D
S. P. Chavan et al.
Paper
Synthesis
purification of the obtained residue by silica gel column chromatogra-
phy (EtOAc–PE, 40:60) afforded pure 6 as a pale yellow solid; yield:
6.0 g (63%).
Mp 121 °C (Lit.5d 122 °C); Rf = 0.2 (EtOAc–PE, 50:50).
1-Benzyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one (8)
To a stirred solution of benzylamine (5.45 mL, 50 mmol, 1.14 equiv)
in isopropyl alcohol (45 mL), compound 5 (5 g, 43.8 mmol, 1 equiv)
was added at rt. The reaction mixture was stirred at 40 °C for 1 h,
then cooled to 0 °C and treated with a freshly prepared solution of
NaBH4 (1.06 g, 28 mmol, 0.64 equiv) in water (15 mL) containing
NaOH (1 mL, 50% w/w in water) while maintaining the internal tem-
perature below 25 °C. The reaction mixture was stirred for 1.5 h at
that temperature. Excess NaBH4 was quenched by addition of acetone
to the reaction mixture while maintaining the internal temperature
below 30 °C. The mixture was filtered and AcOH (1 mL) was added to
the filtrate to adjust the pH between 7–8 and the reaction mixture
was heated to 50 °C for 16 h. The mixture was allowed to cool to rt
and the solvent was evaporated under reduced pressure. The obtained
residue was extracted with EtOAc (3 × 100 mL). The combined organic
layer was washed with brine (100 mL), dried over anhydrous Na2SO4,
and filtered. Concentration of the organic layer in vacuo followed by
purification of the obtained residue by silica gel column chromatogra-
phy (EtOAc–PE, 50:50) afforded pure 8 as a yellow solid; yield: 5.65 g
(69%).
IR (CHCl3): 1674, 1222, 760 cm–1
.
1H NMR (200 MHz, CDCl3): = 7.17 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4
Hz, 2 H), 5.86 (d, J = 1.1 Hz, 1 H), 4.52 (s, 2 H), 3.79 (s, 3 H), 3.69 (s, 2
H), 2.00 (d, J = 1.1 Hz, 3 H).
Spectroscopic data were consistent with the earlier reported analyti-
cal information.
3-Ethyl-1-(4-methoxybenzyl)-4-methyl-1,5-dihydro-2H-pyrrol-2-
one (7)5d
To a stirred solution of compound 6 (1 g, 4.6 mmol, 1 equiv) in anhy-
drous THF (25 mL), NaH (0.121 g, 5.06 mmol, 1.1 equiv) was added
slowly at 0 °C. The reaction mixture was stirred for 15 min, ethyl bro-
mide (0.41 mL, 5.52 mmol, 1.2 equiv) in anhydrous THF (5 mL) was
added dropwise at 0 °C, and stirring was continued for 3 h at that
temperature. The progress of the reaction was monitored by TLC. Af-
ter completion, the reaction mixture was treated with saturated
NH4Cl solution and extracted with EtOAc (3 × 100 mL). The combined
organic layer was washed with brine (50 mL), dried over anhydrous
Na2SO4, and filtered. Concentration of the organic layer in vacuo fol-
lowed by purification of the obtained residue by silica gel column
chromatography (EtOAc–PE, 20:80) afforded pure 7 as a yellow solid
[yield: 0.62 g (55%)] along with recovery of the starting material (0.3
g).
Mp 96–98 °C; Rf = 0.3 (EtOAc–PE, 30:70).
IR (CHCl3): 1674, 1217, 763 cm–1
.
1H NMR (200 MHz, CDCl3): = 7.32–7.09 (m, 5 H), 5.82 (q, J = 1.4 Hz, 1
H), 4.53 (s, 2 H), 3.65 (s, 2 H), 1.95 (d, J = 1.4 Hz, 3 H).
13C NMR (50 MHz, CDCl3): = 171.9, 155.2, 137.3, 128.5 (2 C), 127.8
(C), 127.3, 122.5, 54.9, 45.6, 15.1.
