C-H bonds as ubiquitous functionality: A general approach to complex arylated imidazoles via regioselective sequential arylation of all three C-H bonds and regioselective n -alkylation enabled by SEM-group transposition

Article abstract of DOI:10.1021/jo100727j

(Figure presented) Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.

Full text of DOI:10.1021/jo100727j

pubs.acs.org/joc
C-H Bonds as Ubiquitous Functionality: A General Approach to Complex
Arylated Imidazoles via Regioselective Sequential Arylation of All Three
C-H Bonds and Regioselective N-Alkylation Enabled by SEM-Group
Transposition
ꢀ †
Jung Min Joo, B. Barry Toure, and Dalibor Sames*
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027.
†Current address: Novartis Institutes for Biomedical Research, Inc. Oncology, Global Discovery Chemistry,
250 Massachusetts Avenue, Cambridge, MA 02139.
sames@chem.columbia.edu
Received April 15, 2010
Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceu-
ticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials.
Owing to their wide application in academia and industry, new methods and strategies for the generation
of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive
approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core
can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective
C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed
positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly,
aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory
conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that
transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and
sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the
SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imida-
zoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-,
di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of
individual compounds or libraries of analogues can begin from either the parent imidazole or a
substituted imidazole, providing rapid access to complex imidazole structures.
Introduction
antibacterial,2 anticancer,3 anti-inflammatory activity4). The
imidazole ring serves as a rigid scaffold for the presentation
of attached substituents in a fixed spatial orientation, creating
Imidazoles are essential components of biologically active
compounds, including natural products and synthetics, and
display a broad range of biological activities1 (for example,
(3) 4,5-Diarylimidazoles were found to have strong antitubulin and
cytotoxic activity. Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey,
R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.;
Warner, R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S. H.;
Sham, H. L. J. Med. Chem. 2002, 45, 1697–1711.
(4) 2,4,5-Triarylimidazoles inhibit mitogen-activated protein kinase ac-
tivity. Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar,
S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter,
S. W.; Strickler, J. E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi,
G. P.; White, J. R.; Adams, J. L.; Young, P. R. Nature 1994, 372, 739–746.
(1) Reviews: (a) Xi, N.; Huang, Q.; Liu, L. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Eds.; Elsevier: Oxford, 2008; Vol. 4, pp 143-364. (b) Luca, L. D. Curr. Med.
Chem. 2006, 13, 1–23.
(2) 4,5-Diarylimidazoles showed antibacterial activity. Antolini, M.;
Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.; Ursini, A. Bioorg. Med.
Chem. Lett. 1999, 9, 1023–1028.
DOI: 10.1021/jo100727j
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Joo et al.
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desirable motifs for high affinity protein ligands. For example,
di-, tri-, and tetra-substituted imidazoles have recently emerged
as potent kinase inhibitors.5 Also, 2-arylimidazoles were found
to be selective ligands for histamine receptors6 and 1,5-diaryl-
imidazoles to display vascular disrupting activity.7 Moreover,
imidazole-based N-heterocyclic carbenes have been actively
pursued as transition metal ligands for the development of
new catalysts,8 and imidazolium ionic liquids are used as
recyclable solvents for industrial catalytic processes, affording
“green” alternatives to standard organic solvents.9 The wide use
of imidazoles generated a considerable interest in imidazole
chemistry and revealed the need for more efficient synthetic
strategies.10
There are a number of established de novo methods for the
synthesis of substituted imidazoles where the imidazole ring
is constructed via cyclo-condensation reactions. Although
these traditional approaches have been greatly improved
over the past decade, each method has its scope and effi-
ciency limitations.11,12 Often, the condensation methods are
inefficient for the assembly of series of compounds: for
example, regioisomers (2,4- versus 4,5-substitution pattern)
or focused analogues (different arene rings in the 4-position).
In most cases, the synthesis of each analogue of the library
will require the entire de novo synthetic sequence, which
translates to parallel repetition of linear synthetic sequences.
To address this problem, in part of a broad program dedicated
to development of new synthetic methods and strategies based
on C-H bond functionalization,13,14 we have been developing
catalytic arylation transformations, where multiple C-H bonds
of heteroarenes are functionalized in a selective and sequential
manner (topologically obvious synthesis).13,15 We have recently
reported catalytic arylation of pyrazoles and a synthetic strategy
based on SEM-group transposition that enables sequential
arylation and preparation of complex aryl pyrazoles.15a We here
FIGURE 1. Rapid access to complex imidazoles via direct C-H
arylation.
report a general and comprehensive strategy for the preparation
of highly functionalized aryl imidazoles through direct arylation
of the imidazole core (Figure 1).16-18 All three C-H bonds of
the imidazole ring can selectively and sequentially be replaced
by arene rings using aryl bromides or aryl chlorides, and the
amino group can be alkylated in a regioselective manner, pro-
viding rapid access to all regioisomers of mono-, di-, and
triarylimidazoles.19-21
Guided by the general reactivity of imidazoles, we devel-
oped Pd-catalyzed regioselective C5- and C2-arylation pro-
tocols together with the SEM-switch and trans-N-alkylation.
