Mar-Apr 2001
An Improved Coupling Procedure for the Barton-Zard Pyrrole Synthesis
529
MHz (proton) and 75 MHz (C-13) in deuteriochloroform solvent.
Chemical shifts are reported in ppm referenced to the residual chlo-
roform proton signal at 7.26 ppm and the C-13 signal at 77.0 ppm.
Melting points were taken on a Mel-Temp capillary apparatus and
are uncorrected. Analytical thin layer chromatography was on J.T.
Baker silica gel IB-F plates (125 µm layers). Flash column chro-
matography used silica gel, 60-200 mesh (M. Woelm). All solvents
were reagent grade obtained from Fisher. Acetic acid, hydrogen
peroxide, potassium fluoride, potassium carbonate and acetic
anhydride were from Fisher. Nitromethane, methyl acrylate,
acetaldehyde, tetra-n-butylammonium bromide, p-dimethyl-
aminopyridine and sodium borohydride were purchased from
Acros. Deuterated chloroform was from Cambridge Isotope
Laboratories. p-Toluenesulfonylmethyl isocyanide (TosMIC) [13]
and benzyl isocyanoacetate [7a] were prepared according to litera-
ture procedures. 2-Nitro-3-pentyl acetate (7a) and 3-nitro-2-pentyl
acetate (7b), prepared according to literature procedures [6,12a].
Methyl 5-hydroxy-4-nitrohexanoate (12) was prepared in 88%
yield as described previously [12]. Methyl 5-acetoxy-4-nitrohexa-
noate (8) [12b] was prepared in 90% yield by acetylation of 12 [6].
methyl isocyanide (10) (TosMIC) (1.95 g, 0.01 mole) and potas-
sium carbonate (2.9 g, 0.021 mole) in a 1:1 by volume mixture of
tetrahydrofuran:methanol (30 ml) at room temperature over 20
minutes. The mixture was stirred at room temperature for 3 days.
After cooling in an ice bath, the reaction was quenched with 30
ml of 5% hydrochloric acid added dropwise during 2 hours. The
precipitated white product was collected by filtration, washed
with water and dried under vacuum to afford 2.33 g (89%) of 1
1
[8,10,14]. It had mp 122-123 °C (lit [8] mp 114-116 °C); H nmr:
δ 8.96 (bs, 1H), 7.76 (d, 2H, J = 8.2 Hz), 7.26 (d, 2H, J = 8.2 Hz),
6.69 (d, 1H, J = 2.6 Hz), 2.61 (q, 2H, J = 7.5 Hz), 2.39 (s, 3H),
1.98 (s, 3H), 0.97 (t, 3H, J = 7.5 Hz).
4-Ethyl-3-methyl-2-(p-toluenesulfonyl)-1H-pyrrole (2b).
This pyrrole was prepared in 82% yield using the method
above for 3-ethyl-4-methyl-2-(p-toluenesulfonyl)-1H-pyrrole
1
(2a) [5c,11,14]. It had mp 116-117 °C (lit [5c] mp 117-118 °C; H
nmr: δ 8.85 (bs, 1H), 7.76 (d, 2H, J = 8.2 Hz), 7.27 (d, 2H, J = 8.2
Hz), 6.69 (d, 1H, J = 2.9 Hz), 2.40 (s, 3H), 2.35 (q, 2H, J = 7.6
Hz), 2.15 (s, 3H), 1.12 (t, 3H, J = 7.6 Hz).
Ethyl 3-Ethyl-4-methyl-1H-pyrrole-2-carboxylate (1a).
Benzyl 4-(Methoxycarbonylethyl)-3-methyl-1H-pyrrole-2-car-
boxylate (3).
