Triethanolamine-mediated palladium-catalyzed regioselective C-2 direct arylation of free NH-pyrroles

Article abstract of DOI:10.1021/jo902739n

An atom-economical phosphane-free palladium-catalyzed direct C-2 arylation of unactivated free NH-pyrroles is devised. This method provides a straithforward route to a wide variety of substituted 2-aryl-1H-pyrroles from readily accessible starting materials. Iodoarenes bearing electron-withdrawing and electron-donating substituents are tolerated under the presented reaction conditions. The scope of the reaction is also expanded to N-aryl and -alkylpyrroles albeit in lower yields.

Full text of DOI:10.1021/jo902739n

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statins, used for lowering blood cholesterol (Figure 1).3
Triethanolamine-Mediated Palladium-Catalyzed
Regioselective C-2 Direct Arylation
of Free NH-Pyrroles
Diaryl-1H-pyrroles 2 and 3 have been identified as p38
mitogen-activated protein (MAP) kinases4 and cyclooxygen-
ase-2 (COX-2)-selective inhibitors,5 respectively (Figure 1).
Farnaz Jafarpour,* Soraya Rahiminejadan, and
Hamideh Hazrati
School of Chemistry, University College of Science,
University of Tehran, P.O. Box 14155-6455, Tehran, Iran
jafarpur@khayam.ut.ac.ir
Received December 31, 2009
FIGURE 1. Biologically active compounds containing the 2-aryl-
pyrrole framework.
Furthermore, the pyridyl diaryl-1H-pyrrole 4 has been
reported to be a glucagon receptor antagonist, which is able
to block glucose production (Figure 1).6 Thus, several syn-
thetic challenges have stimulated the development of milder
and more efficient methods for the synthesis of these hetero-
cyclic compounds. Direct functionalization of desired scaf-
fold through regioselective C-H bond activation in the
presence of a reactive N-H functionality provides an effi-
cient cost-effective, environmentally attractive and atom-
economical entry to these compounds as it eliminates
the need for introducing protecting groups and reactive
An atom-economical phosphane-free palladium-catalyzed
direct C-2 arylation of unactivated free NH-pyrroles is
devised. This method provides a straithforward route
to a wide variety of substituted 2-aryl-1H-pyrroles from
readily accessible starting materials. Iodoarenes bearing
electron-withdrawing and electron-donating substituents
are tolerated under the presented reaction conditions.
The scope of the reaction is also expanded to N-aryl
and -alkylpyrroles albeit in lower yields.
(4) de Laszlo, S. E.; Visco, D.; Agarwai, L.; Chang, L.; Chen, J.; Croft, G.;
ꢀ
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Kostura, M.; Li, B.; Luell, S.; MacCoss, M.; Mantlo, N.; O’Neill, E. A.;
Orevillo, C.; Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Sidler, K.;
Widmer, W. R.; O’Keefe, S. Bioorg. Med. Chem. Lett. 1998, 8, 2689.
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Nitrogen-containing biaryls have attracted considerable
attention as they are common motifs in biologically active
products.1 2-Arylpyrroles continue to attract the attention of
synthetic organic chemists as they are integral components of
natural products and pharmaceuticals. Several synthetic
2-arylpyrrole derivatives have been shown to possess inter-
esting biological and biomedical properties.2 For instance,
atorvastatin 1, is a member of the drug class known as
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J. Chem. Soc., Chem. Rev. 2007, 36, 1173. (g) Campeau, L.-C.; Stuart, D. R.;
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Angew. Chem., Int. Ed. 2009, 48, 5094. For recent examples of direct arylation of
pyrroles, see: (j) Blaszykowski, C.; Aktoudianakis, E.; Bressy, C.; Alberico, D.;
Lautens, M. Org. Lett. 2006, 8, 2043. (k) Toure, B. B.; Lane, B. S.; Sames, D.
Org. Lett. 2006, 8, 1979. (l) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 12072. (m) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li,
Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2007, 47, 1473. (n) Blaszykowski, C.;
Aktoudianakis, E.; Alberico, D.; Bressy, C.; Hulcoop, D. G.; Jafarpour, F.;
Joushaghani, A.; Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73, 1888. (o)
Gracia, S.; Cazorla, C.; Metay, E.; Pellet-Rostaing, S.; Lemaire, M. J. Org. Chem.
2009, 74, 3160. (p) Fall, Y.; Doucet, H.; Santelli, M. ChemSusChem 2009, 2, 153.
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Buchanan, J. L.; Buckner, W. H.; DiMauro, E. F.; Emkey, R.; Fremeau, R. T.;
Harmange, J.-C.; Hoffman, B. J.; Huang, L.; Huang, M.; Lee, J. H.; Lin, F.-F.;
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DOI: 10.1021/jo902739n
r
Published on Web 04/12/2010
J. Org. Chem. 2010, 75, 3109–3112 3109
2010 American Chemical Society