Figure 2 illustrates some of many possible synthetic path-
ways. Schematically, C5-arylation provides compound I,
which can be arylated at the 2-position to give compound
II, a protected 2,5-diarylimidazole. This compound could
alternatively be prepared by C2-arylation, followed by C5-
arylation (not shown), and depending on the specific struc-
tural context, one sequence may provide better yield than the
other. The subsequent arylation of the 4-position in II is low
yielding (<10%); therefore the unreactive C-4 position is
converted to a reactive C-5 position via the SEM-switch, and
subsequent arylation affords IV, a protected 2,4,5-triaryl-
imidazole. This compound could be deprotected or converted
to V via selective trans-N-alkylation (Figure 2A). Note that
all substituents of the imidazole ring are introduced in a
(5) Jackson, P. F.; Bullington, J. L. Curr. Top. Med. Chem. 2002, 2, 1011–
1020.
(6) Leschke, C.; Elz, S.; Garbarg, M.; Schunack, W. J. Med. Chem. 1995,
38, 1287–1294.
(7) Bonezzi, K.; Taraboletti, G.; Borsotti, P.; Bellina, F.; Rossi, R.;
Giavazzi, R. J. Med. Chem. 2009, 52, 7906–7910.
ꢀ
(8) Review: Dıez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. Rev.
´
2009, 109, 3612–3676.
(9) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667–3692.
(10) (a) Science of Synthesis; Grimmett, M. R., Ed.; Thieme: Stuttgart, 2002;
Vol. 12, pp 325-512. (b) Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007,
63, 4571–4624.
(16) (a) A comprehensive review on arylation of heteroarenes including
azoles: Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269–10310. (b) Since
the publication of this review, C5-arylation of 1-alkylimidazoles with aryl
bromides has been reported: Roger, J.; Doucet, H. Tetrahedron 2009, 65,
9772–9781.
(11) Murry, J. A. Curr. Opin. Drug Discovery Dev. 2003, 6, 945–965.
(12) Review: (a) Kamijo, S.; Yamamoto, Y. Chem. Asian J. 2007, 2, 568–
578. Recent examples: (b) Kanazawa, C.; Kamijo, S.; Yamamoto, Y. J. Am.
Chem. Soc. 2006, 128, 10662–10663. (c) Siamaki, A. R.; Arndtsen, B. A. J.
Am. Chem. Soc. 2006, 128, 6050–6051. (d) Frantz, D. E.; Morency, L.;
Soheili, A.; Murry, J. A.; Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6,
843–846. (e) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.;
Olsen, M. A. J. Org. Chem. 2000, 65, 1516–1524.
(13) For global analysis of approaches toward C-H bond functionaliza-
tion and its consequences in organic synthesis, see: Godula, K.; Sames, D.
Science 2006, 312, 67–72.
(14) Recent reviews on catalytic C-H bond functionalization: (a)
Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077–1101. (b)
Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. (c) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (d)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094–5115.
(17) For recent reviews on C-H bond arylations, see: (a) Campeau, L.-
C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35–41. (b) Satoh,
T.; Miura, M. Chem. Lett. 2007, 36, 200–205. (c) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. Rev. 2007, 36, 1173–1193. (d) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174–238. (e) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
(18) For recent examples of catalytic C-H arylation of arenes and
heteroarenes, see: (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–
1597. (b) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008,
ꢁ
ꢁ
ꢀ
47, 3004–3007. (c) Cernova, M.; Pohl, R.; Hocek, M. Eur. J. Org. Chem.
2009, 3698–3701. (d) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473–1476.
(19) Synthesis of diarylimidazoles via sequential arylation of N-benzyl-
imidazoles has been reported: Bellina, F.; Cauteruccio, S.; Fiore, A. D.;
Marchetti, C.; Rossi, R. Tetrahedron 2008, 64, 6060–6072.
(20) For sequential arylation of imidazole N-oxides, see: Campeau,
L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.;
Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am.
Chem. Soc. 2009, 131, 3291–3306.
(15) (a) Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009,
131, 3042–3048. (b) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007,
ꢀ
72, 1476–1479. (c) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8,
(21) For recent examples of sequential arylation to produce highly
substituted heteroarenes, see: (a) Ref 15a. (b) Yanagisawa, S.; Ueda, K.;
1979–1982. (d) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050–8057. (e) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005,
127, 4996–4997. (f) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897–2900.
