11036
S. D. Roth et al. / Tetrahedron 63 (2007) 11030–11039
A combination of heteronuclear multiple bond correlation
(HMBC) spectra and 1H{1H} NOE data was used to assign
1H and 13C NMR spectra. UV–visible spectra were recorded
on a Perkin–Elmer Lambda-12 spectrophotometer. Melting
points were taken on a Mel Temp capillary apparatus and
are corrected. Combustion analyses were carried out by
Desert Analytics, Tucson, AZ. Analytical thin layer chroma-
tography was carried out on J. T. Baker silica gel IB-F
plantes (125 mm layers). Radial chromatography was carried
out on Merck silica gel PF254 with gypsum preparative layer
grade, using a Chromatotron (Harrison Research, Palo Alto,
CA). Spectral data were obtained in spectral grade solvents
(Aldrich or Fisher). Deuterated chloroform and dimethyl-
sulfoxide were from Cambridge Isotope Laboratories.
3,4-Diethyl-1H-pyrrole (6)11 and 3,4-dimethyl-1H-pyrrole
(7)9e,22 were prepared as reported previously from ethyl
3,4-diethyl-1H-pyrrole-2-carboxylate11 and ethyl 3,4-di-
methyl-1H-pyrrole-2-carboxylate,9e,22 respectively.
extracted with ether (5ꢃ20 mL) and dried over Na2SO4.
The ether solution was filtered and then evaporated at
reduced pressure to yield 2.0 g (68%) of 812 as a yellow
1
oil that is very sensitive to air and light; H NMR (CDCl3)
d: 1.23 (t, J¼7.7 Hz, 6H), 2.5 (q, J¼7.7 Hz, 4H), 6.56 (d, J¼
2.5 Hz, 2H), 8 (br s, 1H) ppm; 13C NMR (CDCl3) d: 14.4 (q),
18.25 (t), 114.2 (d), 124.4 (s) ppm. 3,4-Diethylpyrrole 8 was
used directly in the next step.
3,4-Diethylpyrrole 8 (0.5 g, 4.1 mmol) was heated at reflux
with H2O2 (1 mL), dry pyridine (1 mL), and methanol
(about 0.3 mL) for about 25 min; then more H2O2
(0.5 mL) was added, and the mixture was heated at reflux
for a short period (until no more starting material was
detected by TLC, eluent 1% MeOH–99% CH2Cl2). After
the reaction was complete, the solvent volume was reduced
under vacuum (rotovap), and the residue was dissolved in
diethyl ether, washed with water and dilute (3%) HCl,
followed by satd NaCl. The ether layer was evaporated
(rotovap) to yield 0.44 g (80%) of the pyrrolinone product
4.1.1. Ethyl 3,4-diethyl-1H-pyrrole-2-carboxylate (6).
The following is an improved procedure, which avoids the
use of DBU base.11,12b 3-Acetoxy-4-nitrohexane11,12b (2.4 g)
and ethyl isocyanoacetate11,12b,23 (1.4 g) were placed in a
100-mL round bottom flask together with a 1:1 mixture of
THF and ethanol (30 mL). Anhydrous potassium carbonate
(3.5 g) was added in portions while the mixture was stirred
vigorously. The reaction mixture was then stirred at room
temperature for 3 days. After ascertaining that the reaction
was complete (TLC), the mixture was poured into water
(100 mL), acidified to pH 5 with 5% HCl, and extracted
with diethyl ether (4ꢃ25 mL). The solvent was removed at
reduced pressure (rotovap) after drying over Na2SO4. The
resulting oil was passed through a short column of silica
gel using 1% CH3OH in CH2Cl2 as eluent. The eluate was
collected, and the solvent was evaporated to yield a brown
oil (one spot on TLC, eluent CH2Cl2): 2 g, 81% [lit.11 oil].
1
4 as yellow oil.8 It had H NMR (CDCl3) d: 1.1 (m, 6H),
2.3 (q, J¼7.7 Hz, 2H), 2.42 (m, 2H), 3.84 (s, 2H), 6.8 (br
s, 1H) ppm. GC–MS, m/z: 139, 124, 110, 96, 92, 82, 67,
55 amu.