Jafarpour et al.
JOCNote
functionalities prior to C-C bond formation. Transition-
metal-catalyzed cross-coupling reactions are among the
most important methods published to allow for direct
C-H functionalization of pyrroles.7
Despite significant progress in this area, C-arylation of
unactivated free NH-pyrroles with haloarenes remains an
unsolved problem. Free pyrroles are unreactive under
known arylation conditions, yielding little or no C-arylated
products. One approach relies on arylation of pyrrolyl salts
which was first reported by Filippini and later improved by
Sadighi.8
The use of such salts produces a metallic salt as
waste. Furthermore, it suffers from considerable moisture
sensitivity and limited functional group scope. Alternative
procedures include two examples of phosphine-free palla-
dium-catalyzed 5-arylation of 2-substituted pyrroles9 and
an example of rhodium-catalyzed direct C-arylation of free
NH-pyrrole10 in the presence of a mild base. The major
drawbacks of these methods were low yields of the pre-
activated arylated pyrroles and no system tolerance with
hindered substrates, respectively. Sanford also applied
her recently disclosed arylation procedure to both pro-
tected and nonprotected pyrroles by the use of a noncom-
mercially available IIII arylating agent in which C-2
arylation occurred selectively in moderate yields.11 One
might therefore expect that general and versatile syn-
thetic methods for direct C-2 arylation of unactivated free
NH-pyrroles would find significant utility in organic
synthesis.
As part of our continuing efforts in C-H bond functio-
nalization of nitrogen-containing heterocycles,12 herein we
set out to explore a cost-effective and atom-economical
regioselective C-2 arylation of free pyrroles. This protocol
takes advantage of the regioselectivity for pyrrole C-2 func-
tionalization in the presence of unprotected N-H function-
ality, compatibility with sterically encumbered iodoarenes,
and readily available triethanolamine as base, ligand, and
preferred solvent.
observed with 10 mol %. A substrate ratio screen showed
that 1:3 pyrrole/iodoarene ratio was the best. An additional
increase of the iodoarene amount had no effect on the yield
of the reaction. Subsequent optimization of other reaction
parameters, notably, substrate concentration, reaction time,
and temperature led to an efficient and selective catalytic
system. We were delighted to see that under the optimized
reaction conditions iodoarene 6 (3 equiv), Pd(OH)2/C
(10 mol %), in triethanolamine (0.2 M) at 100 °C in a sealed
tube for 24 h, the product of the cross-coupling reaction,
2-arylpyrrole 7, was obtained in 80% yield with excellent
regioselectivity (Table 1, entry 1). We next studied the scope
and limitations of the phosphane-free regioselective cross-
coupling procedure with various substituted iodoarenes
(Table 1). The results showed that various electron-with-
drawing and electron-donating substituents were tolerated
under the optimized reaction conditions. The reactivity of
aryl halides was enhanced by the presence of electron-with-
drawing substituents. As a decomposition of the product
occurred via the purification course, iodobenzene 8 furni-
shed 2-phenylpyrrole 9 in only 56% yield under the standard
reaction conditions (Table 1, entry 2). Sterically demanding
iodoarenes 10, 12, and 14 resulted in the corresponding
C-2 arylated pyrroles 11, 13, and 15 in moderate to good