ꢀ
Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622–14623. (c) Liegault,
B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047–1060.
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FIGURE 2. C2- and C5-arylation methods, together with the SEM-switch, provide rapid access to complex arylimidazoles with complete control of
regioselectivity. The SEM group also allows for regioselective N-alkylation (trans-N-alkylation). (A) An example of sequential elaboration of SEM-
imidazole to furnish 1-alkyl-2,4-diarylimidazoles and 1-alkyl-2,4,5-triarylimidazoles. (B) Advanced intermediates (accessed for example by
condensation methods) may also be arylated and alkylated in a regioselective manner via the strategy based on the SEM group.
regioselective manner. Another possibility involves trans-N-
alkylation of compound II to furnish VI, a 2,4-diaryl-1-
alkyl-imidazole, which can be further arylated to give VII,
a regioisomer of V. This latter pathway affords access to 2,4-
diaryl-1-alkyl-imidazoles and would be the route of choice
for preparation of 2,4,5-triarylimidazoles in cases where the
arene ring Ar3 is not compatible with trans-N-alkylation.
We also wish to point out that the C5- and C2-arylation
methods and the strategy based on the SEM-switch described in
this paper are applicable to arylation and N-alkylation of
advanced imidazole intermediates with various substitution
patterns and substituents other than arene rings. For example,
as illustrated in Figure 2B, compound VIII, a 2,4(5)-disubsti-
tuted imidazole, can be protected in a regioselective manner to
give compound IX, which can be arylated in the 5-position and
alkylated to furnish product XI. Both the aryl group and the
alkyl group are introduced in a regioselective manner in three
steps. Thus, complex aryl imidazoles can be prepared from
either the parent imidazole (which is readily available and inex-
pensive) or substituted imidazole intermediates.
conditions revealed a critical role of base in the C2-arylation.
Employing the stronger base sodium tert-butoxide in a nonpolar
solvent, we developed a new protocol for C2-arylation of SEM-
imidazoles that shows good selectivity for the 2-position (6:1,
Figure 3B). To overcome the low reactivity of the 4-position,
we developed the SEM-group transposition (“SEM-switch”),
which leads to the rearrangement of the SEM-group from the
N-1 to N-3 nitrogen. 4-Phenyl-1-SEM-imidazole can be accessed
in one step by the SEM-switch (compound 2 f 5, Figure 3C).
Similarly, alkylation of N-3 nitrogen and SEM-group deprotec-
tion provides 4-phenyl-1-methylimidazole (“trans-N-alkyla-
tion”, compound 2 f 6, Figure 3C).
Mechanistic Hypothesis for Positional Selectivity: Electro-
nic Properties of C-H Bonds and the Heteroarene Ring. The
C5-arylation of imidazoles may occur via electrophilic metala-
tion-deprotonation (EMD) or concerted metalation-deprotona-
tion (CMD), as illustrated in Figure 4A. In both mechanisms,
the carboxylate or carbonate ligand is directly involved in the
intramolecular deprotonation. The EMD mechanism is a step-
wise metalation process similar to SEAr, while CMD is a con-
certed one-step process. In our previous work, we have demon-
strated the importance of the carboxylate ligand both in the
palladium-catalyzed15b,c,f and rhodium-catalyzed arylation15e of
electron-rich heteroarenes. We have also provided kinetic evi-
dence for the direct involvement of the pivalate ligand in the
C-H activation step.15e With triarylphosphine ligands (rela-
tively weak σ-donors), our data pointed toward the carboxylate-
assisted EMD mechanism.15e,f Alternatively, other groups pro-
vided experimental and computational evidence for the CMD
mechanism for the catalytic systems using strong σ-donor phos-
phines, where formation of the carbon-metal bond and break-
ing of the carbon-hydrogen bond take place simultaneously,
while maintaining the aromaticity of arenes or heteroarenes.22
Results and Discussion
Regioselectivity of the Palladium-Catalyzed Arylation of
Imidazoles. The general reactivity trends of imidazole are
shown in Figure 3A: the C-5 position shows high reactivity
toward electrophilic substitution, the C-4 position is relatively
less reactive in this respect, and the C-2 position bears the most
acidic C-H bond. We have previously introduced the SEM
group [SEM=2-(trimethylsilyl)ethoxymethyl] as a suitable pro-
tecting group for azoles, including indoles, pyrroles, pyrazoles,
and imidazoles, in the context of palladium-catalyzed C-H
arylation.15a,c In this work, we developed new and practical
protocols for C5- and C2-arylation of SEM-imidazoles using
both aryl bromides and aryl chlorides as the arene donors
(Figure 3B). With the parent SEM-imidazole, the optimized
palladium protocol for C5-arylation afforded the desired pro-
duct 2 in good yield along with 2,5-diphenyl-1-SEM-imidazole,
in 7:1 ratio (Figure 3B). Careful examination of the reaction
(22) (a) Garcıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
´
A. M. J. Am. Chem. Soc. 2006, 128, 1066–1067. (b) Gorelsky, S. I.; Lapointe,
D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849 and references
therein.