HRMS (ESI): m/z calcd for C12H14NO [M + H]+: 188.1070; found:
Mp 128 °C (Lit.5d 127–131 °C); Rf = 0.6 (EtOAc–PE, 50:50).
188.1062.
IR (CHCl3): 1674, 1216, 762 cm–1
.
1-Benzyl-3-ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one (9)
1H NMR (200 MHz, CDCl3): = 7.17 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6
Hz, 2 H), 4.54 (s, 2 H), 3.79 (s, 3 H), 3.58 (s, 2 H), 2.29 (q, J = 7.5 Hz, 2
H), 1.91 (s, 3 H), 1.08 (t, J = 7.5 Hz, 3 H).
To a stirred solution of compound 8 (8 g, 42.7 mmol, 1 equiv) in anhy-
drous THF (200 mL), NaH (1.13 g, 47.0 mmol, 1.1 equiv) was added
slowly at 0 °C. The reaction mixture was stirred for 15 min, ethyl bro-
mide (3.83 mL, 51.3 mmol, 1.2 equiv) in anhydrous THF (40 mL) was
added dropwise at 0 °C, and stirring was continued for 3 h at that
temperature. The progress of the reaction was monitored by TLC. Af-
ter completion, the reaction mixture was treated with saturated
NH4Cl solution and extracted with EtOAc (3 × 200 mL). The combined
organic layer was washed with brine (10 mL), dried over anhydrous
Na2SO4, and filtered. Concentration of the organic layer in vacuo fol-
lowed by purification of the obtained residue by silica gel column
chromatography (EtOAc–PE, 35:65) afforded pure 9 as a sticky yellow
solid [yield: 5.25 g (57%)] along with recovery of the starting material
(1.5 g).
Spectroscopic data were consistent with the earlier reported analyti-
cal information.
3-Ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one (3)5d
To a stirred solution of compound 7 (0.2 g, 0.816 mmol, 1 equiv) in
anisole (2 mL), TFA (2 mL) was added and the reaction mixture was
heated at 80 °C for 3 h. The progress of the reaction was monitored by
TLC. After completion, the reaction mixture was allowed to cool to rt,
quenched with saturated NaHCO3 solution (4 mL), and extracted with
EtOAc (3 × 20 mL). The combined organic layer was washed with
brine (10 mL), dried over anhydrous Na2SO4, and filtered. Concentra-
tion of the organic layer in vacuo followed by purification of the ob-
tained residue by silica gel column chromatography (EtOAc–PE,
50:50) afforded pure 3 as a pale yellow solid; yield: 82 mg (81%).
Mp 103 °C (Lit.5d 102 °C); Rf = 0.3 (EtOAc–PE, 70:30).
IR (CHCl3): 3440, 1722, 1216, 765 cm–1
1H NMR (400 MHz, CDCl3): = 7.74 (br s, 1 H), 3.77 (s, 2 H), 2.24 (q,
J = 7.5 Hz, 2 H), 1.96 (s, 3 H), 1.04 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 176.3, 148.6, 133.9, 50.0, 16.5, 13.1,
Rf = 0.26 (EtOAc–PE, 50:50).
IR (CHCl3): 1703, 1216, 765 cm–1
.
1H NMR (400 MHz, CDCl3): = 7.37–7.15 (m, 5 H), 4.60 (s, 2 H), 3.60
(s, 2 H), 2.31 (q, J = 7.5 Hz, 2 H), 1.62 (s, 3 H), 1.09 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 172.2, 145.4, 137.6, 134.1, 128.6 (2 C),
128.0 (2 C), 127.3, 53.5, 45.9, 17.0, 13.1, 12.7.
HRMS (ESI): m/z calcd for C14H18NO [M + H]+: 216.1383; found:
.
216.1379.
12.9.
HRMS (ESI): m/z calcd for C7H12NO [M + H]+: 126.0913; found:
126.0910.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E