Direct arylation of pyrrole derivatives in ionic liquids

Article abstract of DOI:10.1002/ejoc.201100004

An efficient methodology for the direct arylation of pyrrole derivatives has been developed. The reaction proceeds smoothly with a wide range of structurally diverse aryliodides. Derivatives bearing an N,N-dimethylamino group at the 1-position and an aryl substituent at the 2-position were prepared for the first time. This protocol is more environmentally friendly than those previously reported because it is free of transition metals and utilizes ionic liquids rather than volatile organic solvents.

Full text of DOI:10.1002/ejoc.201100004

FULL PAPER
DOI: 10.1002/ejoc.201100004
Direct Arylation of Pyrrole Derivatives in Ionic Liquids
Olena Vakuliuk[a] and Daniel T. Gryko*[a]
Keywords: C–C coupling / Heterocycles / Ionic liquids / Halides
An efficient methodology for the direct arylation of pyrrole
derivatives has been developed. The reaction proceeds
smoothly with a wide range of structurally diverse aryl
iodides. Derivatives bearing an N,N-dimethylamino group at
the 1-position and an aryl substituent at the 2-position were
prepared for the first time. This protocol is more environmen-
tally friendly than those previously reported because it is free
of transition metals and utilizes ionic liquids rather than vola-
tile organic solvents.
cently, several protocols for the efficient direct arylation of
pyrrole derivatives were discovered.[7] To the best of our
knowledge, methodology based on direct arylation of aro-
matic compounds in ILs has not yet been developed. How-
ever, direct arylation of allylic alcohols has been reported.[8]
The application of ILs as reaction media for Stille, Sonoga-
shira, Heck, and Suzuki couplings is well established.[9]
Introduction
Of the various approaches available to make aryl–aryl
bonds, direct arylation of both homo- and heteroaromatic
compounds with aryl halides is currently undergoing the
most rapid development.[1] Extensive research performed in
the last 15 years has shown that heterocyclic systems can be
arylated in the presence of transition metal salts in various
organic solvents.[2] The efficiency of these reactions depends
strongly on the structure of the particular heterocyclic com-
pound.
Results and Discussion
There are many challenges to developing metal-free cou-
pling reactions. Thus, in the early stage of our research we
decided to investigate the use of ILs in palladium-catalyzed
direct couplings. The reaction of N-methylpyrrole (1) with
4-iodobenzonitrile (2) was chosen as a model system for the
optimization study (Scheme 1).
As part of our project involving direct arylation of elec-
tron-rich heterocycles, we aim to improve the efficiency of
the reaction and to reduce its environmental impact. Most
chemical reactions are still carried out in molecular sol-
vents. However, over the last two decades ionic liquids (ILs)
have attracted attention due to their vanishingly low vapor
pressures and their capacity to solvate an array of organic
and inorganic substances.[3] To date, ILs have found appli-
cations in hydrogenations; Friedel–Crafts, Diels–Alder,
Baylis–Hillman, and Wittig reactions; ring-closing meta-
thesis, Knoevenagel condensation, Robinson annulation, ki-
netic resolution, and biocatalysis, to name just a few.[4] ILs
are also practical from a synthetic standpoint since they
are effective at recycling transition metal species, which are
widely used to promote coupling reactions.[5]
Scheme 1.
Given these unique properties, we wondered whether per-
forming direct arylation in ILs could be beneficial in terms
of yield and “green aspect” of the reaction. We focused on
arylpyrrole derivatives, whose importance in the synthesis
of target molecules with valuable biological and photo-
physical properties is difficult to overestimate.[6] Very re-
An efficient, ligand-free, palladium-catalyzed protocol
recently reported by Doucet for direct arylation of pyrroles
and thiophenes[10] was performed by using ILs as the reac-
tion medium. Several commercially available ILs were
screened (Table 1).
According to the above experimental results, ILs 5 and 6
with the basic acetate counteranion were more efficient at
promoting the desired transformation (Table 1, Entries 1
and 2). Therefore, ILs 5–7 were used for further optimiza-
tion studies.