yields (Table 1, entries 3-5). Even less activated 2-fluoroio-
dobenzene led to the corresponding product 17 in mode-
rate yield (Table 1, entry 6). Iodoarenes bearing o- and
p-trifluoromethyl and nitro substituents 18 and 20 furnished
the desired products 19 and 21 in low and moderate yields,
respectively (Table 1, entries 7 and 8). The inferior reactivity
of these iodoarenes was as a result of a relatively important
amount of biphenyl byproduct formation during the course
of the reaction. The reactivity of o-methoxy-substituted aryl
iodide was also explored. Under the optimized reaction
conditions, the 2-arylated pyrrole 23 was obtained, albeit
in low yield (Table 1, entry 9). Arylpalladium species with the
palladium ortho to a methoxy group can undergo C-H
activation with the methoxy C-H bond to form a stable
five-membered palladacycle14 and result in several bypro-
ducts. On the other hand, a moderate yield of 46% of 25
was obtained using 4-iodobenzonitrile as a result of signifi-
cant competing homocoupling reaction and formation
of a larg amount of biphenyl-4,40-dicarbonitrile (Table 1,
entry 10).
To test the feasibility of this reaction, we directed our
efforts toward the phosphane-free palladium-catalyzed
direct arylation reactions. To this end, iodobenzene 6 and
1H-pyrrole were initially treated with Pd(OAc)2 (5 mol %) in
triethanolamine (TEA) (unoptimized conditions) which was
recently established as an efficient and reusable medium for
palladium-catalyzed Heck reactions.13 To our delight, com-
pound 7 was obtained as a single product in 24% yield. Next,
the screening reactions were performed with respect to palla-
dium sources including Pd(OAc)2, PdCl2, Pd(dba)2, and
Pd(OH)2/C which revealed that the last one is superior to
other choices. While the yield was further improved by
increasing the amount of the catalyst to 10 mol %, a further
increase in its amount did not improve the yield beyond that
Furthermore, we performed a gram-scale experiment em-
ploying 2.5 mol % of Pd(OH)2/C which offered 2-arylpyrrole
21 in 39% yield (Table 1, entry 8).
We next investigated the scope of the reaction using
N-protected pyrroles. In this regard, para-substituted
electron-rich and -deficient aryl iodides were reacted
with 1-methylpyrrole. While with p-methoxy-substituted
iodoarene 26 C-2-arylated product 27 was obtained
in 48% yield, inferior reactivity was associated with
electron-deficient aryl iodides 6 and 20 (Table 2, entries
1-3).
(8) (a) Filippini, L.; Gusmeroli, M.; Riva, P. Tetrahedron Lett. 1992, 33,
1755. (b) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett.
2004, 6, 3981.
Finally, we turned our attention to the synthesis of
1,2-diaryl-1H-pyrroles of type 5 which have been also iden-
tified as COX-2 inhibitors.5 Accordingly, 1-iodonaphthalene
14 was reacted with 1-phenylpyrrole. Under the standard
(9) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72,
1476.
(10) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127,
4996.
(11) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem.
Soc. 2006, 128, 4972.
(12) (a) Jafarpour, F.; Ashtiani, P. T. J. Org. Chem. 2009, 74, 1364.
(b) Jafarpour, F.; Hazrati, H. Adv. Synth. Catal. 2010, 352, 363.
(13) Li, H. J.; Wang, L. Eur. J. Org. Chem. 2006, 5099.
(14) (a) Dyker, G. J. Org. Chem. 1993, 58, 6426. (b) Dyker, G. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1023.
3110 J. Org. Chem. Vol. 75, No. 9, 2010

