78 JOURNAL OF CHEMICAL RESEARCH 2013
N-(4-Methoxybenzyl)-2-phenylacetamide (2f): A white solid, yield
43%, m.p. 142–144 °C (lit.13 142–144 °C). IR (KBr, νmax, cm−1): 1628
(C=O). 1H NMR (400 MHz, DMSO-d6) δ 3.48 (s 2H, CH2CO), 3.73
(s, 3H, OCH3), 4.21 (d, J = 5.6 Hz, 2H, NCH2), 6.87 (d, J = 8.4 Hz,
2H, ArH), 7.17 (d, J = 8.4 Hz, 2H, ArH), 7.21–7.31 (m, 5H, ArH),
8.50 (brs, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 42.2, 42.9,
55.5, 114.1, 126.8, 128.7, 129.0, 129.5, 131.8, 136.9, 158.7, 170.5.
Crystallisation solvent: EtOAc: PE = 1: 5.
1-benzylurea to 1-benzoylurea. Our method features a cheap
and bench-stable oxidant, water as a solvent and mild reaction
conditions.
Experimental
Amide 2d7 and 1-benzylureas 2i–k8 were prepared according to the
literature procedure. Compound 2l was prepared from 1-nitrobiuret9
and benzylamines according to the reported procedure.10 1H and 13C
NMR spectra were recorded on a MercuPlus 400 NMR spectrometer.
IR spectra were recorded on a Thermo Nicolet Avatar 360 IR spec-
trometer. Electrospray ionisation mass spectra were obtained on an
LCQ Advantage MAX (Finnigan) instrument. All melting points were
measured on a melting apparatus with microscope and hot stage and
were uncorrected. Ammonium persulfate, CuSO4·5H2O, and AgNO3
were purchased from Jiangtian Chemical Reagent Company, China.
These chemicals were used directly as received. The deionised water
purchased from Water Centre of Nankai University, China, was
distilled before use. All reactions were necessarily carried out under
nitrogen. PE = petroleum ether (b.p. 60–90 °C).
N-(4-Methoxybenzyl)cyclohexanecarboxamide (2g): A white solid,
yield 17%, m.p. 119–121 °C (lit.14 118 °C). IR (KBr, νmax, cm−1): 1634
(C=O). 1H NMR (400 MHz, DMSO-d6) δ 1.13–1.27 (m, 3H,
cyclohexyl-H), 1.33–1.42 (m, 2H, cyclohexyl-H), 1.61–1.64 (m, 1H,
cyclohexyl-H), 1.70–1.73 (m, 4H, cyclohexyl-H), 2.12–2.19 (m, 1H,
CHC=O), 3.73 (s, 3H, OCH3), 4.19 (d, J = 6.0 Hz, 2H, NCH2), 6.87 (d,
J = 8.6 Hz, 2H, ArH), 7.15 (d, J = 8.6 Hz, 2H, ArH), 8.12 (t,
J = 5.6 Hz, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 25.8, 26.0,
29.8, 41.7, 44.5, 55.5, 114.1, 128.7, 132.3, 158.6, 175.5. Eluent:
EtOAc: PE = 1: 3 (Rf = 0.29).
Phenyl(pyrrolidin-1-yl)methanone (2h): A colourless oil (mp: lit.15
1
46–47 °C), yield 20%. IR (KBr, νmax, cm−1): 1625 (C=O). H NMR
(400 MHz, CDCl3) δ 1.73–1.79 (m, 2H, pyrrole-CH2), 1.81–1.86 (m,
2H, pyrrole-CH2), 3.31 (t, J = 7.0 Hz, 2H, pyrrole-CH2), 3.54 (t,
J = 7.0 Hz, 2H, pyrrole-CH2), 7.28–7.30 (m, 3H, ArH), 7.40–7.44 (m,
2H, ArH). 13C NMR (100 MHz, CDCl3) δ 24.4, 26.3, 46.1, 49.5, 127.0,
128.1, 129.7, 137.2, 169.6. Eluent: EtOAc: PE = 1: 3 (Rf = 0.13).