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The electronic rationale provided above explains the low
reactivity of C-4; arylation of the C-4 position gives low yields
even under forcing conditions when C-2 and C-5 positions are
substituted (<10% yield). The C-5 to C-2 selectivity of the Pd/
carbonate method is moderate, and so is the C-2 to C-5 selec-
tivity of the Pd/NaOt-Bu system, which is attributed to rela-
tively high reactivity of both positions (that are adjacent to the
substituted nitrogen N-1) under Pd/base conditions.
Development of C5-Arylation of SEM-Protected Imida-
zoles. We have previously introduced the air- and moisture-
stable mixed phosphine-NHC palladium complexes, exem-
plified by 7 (Table 1), as a new class of catalysts for the arylation
of heteroarenes and reported selective C5-arylation of 1-SEM-
imidazole 1 with iodobenzene using complex 7 as the catalyst.15c
We here show that a wide range of aryl donors could be
employed for the arylation of SEM-imidazole (Table 1, Method
A). However, this method is not compatible with chloroarene
donors and the catalyst requires a multistep synthesis.
In the hope of identifying a practical and versatile catalytic
procedure, we thoroughly examined the reaction parameters
including metal catalyst, ligand, base, solvent, and temperature.
This search found that the treatment of SEM-imidazole 1 with
5.0 mol % Pd(OAc)2, 7.5mol%P(n-Bu)Ad2, 1.2 equiv of PhBr,
and 2.0 equiv of K2CO3 in DMA (0.5 M) at 120 °C led to full
conversion of the starting material, giving the desired product 2
in 72% yield along with the 2,5-diarylation product 3 in
11% yield (Table 1). Unlike our catalytic method for pyrazole
C-arylation, where potassium carbonate and a substoichiometric
quantity of pivalic acid (or potassium pivalate) were used,15a
potassium carbonate alone proved to be an optimum base for
the coupling of SEM-imidazole and bromobenzene. When we
added 0.25 equiv of pivalic acid in conjunction with 3.0 equiv
of potassium carbonate, a significant amount of the overaryla-
tion product 3 (21% isolated yield) was formed in addition to
the monoarylation product 2 (56% yield). While the use of the
carboxylic acid additive improves the performance of many
palladium-catalyzed C-arylations of arenes and heteroarenes,
the highly active catalytic system can decrease the regioselectivity
of this reaction in cases where the substrate contains multiple
C-H bonds susceptible to C-H arylation.23
Superior results to the Pd/NHC complex were achieved
when the new optimized catalytic system was used (Table 1,
Method B). The substituents on aryl donors did not greatly
affect the coupling yields; both electron-rich and electron-poor
aryl bromides coupled with SEM-imidazole, affording 5-aryl-
imidazoles in good yields. Importantly, the optimized protocol
employing the electron-rich trialkylphosphine P(n-Bu)Ad2 also
enables the use of aryl chlorides as arene donors with good
efficiency (Table 1).24 In addition, the reaction can be conducted
on the benchtop using the air-stable phosphonium salt [P(n-
Bu)Ad2H]BF4, prepared by mixing the phosphine and tetra-
fluoroboric acid.25 For the C5-arylation with aryl bromides and
chlorides, other sterically hindered trialkylphosphines, such as
tricyclohexylphosphineand2-(dicyclohexylphosphino)biphenyl,
gave comparable results to those with n-butyl-di(1-adaman-
tyl)phosphine (see Supporting Information for experimental
details).
FIGURE 3. (A) General reactivity trends of imidazole. (B) Two
methods for palladium-catalyzed C-H arylation of SEM-imida-
zoles were developed with complementary regioselectivity (C5
and C2). The C2- and C5-arylation protocols enable the use of both
aryl bromides and aryl chlorides, providing a practical method for
synthesis of arylimidazoles. (C) The SEM-group transposition
(SEM-switch) leads to 4-arylimidazoles and allows for subsequent
arylation and preparation of complex arylimidazoles. Similarly, the
SEM group enables regioselective N-alkylation (trans-N-alkyla-
tion) to afford 1-alkyl-4-arylimidazoles.