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22-6326681
E-mail: daniel@icho.edu.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100004.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Direct Arylation of Pyrrole Derivatives in Ionic Liquids
Table 1. Results of N-methylpyrrole (1) and 4-iodobenzonitrile (2) coupling reactions.[a]
Entry
Ionic liquid or conventional solvent
Yield of 3 [%]
Yield of 4 [%]
1
2
3
4
5
6
1-butyl-3-methylimidazolium acetate (5)
1-ethyl-3-methylimidazolium acetate (6)
7
4
1
32
3
2
0
0
1-methylimidazolium hydrogen sulfate (7)
1-butyl-3-methylimidazolium methanesulfonate (8)
1-butyl-3-methylimidazolium hexafluorophosphate (9)
tris(2-hydroxyethyl)methylammonium methylsulfate (10)
trace
0
0
15
[a] Reactions were performed under the following conditions: 4-iodobenzonitrile (1 equiv.), N-methylpyrrole (5 equiv.), IL (6 equiv.),
Pd(OAc)2 (5 mol-%), 145 °C, overnight; yields were determined by HPLC.
The use of PdCl2 instead of Pd(OAc)2 in the case of 1- (Table 2, Entries 7–10). For comparison, the model reaction
ethyl-3-methylimidazolium acetate ([emim][OAc], 6) slightly
improved the yield of the desired product and, at the same
time, suppressed the formation of homocoupling product 4
(Table 2, Entries 2–4). The replacement of simple palladium
salts with complexes such as Pd(PPh)3Cl2 significantly di-
minished the yield of expected product 3 (Table 2, Entry 6).
was also carried out in some typical organic solvents (DMF,
DMA, NMP, DMSO); the yield of 3 was 0–1% regardless
of solvent.
Examples of highly effective, transition-metal-free direct
coupling protocols are scarce. Recently, Kwong, Lei, and
co-workers discovered an N,NЈ-dimethylethylenediamine
(DMEDA) catalyzed system for the direct coupling of benz-
ene with aryl iodides.[12] Several examples of tBuOK-medi-
ated arylation and alkylation of N-heterocycles were suc-
cessfully performed by the group of Itami and Li.[13] Beau-
lieu efficiently coupled azoles with 2- and 3-haloindoles
using thermal or microwave-mediated heating.[14]
To further improve the yield of compound 3, we pre-
dicted that the addition of stronger bases might lead to
higher reaction efficiency. Three bases were therefore evalu-
ated in IL 6. When KOAc was replaced by CsOAc or
CsOPiv, no significant improvement was observed (Table 2,
Entries 11 and 12). In the case of K2CO3, the yield of 3
decreased (Table 2, Entry 13). Increasing the amount of
KOAc (4 equiv.) combined with the use of a large excess
amount of N-methylpyrrole improved the yield of hetero-
coupled product 3 to 89% (Table 2, Entries 14–17). Chang-
ing parameters such as temperature and time had no posi-
tive effect on the reaction outcome (Table 2, Entries 18 and
19).
Table 2. Influence of reaction conditions on the coupling of N-
methylpyrrole (1) with 4-iodobenzonitrile (2).[a]
Entry
Catalyst
Base
IL
Yield of 3 [%]
1
2
3
4
5
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
KOAc
KOAc
KOAc
KOAc
KOAc
6
5
4
7
14
5
6
7
8
trace
trace
63
61
60
61
59
57
23
77
81
87
89
20
51
6
Pd(PPh)3Cl2 KOAc
5–8
6
7[b]
8[c]
9[d]
10
PdCl2
PdCl2
PdCl2
none
none
none
none
none
none
none
none
none
none
KOAc
KOAc
KOAc
KOAc
CsOAc
CsOPiv
K2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
6
6
6
11
12
13
6
6
6
14[e]
15[f]
16[g]
17[h]
18[i]
19[j]
6
6
6
6
6
6
With these encouraging results in hand, the scope and
limitations of the developed methodology [aryl iodide
(1 equiv.), pyrrole (10 equiv.), KOAc (4 equiv.), 1-ethyl-3-
methylimidazolium acetate, 145 °C, overnight] were exam-
ined by using a variety of structurally diverse aryl iodides
[a] Unless otherwise noted, reactions were performed under the fol-
lowing conditions: iodobenzonitrile (1 equiv.), N-methylpyrrole
(5 equiv.), base (2 equiv.), catalyst (5 mol-%), 145 °C, overnight, IL
(6 equiv.); yields were determined by HPLC. [b] Reaction was per-
formed in the presence of PdCl2 (1 mol-%). [c] Reaction was per-
formed in the presence of PdCl2 (0.1 mol-%). [d] Reaction was per- and a number of pyrrole derivatives as coupling partners
formed in the presence of PdCl2. (0.01 mol-%). [e] KOAc (4 equiv.)