Synthesis of amides 2a–c and 2e–h; general procedure
CH2Cl2 (100 mL) was added to a flask (250 mL) containing a carbox-
ylic acid (10 mmol) and HOBt (1.5 g, 11 mmol). After stirring at room
temperature for 15 min under nitrogen, the mixture was cooled to 0 °C
with ice-water bath and N,N′-dicyclohexylcarbodiimide (DCC) (2.3 g,
11 mmol) was added in portions. The reaction mixture was stirred for
15 min and then a solution of an amine (11 mmol) and triethylamine
(1.0 g, 10 mmol) in CH2Cl2 (5 mL) was added dropwise over about
5 min. The reaction mixture was allowed to stir at 0 °C for 30 min and
then at room temperature overnight. Then a solution of citric acid
(10%, w/w, 100 mL) was added to decompose unreacted DCC, and
the resulting mixture was stirred at room temperature for 1 h. The
white solids (1,3-dicyclohexylurea) were washed with CH2Cl2 (5 mL
× 2) after filtration. The combined filtrate was washed with citric acid
solution (10%, w/w, 100 mL × 2), saturated Na2CO3 (100 mL × 2), and
brine (50 mL), sequentially. The separated organic layer was dried
over anhydrous Na2SO4, evaporated under reduced pressure, and the
residue was purified by column chromatography (silica gel) or cryst-
allisation using solvent as specified to give amides 2a–c and 2e–h.
N-(4-Methoxybenzyl)benzamide (2a): A white solid, yield 75%,
m.p. 91–93 °C (lit.11 91–94 °C). IR (KBr, νmax, cm−1): 1634 (C=O). 1H
NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H, OCH3), 4.44 (d, J =
5.6 Hz, 2H, NCH2), 6.90 (d, J = 8.4 Hz, 2H, ArH), 7.28 (d, J =
8.4 Hz, 2H, ArH), 7.45–7.56 (m, 3H, ArH), 7.92 (d, J = 7.6 Hz, 2H,
ArH), 9.02 (t, J = 5.6 Hz, 1H, NH). 13C NMR (100 MHz, DMSO-d6)
δ 42.6, 55.5, 114.1, 127.7, 128.7, 129.1, 131.6, 132.1, 134.9, 158.7,
166.6. Crystallisation solvent: EtOAc: PE = 1: 5.
Oxidation of amides and benzylureas; general procedure
AgNO3 (13.6 mg, 0.08 mmol), CuSO4⋅5H2O (powder, 20.0 mg,
0.08 mmol), 1-benzylurea or amide (0.4 mmol), and (NH4)S2O8
(273.8 mg, 1.2 mmol) were added to a plastic tube (25 mL). Then a
solution of KF in water (0.8 M, 10 mL), which was degassed by purg-
ing with N2 before use, was added by syringe. After stirring at room
temperature for 6 h or overnight, the reaction mixture was treated with
EtOAc (10 mL), and was allowed to stir for 5 min. The organic layer
was separated, and the aqueous layer was extracted with EtOAc
(10 mL × 2). The combined extracts were dried over anhydrous
Na2SO4, evaporated, and separated by preparative TLC to give the
product 3a–k. For 2l, after reaction, the reaction mixture was directly
filtered, and the brown solids were washed with water (5 mL × 4)
and EtOAc (5 mL x 4), sequentially, and then dried under reduced
pressure to give the product 3l.
N-Benzoyl-4-methoxybenzamide (3a): A pale yellow solid, yield
79%, m.p. 103–105 °C (lit.16 109–110 °C). IR (KBr, νmax, cm−1): 1719
and 1665 (C=O). 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H,
OCH3), 7.06 (d, J = 8.8 Hz, 2H, ArH), 7.50–7.55 (m, 2H, ArH), 7.61–
7.66 (m, 1H, ArH), 7.90 (d, J = 7.2 Hz, 2H, ArH), 7.94 (d, J = 8.8 Hz,
2H, ArH), 11.18 (brs, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ
56.0, 114.1, 126.2, 128.8, 129.0, 131.4, 132.9, 134.6, 163.3, 167.2,
168.4. Eluent: EtOAc: PE = 1:2 (Rf = 0.22).
N-(4-Methoxybenzyl)-4-nitrobenzamide (2b): Yellow needles, yield
18%, m.p. 136–138 °C (lit.12 137–138.5 °C). IR (KBr, νmax, cm−1):
4-Methoxy-N-(4-nitrobenzoyl)benzamide (3b): A pale yellow solid,
yield 59%, m.p. 182–184 °C. IR (KBr, νmax, cm−1): 1709 and 1671
1
1641 (C=O). H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H, OCH3),
1
(C=O). H NMR (400 MHz, acetone-d6) δ 3.92 (s, 3H, OCH3), 7.07
4.44 (d, J = 6.0 Hz, 2H, NCH2), 6.90 (d, J = 8.4 Hz, 2H, ArH),
7.27 (d, J = 8.4 Hz, 2H, ArH), 8.11 (d, J = 8.8 Hz, 2H, ArH), 8.32
(d, J = 8.8 Hz, 2H, ArH), 9.32 (t, J = 5.6 Hz, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ 42.8, 55.5, 114.2, 124.0, 129.20, 129.21,
131.5, 140.5, 149.5, 158.8, 164.9. Crystallisation solvent: absolute
alcohol.