The C5 selectivity can readily be explained by EMD as the
5-position is more nucleophilic than the 2- and 4-positions;
standard electrophilic aromatic substitutions occur preferen-
tially at C5. To further rationalize the high selectivity for the
C-5 position, we propose that the inductive effect of the N-1
nitrogen stabilizes the carbon-palladium bond at C5 (and the
partially formed carbon-palladium bond in the transition
state), and thus the C5-metalation is preferred considering
both thermodynamic and kinetic factors (Figure 4A). In
contrast, metalation of the C-2 and C-4 positions is disfavored
by the electronic repulsion between the electron lone pair on
the N-3 and the carbon-palladium bond, which may be
particularly important in the CMD mechanism (Figure 4B).
In the presence of a strong base (NaOt-Bu), deprotonation
of the C-2 position becomes efficient, presumably facilitated
by complexation of the palladium complex to the N-3
nitrogen (Figure 4C). The inductive effect of two nitrogen
atoms renders the C-H bond most electron-deficient and
most acidic. The C2-nucleophile subsequently displaces
either a halide or tert-butanol at the palladium metal to form
the C2-palladium intermediate, eventually leading to the
C2-arylated product.
(23) Campeau, L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.;
Gorelsky, S.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276–3277.
(24) C5-Arylation of N-butylimidazole with chlorobenzene (in 52% yield)
was reported: Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449–1451.
(25) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295–4298.
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FIGURE 4. Mechanistic rationales for the observed regioselectivity of the imidazole arylation. (A) In the presence of carbonate or carboxylate
base (R00 = alkyl or alkoxide), the C-H activation occurs via ligand-assisted palladation (via either EMD or CMD mechanism). The C-5
position is preferred over the C-2 and C-4 due to stabilization of the C-Pd bond by the inductive effect of N-1 nitrogen. (B) In contrast,
palladation at the C-4 position is disfavored by electronic repulsion between the nitrogen e- pair and the polarized C-Pd bond. (C) In the
presence of a strong base, deprotonation occurs at the C-2 position, presumably facilitated by complexation of the palladium complex to N-3.
The same rationale applies to other azoles including oxazoles, thiazoles, and triazoles.
SCHEME 1. C2-Arylation of SEM-Imidazoles
Development of New Conditions for C2-Arylation of Imi-
dazoles. Empirical studies have found that the C-5 position
of imidazoles exhibited reactivity higher than that at the C-2
position for the palladium-catalyzed arylation in the presence of
weak bases, as originally demonstrated by Miura and colleagues
with N-methylimidazole and aryl iodides.26 It was also shown in
their paper that the addition of copper(I) salts altered the bias
toward the C-2 position. The latter method has subsequently
been optimized by others and applied to N-methylimidazole
and other azole heteroarenes.19,27 Alternatively, a rhodium-
catalyzed C2-arylation of 1,3-azoles has been developed; how-
ever, only arylation of 4,5-disubstituted imidazoles has been
reported.28 In sum, existing methods for C2-arylation of imida-
zoles are limited to aryl iodides, while aryl bromides require high
temperatures (g140 °C).16,28,29 Furthermore, the Pd/Cu bime-
tallic system gave only a trace amount of the desired product
with SEM-imidazole 1 (5 mol % of Pd(OAc)2, 2 equiv of CuI, 2
equiv of bromoarene, DMF, 140 °C, 24 h).
Consequently, we carefully examined the palladium-cata-
lyzed conditions and developed a versatile and practical method
for C2-arylation of SEM-imidazoles with both aryl bromides
and aryl chlorides. Inspired by the base-promoted tautomeriza-
tion of imidazole ligands to N-heterocyclic carbenes,30 we
envisioned that upon coordination of the palladium complex
to the N-3 nitrogen of imidazole, an alkali metal alkoxide would
be sufficiently basic to produce a C2-metalated intermediate.
Moreover, since an electron-rich phosphine ligand should en-
able the activation of chloroarenes, which are not efficient
donors for the previously reported procedures as discussed
above, we decided to take advantage of the palladium-phos-
phine pair that we identified for the C5-arylation of imidazoles
(and C5-arylation of pyrazoles15a).
Screening experiments with different bases and solvents led us
to establish a new set of conditions, where imidazole 1 gave
2-phenylimidazole 4 in 61% yield after heating in toluene
(0.5 M) in the presence of 1.5 equiv of NaOt-Bu (Scheme 1).
Weaker bases were much less effective than NaOt-Bu. As
expected, the formation of the double arylation product was
not negligible, and it was isolated in 11-15% yield. Importantly,
chlorobenzene gave a similar yield and higher C2:C5 selectivity
(from 4:1 to 6:1) compared to that of bromobenzene. Not only
the simple phenyl halides but also functionalized arene donors
(26) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc.Jpn. 1998, 71, 467–473. (b)For other examples of C2-arylation of
N-methylimidazole using the Pd/CuI system, see the comprehensive review in ref 16a.