(Table 3).
was used. [f] KOAc (6 equiv.) was used. [g] N-Methylpyrrole
Pyrroles bearing typical electron-donating groups such
(10 equiv.) was used. [h] N-Methylpyrrole (15 equiv.) was used.
as N-methyl-, N-benzyl-, and N-phenylpyrrole can be ef-
ficiently arylated with a number of aromatic iodides
(Table 3). Complete regioselectivity was observed in all
[i] Reaction was performed at 100 °C. [j] Yield was determined after
5 h.
Our investigation began with the use of palladium salt cases, with 2-arylated products being obtained. Reactions
(5 mol-%). It is well known that similar transformations can were also carried out with pyrroles bearing more elaborate
be catalyzed by similarly low loadings of transition metal substituents (Table 3, Entries 11–14). 1-(N,N-dimeth-
salts.[10,11] In order to investigate whether the catalyst load- ylamino)pyrrole (14) reacted with 1-iodo-3-nitrobenzene to
ing influences the reaction, we continuously decreased the give product 34 in moderate yield. The low yield may be
amount of palladium salt used in the reaction. We were explained by partial decomposition of the very electron-rich
delighted to find that the catalyst had no impact on the substrate during the reaction. 1,2,5-Trimethylpyrrole (15)
reaction outcome and that even in the absence of a palla- and N-SEM-pyrrole {16, SEM = [2-(trimethylsilyl)ethoxy]-
dium source the reaction afforded 3 in about 60% yield methyl} also afforded expected products 35 and 36, respec-
Eur. J. Org. Chem. 2011, 2854–2859
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O. Vakuliuk, D. T. Gryko
FULL PAPER
Table 3. Scope of the optimized conditions for pyrrole arylation.[a]
Figure 1. Structure of 2-(4-cyanophenyl)pyrrole (38).
Entry Pyrrole
R
Aryl iodide
RЈ
Product Yield [%][b]
It is known that the introduction of a bulky substituent
to the pyrrole at the 1-position changes the regioselectivity
of substitution reactions.[15] There was no reaction when N-
TIPS-pyrrole was used, probably due to the lability of the
TIPS group under slightly basic reaction conditions.
We have since tried to expand the scope of this reaction
with respect to other electron-rich heterocycles. The hetero-
coupling reaction with benzofuran afforded corresponding
2-arylated product 39 in moderate yield (Figure 2).
1
2
1
1
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2
17
18
19
20
21
22
23
2
2
2
19
2
2
4-CN
4-NO2
3-CN
3-NO2
2-CN
3
70
65
64
56
61
72
7
24
25
26
27
28
29
30
31
32
33
34
35
36
3
1
4
1
5
1
6
1
2-NO2
4-OMe
7
1
[e]
8
1
–
43
42
52
47
36
18
14
9
11
12
13
14
15
16
4-CN
4-CN
4-CN
3-NO2
4-NO2
4-CN
10
11
12
13
14
Bn
[c]
–
NMe2
[d]
–
SEM
[a] Unless otherwise stated, reactions were performed under the following
conditions: iodide (1 equiv.), pyrrole (10 equiv.), base (4 equiv.), 1-ethyl-3-
methylimidazolium acetate (6, 3 equiv.). [b] Yields of isolated product after
column chromatography. [c] 2-[(Pyrrol-1-yl)methyl]pyridine was used as
substrate. [d] 1,2,5-Trimethylpyrrole was used as substrate. [e] 4-Iodo(phen-
ylethynyl).
Figure 2. Structure of arylated benzofuran 39.