(d, J = 8.6 Hz, 2H, ArH), 8.03 (d, J = 8.6 Hz, 2H, ArH), 8.14 (d,
J = 8.8 Hz, 2H, ArH), 8.36 (d, J = 8.8 Hz, 2H, ArH), 10.52 (brs, 1H,
NH). 13C NMR (100 MHz, acetone-d6) δ 55.1, 113.8, 123.3, 125.5,
129.6, 130.8, 140.6, 149.9, 163.7, 165.8, 166.9. HRMS-ESI (posi-
tive): m/z [M+Na]+ calcd for C15H12N2NaO5+: 323.0638; found:
323.0634. Eluent: acetone: PE = 1:1 (Rf = 0.76).
4-Methoxyl-N-(4-methoxybenzoyl)benzamide (3c): A white solid,
yield 34%, m.p. 170–172 °C (known17 compound but no m.p. has
been reported). IR (KBr, νmax, cm−1): 1715 and 1670 (C=O). 1H NMR
(400 MHz, DMSO-d6) δ 3.85 (s, 6H, OCH3), 7.06 (d, J = 8.2 Hz, 4H,
ArH), 7.92 (d, J = 8.2 Hz, 4H, ArH), 11.00 (brs, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ 56.0, 114.1, 126.5, 131.3, 163.2, 167.4.
Eluent: EtOAc: PE = 1:1 (Rf = 0.31).
N-Acetyl-4-methoxybenzamide (3d): A white solid, yield 83%, m.p.
116–118 °C (lit.18 119–119.5 °C). IR (KBr, νmax, cm−1): 1715 and 1676
(C=O). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H, C(O)CH3), 3.83
(s, 3H, OCH3), 7.03 (d, J = 8.8 Hz, 2H, ArH), 7.95 (d, J = 8.8 Hz,
2H, ArH), 10.87 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 26.0,
55.9, 114.2, 125.6, 131.0, 163.3, 166.1, 172.8. Eluent: EtOAc: PE =
1:3 (Rf = 0.15).
Methyl 3-(4-methoxybenzamido)-3-oxopropanoate (3e): A pale
yellow solid, yield 71%, m.p. 153–154 °C (known19 compound but
no m.p. has been reported). IR (KBr, νmax, cm−1): 1740, 1701 and 1679
4-Methoxy-N-(4-methoxybenzyl)benzamide (2c): A white solid,
yield 77%, m.p. 132–134 °C (lit.12 127–129 °C). IR (KBr, νmax, cm−1):
1
1632 (C=O). H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 4.42 (d, J = 5.2 Hz, 2H, NCH2), 6.89 (d, J =
8.2 Hz, 2H, ArH), 7.01 (d, J = 8.4 Hz, 2H, ArH), 7.26 (d, J = 8.2 Hz,
2H, ArH), 7.90 (d, J = 8.4 Hz, 2H, ArH), 8.85 (brs, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ 42.5, 55.5, 55.8, 113.9, 114.1, 127.2, 129.0,
129.5, 132.4, 158.6, 162.0, 166.1. Crystallisation solvent: EtOAc: PE
= 1: 5.
Methyl 3-((4-methoxybenzyl)amino)-3-oxopropanoate (2e): A white
solid, yield 13%, m.p. 71–73 °C. IR (KBr, νmax, cm−1): 1746 (C=O),
1643 (C=O). 1H NMR (400 MHz, DMSO-d6) δ 3.30 (s, 2H,
CH2CONH), 3.63 (s, 3H, COOCH3), 3.74 (s, 3H, ArOCH3), 4.22
(d, J = 5.6 Hz, 2H, NCH2), 6.89 (d, J = 8.6 Hz, 2H, ArH), 7.20 (d,
J = 8.6 Hz, 2H, ArH), 8.53 (brs, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ 42.2, 42.7, 52.3, 55.5, 114.2, 129.0, 131.4, 158.7, 165.5,
168.9. HRMS-ESI (negative): m/z [M+Na]+ calcd for C12H15NO4Na+:
260.0893; found: 260.0897. Eluent: EtOAc: PE = 1: 1 (Rf = 0.32).