(27) Copper-catalyzed C2-arylation of N-methylimidazole with iodoben-
zene has been reported: Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 15185–15192.
(28) (a) Lewis, J. C.; Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2008, 130, 2493–2500. (b) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.;
Ellman, J. A. Angew. Chem., Int. Ed. 2006, 45, 1589–1591.
(29) In the following paper, the authors provide one example of C2-arylation
of N-arylimidazole with 2-bromonaphthalene using the Pd(OAc)2/CuI system in
DMF at 140 °C in the presence of CsF as the base. Bellina, F.; Cauteruccio, S.;
Mannina, L.; Rossi, R.; Viel, S. Eur. J. Org. Chem. 2006, 693–703.
(30) Ruiz, J.; Perandones, B. F. J. Am. Chem. Soc. 2007, 129, 9298–9299.
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TABLE 1. C5-Arylation of 1-SEM-Imidazole
TABLE 2. C2-Arylation of 5-Phenylimidazole 2a
aMethod A: 5.0 mol % 7, 2.0 equiv of ArX, 2.0 equiv of CsOAc, DMA
(1.0 M), 125 °C, 16-20 h. Complex 7 can be prepared according to the pro-
tocol provided in ref 15c. Method B: 5.0 mol % Pd(OAc)2, 7.5 mol %
b
aReaction conditions: 5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2,
1.5 equiv of ArX, 2.0 equiv of NaOt-Bu, toluene (2.0 M), 100 °C, 24 h.
bIsolated yield, average of two runs. cPd(PPh3)2Cl2 (5 mol %) was used
in place of Pd(OAc)2/P(n-Bu)Ad2. For C2-arylation of SEM-imidazole
1, see Supporting Information.
P(n-Bu)Ad2, 1.2 equiv of ArX, 2.0 equiv of K2CO3, DMA (0.5 M), 120 °C,
18 h. The corresponding 2,5-diarylation product was also formed in 5-10%
yield (see Supporting Information). cIn the benchtop experiment, [P(n-Bu)-
Ad2H]BF4 was used, and the amount of K2CO3 was increased (2.5 equiv).
Yields are an average of two separate isolated yields.
method for regioselective arylation of N-alkyl- and N-arylimi-
dazoles as well as other classes of heteroarenes.31 While the
C2/C5 regioselectivity in the reaction of the SEM-imidazole was
modest, the C2-arylation of 5-phenylimidazole 2is efficient under
the newly developed conditions. Once the 5-position of imida-
zoles is substituted, the overarylation is no longer a problem.
can be employed for the C2-arylation of imidazole 1 (e.g.,
3-bromoanisole and 4-bromobenzonitrile afforded the desired
products in 60% and 51% isolated yields, respectively; Scheme
S1 in Supporting Information). This transformation represents
an important advance as regioselective C2-arylation of imida-
zoles can be performed with aryl chlorides (and a single transi-
tion metal as the catalyst). Moreover, the simple switch from
C5- to C2-arylation of SEM-imidazole by using the alkoxide
base and the nonpolar solvent demonstrates the plasticity of
palladium catalysis and suggests potential application of this
(31) Compare with site-selective sp2 and benzylic sp3 arylation of azine N-
oxides: (a) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266–3267. (b) Schipper, D. J.; Campeau, L.-C.; Fagnou, K.
Tetrahedron 2009, 65, 3155–3164.
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SCHEME 2. Synthesis of 4,5-Diarylimidazolesa
aReaction conditions: (a) 5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2, 1.2 equiv of 4-bromoanisole, 2.0 equiv of K2CO3, DMA (0.5 M), 120 °C, 17 h,
63% yield; (b) 5.0 mol % SEMCl, CH3CN, 80 °C, 22 h, 88% yield; (c) 5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2, 1.2 equiv of 3-bromopyridine, 2.0
equiv of K2CO3, DMA (0.5 M), 120 °C, 20 h, 46% yield. Recovered starting material and 2,5-diarylation product were isolated in 17% and 11% yields,
respectively. Yields are an average of two separate isolated yields.