It is known that impurities present in commercially avail-
able metal salts can catalyze various reactions.[16] Taking
into account that trace amounts of transition metals –
which are known to catalyze direct arylation – can be pres-
ent in ILs, some additional experiments were conducted to
eliminate this possibility. A detailed analysis of IL 6 using
inductively coupled plasma–atomic emission spectrometry
(ICP-AES) was performed. Results clearly showed that the
concentration of most transition metals (Pd, Fe, Cu, Rh)
in the 1-ethyl-3-methylimidazolium acetate employed in our
study was less than 5.0 ppm; Ni was found to be present at
less than 2 ppm (see the Supporting Information for de-
tails). Among the metals that are known to catalyze the
desired coupling reactions, Ni was also present in levels less
than 2 ppm. Consequently, we believe that the reaction pro-
ceeds without the participation of redox-active metals in the
catalytic cycle.
There is no direct evidence for the mechanism of the de-
scribed direct arylation reaction. The use of traditional radi-
cal scavengers, such as peroxides, is limited in this case due
to the oxidative lability of the pyrrole core. Another widely
used radical trap is 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO). TEMPO reacts with N-methylpyrrole to give
oxidation products. However, N-phenylpyrrole was found
to be resistant to oxidation. Subsequently, treatment of N-
phenylpyrrole (11) with 4-iodobenzonitrile (2) and TEMPO
did not afford desired arylated compound 31. This result
supports a radical-based mechanism for the described
transformation although other possibilities cannot yet be
excluded.
tively, albeit in low yields (Table 3, Entries 13 and 14). In
the latter case, arylation obviously occurred at the 3-posi-
tion.
Surprisingly, the reaction of 1-(2-cyanoethyl)pyrrole with
1-iodo-4-nitrobenzene (17) did not afford expected 3-[2-(4-
nitrophenyl)-pyrrol-1-yl]propanenitrile. Instead, depro-
tected 2-(4-nitrophenyl)-1H-pyrrole (37) was obtained in
40% yield (Scheme 2). Given that the pyrrole itself can be
transformed into an arylated product in very low yield, it is
believed that the desired transformation initially occurs but
it is subsequently followed by a retro-Michael reaction,
leading to product 37. It is also noteworthy that it was pos-
sible to recover the excess amount of pyrrolic substrate. As
expected, aryl iodides showed higher reactivity compared
to the corresponding bromides and chlorides, affording
compound 3 in 47 and 11% yield respectively.
Scheme 2.
Although most reactions proceeded well for a variety of
substrates, several limitations have been noted. For exam-
ple, 4-iodoanisole (22) proved to be much less effective, af-
fording only a 7% yield of corresponding product 29
(Table 3, Entry 7). Pyrrole derivatives with N-electron-with-
drawing protecting groups (Bz, Ts) were found to be unre-
active. Pyrrole itself was found to react with 1-cyano-4-
Conclusions
In conclusion, we have developed the first protocol that
iodobenzene to afford expected arylated compound 38, al- allows direct coupling of electron-rich heterocycles with
beit in low yield (Figure 1). aryl iodides in ILs. The acetate-promoted reaction between
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Direct Arylation of Pyrrole Derivatives in Ionic Liquids
3.72 (s, 3 H), 6.21 (t, J = 3.5 Hz, 1 H), 6.34 (dd, J = 3.6, 1.7 Hz, 1
H), 6.77 (t, J = 2 Hz, 1 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.73, (d, J =
7.7 Hz, 1 H), 8.13 (dd, J = 8.2, 1.3 Hz, 1 H), 8.25 (t, J = 2 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 35.2, 108.4, 110.3,
121.2, 122.7, 125.2, 129.3, 131.9, 133.9, 134.9, 148.4 ppm. HRMS
(EI): calcd. for C11H10N2O2 [M]+ 202.0742; found 202.0739.
N-alkyl- and N-arylpyrroles affords 2-arylated products in
good yields and with high regioselectivities. In the case of
1-(2-cyanoethyl)pyrrole, a retro-Michael reaction is believed
to occur, eventually leading to a product bearing a hydro-
gen atom the 1-position. The overall transformation is
thought to proceed through a radical-based mechanism.
The procedure described herein offers a greener alternative
to conventional approaches and may become a practical
tool in the synthesis of arylated aromatic compounds.