A mixture of 2-nitro-3-pentyl acetate (7a) (1.75 g, 0.01 mole)
and ethyl isocyanoacetate (9a) (1.13 g, 0.01 mole) was added in
one portion with stirring to powdered potassium carbonate (2.9 g,
0.021 mole) containing tetra-n-butylammonium bromide (65 mg,
0.2 mmole). Stirring was continued for a few hours at room tem-
perature until the mixture solidified. After standing for 3 days at
room temperature, the solid material was triturated with anhy-
drous diethyl ether (4 x 50 ml). The ether solution was washed
with water, then brine and dried over anhydrous magnesium sul-
fate. The solvent was evaporated under reduced pressure to give
an orange liquid, which was purified by column chromatography
on silica gel using dichloromethane-methanol (99:1 by volume)
to afford 1.56 g (86%) of 1a [4a-c,5] as a yellow powder. It had
Methyl 5-acetoxy-4-nitrohexanoate (8) (2.33 g, 0.01 mole) and
benzyl isocyanoacetate (9b) [7a] (1.77 g, 0.01 mole) were added
dropwise to a vigorously stirred suspension of potassium carbon-
ate (2.9 g, 0.021 moles) in a solvent mixture of tetrahydrofuran
(19 ml) and tert-butyl alcohol (1 ml) at room temperature over 20
minutes. The mixture was stirred at room temperature for 5 days
then quenched by pouring into water (60 ml). The pH was
adjusted to 6, and the mixture was extracted with diethyl ether (4
x 20 ml). After drying over anhydrous magnesium sulfate, the
ether was evaporated under reduced pressure to give a brown liq-
uid, which was purified by column chromatography on silica gel
using dichloromethane:methanol (99:1 to 95:5) as eluent to
afford 2.65 g (88%) of 3 [4e,h-j,7] as a pale yellow oil (lit [4h]
1
mp 70-71 °C (lit. [4b] mp 75 °C); H nmr: δ 8.67 (bs, 1H), 6.65
1
(d, 1H, J = 2.2 Hz), 4.31 (q, 2H, J = 7.2 Hz), 2.75 (q, 2H, J = 7.6
Hz), 2.04 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz), 1.12 (t, 3H, J = 7.6 Hz).
When the method employed for the preparation of 1b was used,
1a was isolated in 69% yield.
mp 41-42 °C); H nmr: δ 8.83 (bs, 1H), 7.39-7.32 (m, 5H), 6.68
(d, 1H, J = 2.9 Hz), 5.29 (s, 2H), 3.66 (s, 3H), 2.75 (t, 2H, J = 7.7
Hz), 2.53 (t, 2H, J = 7.7 Hz), 2.30 (s, 3H).
Methyl 4-Nitrobutanoate (11).
Ethyl 4-Ethyl-3-methyl-1H-pyrrole-2-carboxylate (1b).
Methyl acrylate (45.3 ml, 0.5 mole) was added dropwise to a
vigorously stirred suspension of potassium carbonate (6.91 g,
0.05 mole) in nitromethane (270 ml, 5.0 moles) at room tempera-
ture over 20 minutes. The mixture was then stirred at room tem-
perature for 12 hours. The potassium carbonate was removed by
filtration and washed with chloroform (100 ml). The solvent,
including excess nitromethane, was evaporated under reduced
pressure to give a colorless liquid, from which 11 was obtained in
60% yield (44.1 g) as a colorless oil after distillation under
reduced pressure, bp 80-82 °C at 0.5 mm Hg, (lit [15] bp 74-
82 °C at 0.25 mm Hg). A by-product, dimethyl 4-nitro-1,7-hep-
tanedioate, bp 140-150 °C at 0.5 mm Hg, was isolated as a vis-
cous oil, 26.8 g (23%).
3-Nitro-2-pentyl acetate (7b) (1.75 g, 0.01 mole) and ethyl iso-
cyanoacetate (9a) (1.13 g, 0.01 mole) were added dropwise to a
vigorously stirred suspension of potassium carbonate (2.9 g, 0.021
mole) in 30 ml of 1:1 (by volume) tetrahydrofuran-ethanol at room
temperature over 20 minutes. The mixture was stirred at room tem-
perature for 5 days then quenched by pouring into water (80 ml).
The pH was adjusted to 6, and the mixture was extracted with
diethyl ether (4 x 50 ml) and dried over anhydrous magnesium sul-
fate. The ether was then evaporated under reduced pressure to give
an orange liquid, which was purified by column chromatography
on silica gel, eluting with dichloromethane:methanol (99:1) to
afford 1.41 g (78%) of 1b [4d-g] as an orange oil (lit [4f] mp 22-
1
23 °C). H nmr: δ 8.84 (bs, 1H), 6.67 (d, 1H, J = 2.6 Hz), 4.31 (q,
4-Ethyl-3-methyl-5-(p-toluenesulfonyl)-1,5-dihydro-1H-
pyrrolin-2-one (4).
2H, J = 7.1 Hz), 2.43 (q, 2H, J = 7.5 Hz), 2.29 (s, 3H), 1.35 (t, 3H,
J = 7.1 Hz), 1.17 (t, 3H, J = 7.5 Hz).
3-Ethyl-4-methyl-2-(p-toluenesulfonyl)pyrrole (2a) (25 g, 95
mmoles, 1 equivalent) was dissolved in glacial acetic acid (550
ml) at room temperature. After complete dissolution, hydrogen
peroxide (30%, 14.6 ml, 142.5 mmoles, 1.5 equivalent) was
3-Ethyl-4-methyl-2-(p-toluenesulfonyl)-1H-pyrrole (2a).
2-Nitro-3-pentyl acetate (7a) (1.75 g, 0.01 mole) was added
dropwise to a vigorously stirred suspension of p-toluenesulfonyl-