Using the alkoxide base, we were able to obtain SEM-pro-
tected 2,5-diarylimidazoles with a variety of functional groups
on the C2 aryl ring in good to excellent yields (Table 2). For
example, 3-chloroanisole was coupled to 5-phenylimidazole 2,
giving 13 in 75% isolated yield. Naturally, as this method relies
on the use of a strong base, there are limitations in the scope
related to the presence of base-sensitive groups. We addressed
two important limitations: (1) the use of a carboxylic acid ester
and (2) the use of a nitrile. The method is compatible with tert-
butyl esters of carboxylic acids as demonstrated by the efficiency
of C2-arylation with tert-butyl 4-bromobenzoate (Table 2,
entry 5). By using the tert-butyl ester, complications related to
transesterification and hydrolysis were largely eliminated (the
corresponding ethyl ester gave much lower yield). The outcome
of C2-arylation with 4-bromobenzonitrile was less than satis-
factory (Table 2, entry 6). However, when the air- and moisture-
stable catalyst Pd(PPh3)2Cl2 was used in lieu of Pd(OAc)2 and
P(n-Bu)Ad2, it gave a significantly improved result, affording
product 18 in 60% yield. Finding the solution to this problem
was guided by the rationale that the nitrile as an electron-
withdrawing group activates the aryl halide toward oxidative
addition, and therefore a less active palladium system [such as
Pd(PPh3)2Cl2] would be sufficient for the aryl halide activation
and at the same time less prone to inhibition by the product.32
Synthesis of 4-Aryl-1-SEM-imidazoles and 4,5-Diarylimi-
dazoles via the SEM-Switch. The new methods for C2- and
C5-arylation of SEM-protected imidazoles enable direct
access to 5-aryl-1-SEM-imidazoles, 2-aryl-1-SEM-imidazoles,
and 2,5-diaryl-1-SEM-imidazoles, as well as the corresponding
free (NH)-imidazoles (via simple deprotection of the SEM
group, vide infra). However, the C-4 position of SEM-imida-
zoles (and other N-substituted imidazoles) exhibits very low
reactivity in the palladium-catalyzed C-H arylation described
above, precluding direct C-arylation of this position. To ad-
dress this problem, we developed and here describe the SEM-
group switch that transposes the SEM group from the N-1 to
N-3 nitrogen of the imidazole ring and in the process trans-
forms the unreactive C-4 position to the reactive C-5 position.
Analogous to the SEM-switch of pyrazoles,15a the rearrange-
ment proceeds in the presence of a catalytic amount of SEM
chloride (Scheme 2), most likely via formation of an imidazo-
lium intermediate and subsequent loss of the SEM group
through a SN1 type process, to ultimately produce the less
sterically hindered 4-arylimidazole.33 The second arylation at
the C-5 position of the resulting 4-arylimidazole then proceeds
well to generate a 4,5-diarylimidazole.
In practice, 5-arylimidazole 19, prepared by direct arylation of
SEM-imidazole 1 with 4-bromoanisole, was converted in one
step to 4-arylimidazole 21 in 88% isolated yield (Scheme 2).
Despite the increased steric hindrance at the “new” C-5 position,
remarkably, the arylation of the C-5 position was preferred over
the C-2 position, furnishing 4,5-diarylimidazole 22 in 46% iso-
lated yield, accompanied by the starting material and the double
arylation product (17% and 11% yields, respectively). The
second C5-arylation becomes highly efficient with C2-substi-
tuted substrates, which is discussed in the following section.
Synthesis of 2,4,5-Triarylimidazoles via Sequential C-Ary-
lation and the SEM-Switch. Having established the C2-
arylation, the C5-arylation, and the SEM-switch, we now can
access 2,4,5-arylated imidazoles in short order. The three-step
sequence consisting of direct C5-arylation, SEM-switch, and the
second C5-arylation was extended to 2-substituted imidazoles.
2-Phenyl-1-SEM-imidazole 4, prepared by C2-arylation of imi-
dazole 1 or by protection of commercially available 2-phenyl-
imidazole, was used to explore the efficiency of the three-step
sequence (Table 3, entries 1-3). In terms of arene donor
substrate scope, several functional groups, including ester, di-
methylamino, pyridyl, and pyrazyl groups, were well tolerated.34
Note that the second arylation of sterically hindered substrates is
efficient, giving good to excellent yields with a variety of arene
donors.
Synthesis of 2-Alkyl- and 2-Dialkylamino-Substituted
4,5-Diarylimidazoles. To further demonstrate the utility of the
sequential arylation sequence, we also tested 2-alkyl- and 2-di-
alkylamino-imidazole derivatives. Specifically, 2-butyl-1-SEM-
imidazole is an excellent substrate for the arylation and SEM-
switch reactions, giving complex imidazole 34 in high yield
(Table 3, entry 4). Moreover, a dialkylamino functionality on
the imidazole core was compatible with not only the palla-
dium-catalyzed arylation but also the SEM-switch; the 2-
piperidylimidazole was transformed to 37 in good overall
(32) Strong inhibition by electron-withdrawing substituents present in the
bromoarene donors was observed in the sp3 C-H arylation of R-methyl azine-
N-oxides, a method that also depends on the use of NaOt-Bu as the base (see
ref 31). The authors proposed that the catalyst was inhibited by cyclopalla-
dation of the products containing relatively acidic benzylic groups. It is
conceivable that in our case cyclopalladation of the 20-position of the aryl
ring may sequester the palladium catalyst. Inhibition by direct coordination
of the nitrile group to the palladium metal is also possible; however, processes
responsible for the catalyst deactivation are presently not known.