N-Methyl-2-(2-cyanophenyl)pyrrole (27): Following the general pro-
cedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1-cy-
ano-2-iodobenzene (137 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 1:9) afforded 27 (66 mg, 61%). Rf = 0.26 (silica; Et2O/
hexanes, 1:4). M.p. 83–84 °C. Spectral and physical properties of
27 were found to concur with the published data.[7f]
Experimental Section
General Methods: All reagents and solvents were purchased from
commercial sources and were used as received unless otherwise
noted. Reagent grade solvents (Et2O, CH2Cl2, hexanes) were dis-
tilled prior to use. Flash chromatography was performed on silica
N-Methyl-2-(2-nitrophenyl)pyrrole (28): Following the general pro-
cedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1-
iodo-2-nitrobenzene (149.4 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 1:9) afforded 28 (87 mg, 72%). Rf = 0.35 (silica; Et2O/
hexanes, 1:4). M.p. 62–63 °C. Spectral and physical properties of
28 were found to concur with the published data.[7f]
1
(200–400 mesh). H and 13C NMR spectra were measured with a
Bruker AV400 or AV500 spectrometer. All chemical shifts are given
in ppm. Mass spectra were obtained by EI-MS (AMD 604) or ESI-
MS (Marimer). The optimization study was performed by HPLC
(Knauer; samples were first filtered through a pad of silica).
N-Methyl-2-(4-methoxyphenyl)pyrrole (29): Following the general
procedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1-
iodo-4-methoxybenzene (140.4 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 5:95) afforded 29 (crystallized from Et2O/pentane) as fine,
white crystals (8 mg, 7%). Rf = 0.64 (silica; EtOAc/hexanes, 1:4).
M.p. 59–60 °C. Spectral and physical properties of 29 were found
to concur with the published data.[7f]
General Procedure for Arylation of Pyrrole Derivatives: Iodoarene
(0.6 mmol, 1 equiv.), pyrrole (6 mmol, 10 equiv.), and KOAc
(2.4 mmol, 4 equiv.) were placed into a glass tube and flushed with
argon. Subsequently, 1-ethyl-3-methylimidazolium acetate (250 μL)
was added. The resulting reaction mixture was stirred overnight at
145 °C and filtered through a pad of silica and evaporated under
reduced pressure; the coupling products were purified by column
chromatography.
N-Methyl-2-[4-(phenylethynyl)phenyl]pyrrole (30): Following the ge-
neral procedure, N-methylpyrrole (530 mL, 6 mmol) was treated
with 4-iodo-(phenylethynyl)benzene (182 mg, 0.6 mmol) and KOAc
(235 mg, 2.4 mmol). Purification by column chromatography (sil-
ica; Et2O/hexanes, 5:95) afforded 30 (crystallized from hexanes) as
fine crystals (66 mg, 43%). Rf = 0.52 (silica; EtOAc/hexanes, 1:4).
M.p. 96–98 °C. Spectral and physical properties of 30 were found
to concur with the published data.[7f]
N-Methyl-2-(4-cyanophenyl)pyrrole (3): Following the general pro-
cedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1-cy-
ano-4-iodobenzene (137 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 1:9) afforded 3 (crystallized from Et2O/pentane) as fine,
white crystals (76 mg, 70%). Rf = 0.5 (silica; EtOAc/hexanes, 1:4).
M.p. 102–103 °C. Spectral and physical properties of 3 were found
to concur with the published data.[7f]
N-Phenyl-2-(4-cyanophenyl)pyrrole (31): Following the general pro-
cedure, N-phenylpyrrole (860 mg, 6 mmol) was treated with 1-cy-
ano-4-iodobenzene (137 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 5:95) afforded 31 (crystallized from Et2O/pentane) as fine
crystals (62 mg, 42%). Rf = 0.52 (silica; EtOAc/hexanes, 1:4). M.p.
96–98 °C. Spectral and physical properties of 31 were found to con-
cur with the published data.[7f]
N-Methyl-2-(4-nitrophenyl)pyrrole (24): Following the general pro-
cedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1-
iodo-4-nitrobenzene (149.4 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 1:9) afforded 24 (crystallized from CH2Cl2) as fine, yellow
crystals (79 mg, 65%). Rf = 0.5 (silica; EtOAc/hexanes, 1:4). M.p.