4.1.3. 3,4-Diethyl-2,5-diformyl-1H-pyrrole (3). The pro-
cedure reported below gives a higher yield of 3 than that
reported earlier.7 Pyrrole acid 7 (0.5 g, 3.0 mmol) was dis-
solved in TFA (20 mL) at room temperature in the dark;
then triethyl orthoformate (20 mL) was added dropwise at
a rate such that the temperature remained close to room tem-
perature. The mixture was then stirred for about 1 h (or until
the reaction was complete); then the solvent volume was
reduced (rotovap) and the remaining liquid was poured
into water and neutralized with satd aq NaHCO3. After ether
extraction (5ꢃ10 mL), followed by evaporation of the sol-
vent (rotovap), the solid, yellowish product (3) was found
to be pure. The yield was 0.38 g (71%), mp 105–107 ꢀC
[lit.7 mp 106 ꢀC]. The 1H and 13C NMR matched with those
previously reported.7
1
It had H NMR (CDCl3) d: 1.16 (t, J¼6.9 Hz, 3H), 1.2 (t,
J¼7.7 Hz, 3H), 1.36 (t, J¼7.7 Hz, 3H), 2.5 (q, J¼7.7 Hz,
2H), 2.8 (q, J¼7.7 Hz, 2H), 4.3 (q, J¼6.9 Hz, 2H), 6.7 (d,
J¼2.9 Hz, 1H), 9.1 (br s, 1H) ppm; 13C NMR (CDCl3) d:
14.3 (q), 14.8 (q), 15.3 (q), 17.9 (t), 18 (t), 59.6 (t), 118.5
(s), 119 (d), 126 (s), 132 (s) ppm.
4.1.4. 2,3,7,8,12,13-Hexaethyl-15H,17H-tripyrrin-1,14-
dione (1). Procedure A. 3,4-Diethyl-3-pyrrolin-2-one
(1.40 g, 10.0 mmol) was added to 3,4-diethyl-2,5-diformyl-
1H-pyrrole (0.300 g, 1.68 mmol) dissolved in 20 mL of
p-dioxane. Piperidine (30 drops) was then added slowly,
and the reaction mixture was heated at reflux under N2 for 7
days. After cooling to room temperature, the solvent was
evaporated in vacuo (rotovap) and the residue was taken up
in diethyl ether (100 mL). The aqueous layer contained the
side product dipyrrinone (10), which was set aside for further
purification. The organic layer was washed with 5% aq HCl,
satd aq NaHCO3, water, and brine and then dried over
Na2SO4. The ether was evaporated, and the residue was sep-
arated using radial chromatography, 5% MeOH in CH2Cl2 as
eluent to afford 339 mg (48%) of 1, mp 215–217 ꢀC; IR (film)
n: 3228, 2968, 2934, 2874, 1770, 1709, 1676 cmꢁ1; NMR
data are given in Table 1. Anal. Calcd for C26H35N3O2
(421.6): C, 74.07; H, 8.37; N, 9.97. Found: C, 73.84; H,
8.46; N. 9.85.
4.1.2. 3,4-Diethyl-3-pyrrolin-2-one (4). The procedure de-
scribed below provides 4 in twice the yield of converting
8/4 as previously reported.8 Pyrrole 6 (2.0 g, 10.3 mmol)
was dissolved in ethanol (20 mL), then a solution of
NaOH (1.2 g) in water (8 mL) was added, and the mixture
was heated at reflux overnight. The volume was reduced un-
der vacuum (rotovap), and the resulting solid was dissolved
in a minimum amount of water and acidified with 5% HCl to
pH 5 at 0 ꢀC. The precipitated carboxylic acid (7) was
quickly filtered, washed with water, and air-dried overnight
to yield 1.5 g (88%) of almost white, slightly pink solid with
1H NMR (CDCl3) d: 1.03 (t, J¼7.7 Hz, 3H), 1.1 (t, J¼
7.7 Hz, 3H), 2.34 (q, J¼7.7 Hz, 2H), 2.63 (q, J¼7.7 Hz,
2H), 6.64 (d, J¼2.9 Hz, 1H), 11.06 (s, 1H), 11.96 (s,
1H) ppm; 13C NMR (CDCl3) d: 15.37 (q), 16.1 (q), 17.8
(t), 118.7 (s), 119.6 (d), 125.1 (s), 131 (s), 162.7 (s) ppm.
The acid was taken directly to the next step.
Pyrrole acid 7 (4.0 g, 24 mmol) was added to water
(100 mL) and then steam distilled. The distillate was
Procedure B. 3,4-Diethyl-3-pyrrolin-2-one 4 (0.28 g,
1.93 mmol) was dissolved in 3 mL of a 1:1 mixture of