g, 3.85 mmol). Mp:
In step 2,46 to a solution of the bromide obtained in the previous
step (546 mg, 2 mmol, 1 equiv) and DIPEA (0.35 mL, 2 mmol, 1
equiv) in dry acetonitrile (4 mL) under argon was added
benzophenone imine (0.34 mL, 2 mmol, 1 equiv), and the resulting
solution was refluxed for 5 h. The mixture was then cooled, dissolved
in CH2Cl2 (20 mL), and washed with aqueous 5% NaHCO3 (20 mL).
The water phase was extracted with CH2Cl2 (2 × 15 mL), and the
organic phases were combined and dried over MgSO4. The solvent
was eliminated under reduced pressure, and the residue was purified
through flash chromatography on silica gel (eluting with hexane/
EtOAc 60:40) to afford the desired product as a viscous orange oil in
70% yield (520 mg, 1.39 mmol). 1H NMR (300 MHz, CDCl3), major
rotamer: δ 8.00−7.87 (m, 1H), 7.74−7.57 (m, 2H), 7.54−7.42 (m,
3H), 7.43−7.16 (m, 7H), 7.05−6.95 (m, 1H), 3.92 (s, 2H), 3.25 (s,
3H); Minor rotamer: δ 8.00−7.87 (m, 1H), 7.74−7.57 (m, 2H),
7.54−7.42 (m, 3H), 7.43−7.16 (m, 7H), 7.05−6.95 (m, 1H), 3.55 (s,
3H), 3.49 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3), mixture of
rotamers: δ 171.2, 169.2, 146.4, 139.0, 136.8, 135.5, 134.2, 134.0,
131.5, 130.8, 130.3, 130.2, 129.4, 129.2, 128.8, 128.7, 128.6, 128.4,
128.1, 128.0, 127.8, 127.71, 127.5, 125.5, 125.0, 124.0, 114.1, 56.9,
56.4, 53.4, 38.2, 37.1, 29.5. UPLC-DAD-QTOF, HRMS (ESI) m/z:
[M + H]+ calcd for C22H20N3O3, 373.1426; found, 373.1425.
Preparation of Benzophenone Imine of Glycine Methyl
Ester 13.47 To a suspension of glycine ester hydrochloride (377 mg,
3 mmol, 1 equiv) in DCM (6 mL) was added benzophenone imine
(0.5 mL, 3 mmol, 1 equiv). Triethylamine (0.42 mL, 3 mmol, 1
equiv) was then added dropwise, and the reaction mixture was stirred
at room temperature until consumption of the starting material
(monitored by 1H NMR). The mixture was then diluted with Et2O (6
mL), filtered, and washed with H2O (3 × 10 mL) and brine (3 × 10
mL). The combined organic layers were dried over MgSO4 and
evaporated to dryness. The crude was obtained with a quantitative
yield (759 mg, 3 mmol) and was used without further purification. All
of the spectroscopic data were coincident with those previously
reported. 1H NMR (300 MHz, CDCl3): δ 7.74−7.61 (m, 2H), 7.56−
7.42 (m, 4H), 7.43−7.29 (m, 3H), 7.25−7.14 (m, 1H), 4.25 (s, 2H),
3.77 (s, 3H).
1
186−188 °C. H NMR (300 MHz, CDCl3): δ 11.29 (s, 1H), 9.12−
9.02 (m, 2H), 8.43 (dd, J = 9.4, 2.6 Hz, 1H), 5.53 (t, J = 5.7 Hz, 1H),
4.01 (d, J = 6.1 Hz, 2H), 1.45 (s, 9H). 13C{1H} NMR (75 MHz,
CDCl3): δ 169.8, 156.2, 142.0, 139.2, 135.3, 130.2, 122.3, 122.1, 81.5,
46.0, 28.3. UPLC-DAD-QTOF, HRMS (ESI) m/z: [M + Na]+ calcd
for C13H16N4O7Na, 363.0917; found, 363.0911.
N-Deprotection: To a solution of the previously obtained N-Boc
aminoamide (1.02 g, 3 mmol) in CH2Cl2 (12 mL) was added
trifluoroacetic acid (4.5 mL) at 0 °C. The mixture was stirred at room
temperature for 30 min until full conversion. The solvents were
evaporated, and the residue was coevaporated successively with a
mixture of diethyl ether and pentane. Then it was dried in vacuo, and
the resulting solid, which was obtained in a quantitative yield, was
used in the next step without further purification. Yield: quantitative.
Mp: 146−150 °C. 1H NMR (300 MHz, D2O): δ 8.97 (d, J = 2.6 Hz,
1H), 8.57−8.42 (m, 1H), 8.25 (d, J = 9.2 Hz, 1H), 4.11 (s, 2H).
13C{1H} NMR (75 MHz, D2O): δ 166.4, 143.5, 139.3, 136.3, 129.4,
125.4, 121.9, 41.7. UPLC-DAD-QTOF, HRMS (ESI, measured after
neutralization) m/z: [M + Na]+ calcd for C8H8N4O5Na, 263.0392;
found, 263.0403.
Iminoamide formation: To a suspension of the aminoamide
trifluororacetate salt obtained in the previous step (1.06 mg, 3
mmol, 1 equiv) in CH2Cl2 (11 mL) were added benzophenone imine
(0.5 mL, 3 mmol, 1 equiv) and anhydrous MgSO4 (903 mg, 7.5
mmol, 2.5 equiv). The reaction mixture was stirred at room
temperature until consumption of the starting material (monitored
1
by H NMR). The mixture was then filtered to remove the salts and
evaporated in vacuo. The crude was crushed in diethyl ether/hexane
to afford a pure yellow solid. Yield: 66% (800 mg, 1.98 mmol). Mp:
175−180 °C. 1H NMR (300 MHz, CDCl3): δ 12.53 (s, 1H), 9.24 (d,
J = 9.4 Hz, 1H), 9.18 (d, J = 2.7 Hz, 1H), 8.48 (dd, J = 9.4, 2.7 Hz,
1H), 7.87 (dd, J = 8.1, 1.6 Hz, 2H), 7.60−7.38 (m, 6H), 7.23−7.12
(m, 2H), 4.18 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 172.0,
171.1, 139.5, 138.1, 136.2, 132.5, 131.4, 130.2, 130.0, 129.4, 129.3,
128.97, 128.6, 128.4, 127.1, 122.7, 122.2, 57.6. UPLC-DAD-QTOF,
HRMS (ESI) m/z: [M + H]+ calcd for C21H17N4O5, 405.1199; found,
405.1192.
Preparation of α-Pyridyl and Phenyl Acetanilides 18−21.
Synthesis of 2-(Pyridin-2-yl)acetanilides.48 General Procedure.
Preparation of N-Methyl Iminoamide 15.
Cl2CH2/H2O (1:1, 30 mL) was added to the reaction mixture, and it
In step 1,44 N-methyl-2-nitroaniline (1.5 g, 10 mmol, 1 equiv) was
dissolved in toluene (25 mL), and bromoacetyl bromide (1.0 mL, 12
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J. Org. Chem. 2021, 86, 7757−7772