114–115 °C. Spectral and physical properties of 24 were found to
concur with the published data.[7f]
N-Benzyl-2-(4-cyanophenyl)pyrrole (32): Following the general pro-
cedure, N-benzylpyrrole (930 mL, 6 mmol) was treated with 1-cy-
ano-4-iodobenzene (137 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 5:95) afforded 32 (crystallized from CH2Cl2) as fine, yel-
low crystals (81 mg, 52%). Rf = 0.5 (EtOAc/hexanes, 1:4). M.p.
105–106 °C. Spectral and physical properties of 32 were found to
concur with the published data.[7f]
N-Methyl-2-(3-cyanophenyl)pyrrole (25): Following the general pro-
cedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1-cy-
ano-3-iodobenzene (137 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 1:9), afforded 25 (crystallized from Et2O/pentane) as fine,
yellowish crystals (70 mg, 64%). Rf = 0.6 (silica; EtOAc/hexanes,
1:4). M.p. 112–113 °C. Spectral and physical properties of 25 were
found to concur with the published data.[7f]
4-[1-(Pyridyn-2-ylmethyl)pyrrol-2-yl]benzonitrile (33): Following the
general procedure, N-(pyridyn-2-ylmethyl)pyrrole (870 mL,
N-Methyl-2-(3-nitrophenyl)pyrrole (26): Following the general pro-
cedure, N-methylpyrrole (530 mL, 6 mmol) was treated with 1- 6 mmol) was treated with 1-cyano-4-iodobenzene (137 mg,
iodo-3-nitrobenzene (149.4 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
0.6 mmol) and KOAc (235 mg, 2.4 mmol). Purification by column
chromatography (silica; Et2O/hexanes, 1:9) afforded 33 (crystallized
hexanes, 1:9) afforded 26 (crystallized from CH2Cl2/hexanes) as from CH2Cl2/hexanes) as fine, white crystals (73 mg, 47%). Rf =
fine, yellow crystals (70 mg, 56%). Rf = 0.46 (silica; EtOAc/hex- 0.4 (EtOAc/hexanes, 1:4). M.p. 83–84 °C. Spectral and physical
anes, 1:4). M.p. 108.5–109.5 °C. H NMR (500 MHz, CDCl3): δ = properties of 33 were found to concur with the published data.[7f]
1
Eur. J. Org. Chem. 2011, 2854–2859
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O. Vakuliuk, D. T. Gryko
FULL PAPER
N,N-Dimethylamino-2-(3-nitrophenyl)pyrrole (34): Following the ge-
neral procedure, N-dimethylaminopyrrole (690 mL, 6 mmol) was
treated with 1-iodo-3-nitrobenzene (149.4 mg, 0.6 mmol) and
KOAc (235 mg, 2.4 mmol). Purification by column chromatog-
raphy (silica; Et2O/hexanes, 1:9), afforded 34 (crystallized from
Et2O) as fine, yellow crystals (49.9, 36%). Rf = 0.64 (silica; EtOAc/
afforded 39 (crystallized from Et2O/pentane) as fine crystals
(71 mg, 54%). Rf = 0.41 (EtOAc/hexanes, 1:4). M.p. 145–146 °C.
Spectral and physical properties of 39 were found to concur with
published data.[17]
Supporting Information (see footnote on the first page of this arti-
cle): Supporting Information contains ICP-AES for 1-ethyl-3-
1
hexanes, 1:9). M.p. 47 °C. H NMR (400 MHz, CDCl3): δ = 2.84
1
methylimidazolium acetate as well as copies of the H NMR and
(s, 6 H), 6.24 (dd, J = 4.0, 3.2 Hz, 1 H), 6.32 (dd, J = 4.0, 3.2 Hz,
1 H), 7.14 (dd, J = 3.0, 2.0 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H),
7.95, (ddd, J = 8.4, 2.4, 1.2 Hz, 1 H), 8.04 (ddd, J = 8.4, 2.4, 1.2 Hz,
1 H), 8.57 (t, J = 1.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 47.6, 106.4, 107.8, 115.6, 120.6, 122.1, 128.7, 129.4, 131.1,
133.9, 148.2 ppm. HRMS (EI): calcd. for C12H13N3O2 [M]+
231.1007; found 231.1013.
13C NMR spectra for all compounds prepared.
