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M. A. Wilson et al. / Tetrahedron Letters 50 (2009) 4807–4809
Table 1
A comparison of experimental conditions for the conversion of aromatic amines into N-phenyl pyrroles
Entry N-Aryl pyrroles
Literature
Reaction conditions and purification
Acid free
Yield
(%)
Reaction conditions and purification
Yield
(%)
1
P2O5, dry toluene, 125 °C, 45 min.4 Evaporation, flash
chromatography
87
79
89
Water,
Water,
Water,
l
l
l
W, 150 °C, 30 min. Filtration
W, 150 °C, 30 min. Filtration
W, 150 °C, 30 min. Filtration
90
93
95
N
2
P2O5, dry toluene, 125 °C, 45 min.4 Evaporation, flash
chromatography
N
Cl
O
Cl
3
P2O5, dry toluene, 125 °C, 45 min.4 Evaporation, flash
chromatography
N
4
CuI, n-Bu4NBr, NaOH, toluene, reflux, 22 h.6 Extraction, flash
chromatography
84
Water,
lW, 150 °C, 30 min. Filtration
99
95
N
N
5
CuI, N-hydroxysuccinimide, CH3ONa, DMSO, 110 °C, 24 h5 Extraction, 96
flash chromatography
Water,
chromatography
lW, 150 °C, 30 min. Filtration, flash
N
N
6
CuI, N-hydroxyphthalimide, CH3ONa, DMSO, 110 °C, 24 h.5
Extraction, flash chromatography
90
Water,
Water,
l
W, 150 °C, 30 min. Filtration
W, 150 °C, 30 min. Filtration
97
97
N
N
O
CuI, N-hydroxymaleimide, CH3ONa, DMSO, 110 °C, 40 h.5 Extraction, 45
flash chromatography
l
N
N
N+
O–
7
8
9
CuI, n-Bu4NBr, NaOH, toluene, reflux, 22 h.6 Extraction, flash
chromatography
88
83
62
Water,
Water,
lW, 150 °C, 30 min. Filtration
98
98
95
CuI, n-Bu4NBr, NaOH, toluene, reflux, 22 h.6 Extraction, flash
chromatography
lW, 150 °C, 30 min. Filtration, flash
N
N
chromatography
10
CuI, n-Bu4NBr, NaOH, toluene, reflux, 22 h.6 Extraction, flash
chromatography
Water,
chromatography
lW, 150 °C, 30 min. Filtration, flash
economy, we used 1.3 equiv of 2,5-dimethoxytetrahydrofuran for
larger scale reactions. To investigate the role of water in this reac-
tion, the reaction was performed neat. The desired product was
isolated in good yield, implying that water is acting as solvent
and not participating as an acid catalyst under these conditions.
This result supports the importance of the pKa of the substrate in
order for the reaction to work. Nonetheless, the reaction yields
and product purity were better when water was used as solvent.
The reaction concentration could range from 0.5 M to 2.5 M
depending on the scale of the reaction.
With our optimized reaction conditions, we explored the
scope of this methodology using several commercially available
aryl sulfonamides and anilines. Heating an aniline or an aryl
sulfonamide with 2,5-dimethoxytetrahydrofuran in water
(0.64 M) in a microwave reactor at 150 °C for 30 min resulted
in the formation of the corresponding pyrrole in 81–99% yield.
The results are summarized in Tables 1 and 2. There is no
noticeable effect of the electronic nature of the aryl nucleophile
on the reaction yield. Additionally, the products were conve-
niently isolated by filtration to give the desired products with
average purities of greater than 90%. If purification was required,
a simple filtration through a silica plug eluting with 50% ethyl
acetate/hexane was used to purify the product. The reaction
was also amenable to scale up using a CEM 80 mL reaction ves-
sel. The reaction was routinely scaled up to 67 mmol in 2.2 M
water without any difficulties.
In conclusion, we have demonstrated a simple and efficient syn-
thetic route for the synthesis of N-phenyl and N-aryl sulfonyl pyr-
roles. Compared to the classical synthetic method, this approach
has the advantage of being inexpensive, simple, and environmen-
tally benign.
A general experimental procedure for the synthesis of N-sulfonyl
pyrroles and N-phenyl pyrroles. Aniline (200 mg, 1.27 mmol) and
2,5-dimethoxytetrahydrofuran (425 mg, 3.22 mmol) in water
(2.0 mL) were heated to 150 °C for 30 min in a CEM microwave
oven. The reaction was allowed to cool and the resulting