Jafarpour et al.
JOCNote
TABLE 1. Scope of the Regioselective Direct C-2 Arylation of Free
NH-Pyrrolesa
TABLE 2. Scope of the Regioselective Direct C-2 Arylation of
N-Protected Pyrrolesa
aAll reactions were run under the optimized reaction conditions.
hindrance between adjacent naphthyl and phenyl substitu-
ents (Table 2, entry 3).
In summary, we have developed an atom economical and
straightforward approach to palladium-catalyzed regio-
selective direct C-2 arylation of free pyrroles using readily
accessible starting materials. The iodoarenes can be widely
varied according to their electronic and steric effects, which
makes the method versatile for the preparation of these
biologically interesting structural motifs, not easily accessi-
ble by conventional cross-coupling methods. By establishing
phosphane-free conditions, this transformation displayed
low moisture sensitivity, which should provide a valuable
starting point in sp2 C-H activation of heteroarenes.
Expansion of the derived methodology for direct arylation
of other cross-coupling partners is under investigation.
Experimental Section
General Procedure for C-2 Arylation of Pyrroles. A vial
equipped with a stir bar was charged with pyrrole (0.200 mmol,
1.0 equiv), aryl iodide (0.6 mmol, 3.0 equiv), and Pd(OH)2/C
(10 mol %). Triethanolamine (0.2 M) was then added, and the
vial was capped. The resulting mixture was heated in an oil bath
at 100 °C for 24 h, cooled, and then filtered through a short plug
of silica. Removal of the solvent gave a crude mixture which was
purified by flash column chromatography (hexanes/EtOAc
gradient).
2-(2-Methyl-4-nitrophenyl)-1H-pyrrole (7). Following the
general procedure for the direct C-2 arylation of pyrroles,
5-nitro-2-iodotoluene 6 (158.0 mg, 0.600 mmol) and 1H-pyrrole
(13.5 mg, 0.200 mmol) were reacted at 100 °C for 24 h. The crude
mixture was purified by flash column chromatography on silica
gel (EtOAc/hexane, 10%) to afford 7 as a yellowish solid (33 mg,
aAll reactions were run under the following conditions: pyrrole (0.20
mmol, 1 equiv), iodoarene (0.60 mmol, 3 equiv), and Pd(OH)2/C (10 mol %)
in triethanolamine (0.2 M) were heated in a sealed tube at 100 °C for 24 h.
bDue to decomposition of the product via purification, a rough yield is
reported. cPyrrole (0.015 mol, 1.0 g) and Pd(OH)2/C (2.5 mol %) in trietha-
nolamine (0.2 M) were heated at 100 °C for 48 h. dAs the product was conta-
minated by an uncharacterized impurity, an approximate yield is given.
reaction conditions, the corresponding C-2 arylated pyrrole
30 was obtained in 22% yield, presumably due to steric
J. Org. Chem. Vol. 75, No. 9, 2010 3111

Jafarpour et al.
JOCNote
1
80%): mp 118-119 °C; H NMR (500 MHz, CDCl3) δ 2.60
(s, 3H), 6.38-6.40 (m, 1H), 6.56-6.57 (m, 1H), 6.99-7.00 (m,
1H), 7.49 (d, J = 8.5 Hz, 1H), 8.08 (dd, J = 8.5, 2.5 Hz, 1H), 8.13
(d, J = 2.5, 1H), 8.5 (brs, 1H); 13C NMR (125 MHz, CDCl3) δ
22.2, 110.7, 112.0, 120.7, 121.8, 126.7, 127.8, 129.6, 136.0, 139.2,
146.0; IR (KBr) 1093, 1324, 1492, 2922, 3378 cm-1; MS m/z 202
(M•þ, 100), 172 (13), 154 (23), 141 (13), 128 (24). Anal. Calcd for
C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.51; H,
5.09; N, 13.94.
Acknowledgment. We thank the Research Council of the
University of Tehran for financial support of this project
(27827/1/01).
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3112 J. Org. Chem. Vol. 75, No. 9, 2010