Acknowledgments
The authors thank Marie Curie Research Training Network
REVCAT for financial support (contract number MRTN-CT-2006-
035866) and Eva Nichols (California Institute of Technology) for
amending the manuscript.
1,2,5-Trimethyl-3-(4-nitrophenyl)pyrrole (35): Following the general
procedure, 1,2,5-trimethylpyrrole (690 mL, 6 mmol) was treated
with 1-iodo-4-nitrobenzene (149.4 mg, 0.6 mmol) and KOAc
(235 mg, 2.4 mmol). Purification by column chromatography (sil-
ica; Et2O/hexanes, 1:9) afforded 35 (crystallized from Et2O) as fine,
yellow crystals (24.9 mg, 18%). Rf = 0.44 (silica; EtOAc/hexanes,
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1
1:4). M.p. 110–115 °C (decomp.). H NMR (400 MHz, CDCl3): δ
= 2.26 (s, 3 H), 2.37 (s, 3 H), 3.46 (s, 3 H), 6.06 (s, 1 H), 7.45, 8.18
(AAЈBBЈ, J = 8.8 Hz, 2ϫ2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 11.6, 12.3, 30.4, 105.5, 118.6, 123.8, 126.3, 127.4, 128.9, 140.9,
144.6 ppm. HRMS (EI): calcd. for C13H14N2O2 [M]+ 230.1055;
found 230.1051.
1-{[2-(Trimethylsilyl)ethoxy]methyl}-2-(4-cyanophenyl)pyrrole (36):
Following the general procedure, 1-{[2-(trimethylsilyl)ethoxy]-
methyl}pyrrole (1.3 mL, 6 mmol) was treated with 1-cyano-4-iodo-
benzene (137 mg, 0.6 mmol) and KOAc (235 mg, 2.4 mmol). Purifi-
cation by column chromatography (silica; Et2O/hexanes, 5:95) af-
forded 36 as a colorless oil (25 mg, 14%). Rf = 0.45 (EtOAc/hex-
1
anes, 1:4). H NMR (400 MHz, CDCl3): δ = 0.01 (s, 9 H), 0.93 (t,
J = 8.8 Hz, 2 H), 3.58 (dd, J = 8.8, 7.6 Hz, 2 H), 5.22 (s, 2 H), 6.26
(t, J = 2.8 Hz, 1 H), 6.44 (dd, J = 3.6, 1.6 Hz, 1 H), 6.93 (dd, J =
2.8, 1.6 Hz, 1 H), 7.66, 7.70 (AAЈBBЈ, J = 8.8 Hz, 2ϫ2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = –1.4, 17.7, 66.0, 76.2, 109.1,
109.8, 111.7, 119.1, 125.6, 128.4, 132.3, 133.0, 137.2 ppm. HRMS
(EI): calcd. for C17H22N2OSi [M]+ 298.1514; found 298.1493.
2-(4-Nitrophenyl)-1H-pyrrole (37): Following the general procedure,
1-(2-cyanoethyl)pyrrole (680 mL, 6 mmol) was treated with 1-iodo-
4-nitrobenzene (149.4 mg, 0.6 mmol) and KOAc (235 mg,
2.4 mmol). Purification by column chromatography (silica; Et2O/
hexanes, 1:9) afforded 37 (crystallized from CH2Cl2/hexanes) as
fine, orange crystals (45.2 mg, 40%). Rf = 0.54 (silica; EtOAc/hex-
anes, 1:4). M.p. 113–114 °C. 1H NMR (400 MHz, CDCl3): δ = 6.36
(dd, J = 3.8, 2.7 Hz, 1 H), 6.74 (t, J = 3.6 Hz, 1 H), 6.99 (dd, J =
2.8, 1.6 Hz, 1 H), 7.56, 8.21 (AAЈBBЈ, J = 9 Hz, 2ϫ2 H), 8.59 (br.
s, 1 H) ppm. 13C NMR (100 MHz, DMSO): δ = 109.8, 110.3, 122.5,
123.3, 124.3, 129.2, 139.2 144.1 ppm. HRMS (EI): calcd. for
C10H8N2O2 [M]+ 188.0585; found 188.0580.
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2858
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2854–2859

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Received: January 3, 2011
Published Online: April 5, 2011
Eur. J. Org. Chem. 2011, 2854–2859
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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