1
General Procedure for the N-Methylation of Pyrroles
with DMC/DMF/DABCO. (Example: Methyl-N-methyl-2-
pyrrole Carboxylate (7)). A reaction flask was charged with
methyl-2-pyrrole carboxylate, 5 (2.0 g, 16.0 mmol), DMC (20
mL), DABCO (0.18 g, 1.6 mmol), and DMF (1.0 mL). The
resulting mixture was heated to 90-92 °C and stirred at that
temperature for 23 h. HPLC analysis indicated complete
consumption of the starting material. The reaction mixture was
cooled to 21 °C, diluted with EtOAc (25 mL), and transferred
to a separatory funnel. The solution was washed sequentially
with H2O (25 mL) and 10% citric acid (2 × 15 mL). The
washes were combined and back extracted with EtOAc (25
mL). The combined organics were washed with brine (25 mL),
dried over Na2SO4, and concentrated in Vacuo to afford the
desired product as a colorless oil (2.0 g, 90.4%). 1H NMR (400
MHz, DMSO) δ 3.71 (s, 3H), 3.83 (s, 3H), 6.07 (dd, J ) 2.6,
4.0 Hz, 1H), 6.81 (dd, J ) 1.8, 4.0 Hz, 1H), 7.07 (m, 1H); 13C
NMR (75 MHz, DMSO) δ 36.7, 51.2, 108.1, 117.8, 121.9,
130.7, 161.2; IR (neat) 1699, 1435, 1405, 1242, 1104 cm-1;
ESI-HRMS m/z Calcd for (M + H+) 140.0708, found 140.0706.
3-(4-Bromophenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-
2-carboxylic Acid Ethyl Ester (2).3 (Note: this compound was
isolated as a mix of the ethyl and methyl (∼81/19) esters due
to transesterification.) White solid: ESI-HRMS m/z Calcd for
(M + H+) 361.0546, found 361.0546 (ethyl ester); Calcd for
(M + H+) 347.0390, found 347.0389 (methyl ester).
N-Methyl-2-cyano Pyrrole (11): colorless oil: H NMR
(400 MHz, DMSO) δ 3.73 (s, 3H), 6.15 (dd, J ) 2.6, 4.0 Hz,
1H), 6.88 (dd, J ) 1.3, 4.0 Hz, 1H), 7.15 (m, 1H); 13C NMR
(75 MHz, DMSO) δ 35.4, 103.5, 109.4, 114.3, 120.3, 129.3;
IR (neat) 2209, 1476, 1402, 1309 cm-1; ESI-HRMS m/z Calcd
for (M + H+) 107.0604, found 107.0606.
N-Methyl-2-formyl Pyrrole (13): pale yellow oil: 1H NMR
(400 MHz, DMSO) δ 3.86 (s, 3H), 6.19 (dd, J ) 2.6, 4.0 Hz,
1H), 6.97 (dd, J ) 1.8, 4.0 Hz, 1H), 7.21 (m, 1H); 13C NMR
(75 MHz, DMSO) δ 36.2, 109.7, 123.8, 132.0, 133.0, 179.8;
IR (neat) cm-11647, 1487, 1409, 1309, 1384, 1365 cm-1; ESI-
HRMS m/z Calcd for (M + H+) 110.0601, found 110.0603.
N-Methyl-1,5,6,7-tetrahydro-4H-indole-4-one (16): white
solid: mp 84-85 °C; 1H NMR (400 MHz, DMSO) δ 1.98 (m,
2H), 2.26 (m, 2H), 2.71 (t, 2H), 3.52 (s, 3H), 6.22 (d, J ) 3.1
Hz, 1H), 6.71 (d, J ) 3.1 Hz, 1H); 13C NMR (75 MHz, DMSO)
δ 21.2, 23.7, 33.5, 37.8, 104.6, 120.4, 123.9, 144.2, 192.9; IR
(neat) 2938, 1635, 1510, 1465, 1424, 1405, 1339, 1257 cm-1;
ESI-HRMS m/z Calcd for (M + H+) 150.08406, found
150.0913.
N-Methyl-7-azaindole-3-carboxaldehyde (18): white solid:
1
mp 94-95 °C; H NMR (400 MHz, DMSO) δ 3.89 (s, 3H),
7.31 (m, 1H), 8.39 (m, 1H), 8.48 (s, 1H), 9.89 (m, 1H); 13C
NMR (75 MHz, DMSO) δ 32.1, 115.6, 117.2, 119.1, 129.8,
141.9, 145.0, 148.8, 185.1; IR (neat) 3035, 2733, 1647, 1599,
1577, 1532, 1472, 1383, 1205 cm-1; ESI-HRMS m/z Calcd
for (M + H+) 161.0709, found 161.0712.
N-Methyl-2-acetyl Pyrrole (9): colorless oil: 1H NMR (400
MHz, DMSO) δ 2.33 (s, 3H), 3.81 (s, 3H), 6.08 (dd, J ) 2.6,
4.0 Hz, 1H), 7.02 (dd, J ) 1.8, 4.0 Hz, 1H), 7.08 (m, 1H); 13C
NMR (75 MHz, DMSO) δ 27.3, 37.4, 108.0, 120.3, 130.7,
131.9, 188.1; IR (neat) 1640, 1525, 1398, 1379, 1320, 1242
cm-1; ESI-HRMS m/z Calcd for (M + H+) 124.0757, found
124.0758.
Acknowledgment
We are grateful to Mr. Eric Crockett for performing all of
the high-resolution mass spectrometer experiments.
Received for review September 30, 2009.
OP900256T
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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