(33) He, Y.; Chen, Y.; Du, H.; Schmid, L. A.; Lovely, C. J. Tetrahedron
Lett. 2004, 45, 5529–5532.
(34) As long as the functional groups of the substrates are compatible
with the alkoxide base and the 2-position of imidazoles is blocked, the C2-
arylation conditions can be employed for C5-arylation. Namely, diarylimi-
dazole 23 was prepared after the treatment of 2-phenylimidazole 4 with
Pd(OAc)2, P(n-Bu)Ad2, 3-bromoanisole, and NaOt-Bu in toluene in 84%
isolated yield.
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TABLE 3. Sequential Double Arylation Enabled by SEM-Group Switch
a5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2, 1.2 equiv of Ar1Br, 2.0 equiv of K2CO3, DMA (0.5 M), 120 °C, 20 h. b5.0 mol % SEMCl, CH3CN,
80 °C, 24 h. c5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2, 1.5 equiv of Ar2Br, 2.0 equiv of K2CO3, DMA (0.5 M), 120 °C, 20 h. dArCl was used instead of
ArBr. eIn the benchtop experiment, [P(n-Bu)Ad2H]BF4 was used and the amount of K2CO3 was increased (2.5 equiv).
SCHEME 3. Synthesis of 1-Alkyl-4-arylimidazoles
yield (Table 3, entry 5). The SEM group of the resulting
arylation products can be easily removed by either acidic
hydrolysis or fluoride treatment.35 For example, deprotec-
tion of complex imidazole 34 was performed in an aqueous
HCl solution (1 N, 80 °C, 2 h) to give the corresponding free
imidazole in quantitative yield.
Synthesis of 1-Alkyl-4-arylimidazoles from 1-SEM-5-
Arylimidazoles via Trans-N-alkylation. The SEM-switch
idea was extended to accomplish the trans-N-alkylation, which
unlocks a short route to regioselective formation of 1-alkyl-4-
arylimidazoles. Indeed, N-alkylation of 2 with benzyl bromide
and subsequent acidic hydrolysis generated 1-benzyl-4-phenyl-
imidazole 39 in excellent yield (Scheme 3).36,37 Similarly,
trimethyloxonium tetrafluoroborate produced methylimidazo-
lium salt 40, which underwent a SEM cleavage to give 1-methyl-
4-phenylimidazole 6 in 91% yield over 2 steps. Given the fact
that it is difficult to achieve regioselective N-alkylation of 4(5)-
arylimidazoles with a small alkyl group, the procedure using
SEM-imidazoles addresses this problem and enables efficient
preparation of 1-alkyl-4-arylimidazoles.
(35) (a) Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. J. Org. Chem.
1986, 51, 1891–1894. (b) Lipshutz, B. H.; Vaccaro, W.; Huff, B. Tetrahedron
Lett. 1986, 27, 4095–4098.
(36) A report on the exchange of a SEM group with a benzyl group in the
context of 4-arylimidazole synthesis: Nakamura, S.; Kawasaki, I.; Yama-
shita, M.; Ohta, S. Heterocycles 2003, 60, 583–598.
(37) The palladium-catalyzed C5-arylation of 1-benzylimidazoles has
been reported (see ref 19). Similar to the SEM group transposition, the
benzyl group should be transposable in the presence of a catalytic amount of
benzyl bromide. In fact, 1-benzyl-5-phenylimidazole, obtained in 72%
isolated yield through our protocol, underwent a benzyl switch to give
1-benzyl-4-phenylimidazole 39 in 84% isolated yield; however, the reaction
required extended heating (5 days in DMF at 140 °C).
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SCHEME 4. Synthesis of 1-Methyl-2,4,5-triarylimidazoles via Sequential C-Arylation and N-Methylationa
aReaction conditions: (a) 5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2, 1.2 equiv of 1-bromo-3,5-dimethoxybenzene, 2.0 equiv of K2CO3, DMA (0.5 M),
120 °C, 18 h (68% yield). (b) 5.0 mol % Pd(OAc)2, 7.5 mol % P(n-Bu)Ad2, 1.5 equiv of 4-bromobenzotrifluoride, 2.0 equiv of NaOt-Bu, toluene (1.0 M),
100 °C, 24 h (65% yield). (c) 1.5 equiv of Me3O BF4, CH2Cl2, rt, 1 h; 1 N HCl, H2O, 80 °C, 2 h (55% yield over 2 steps). (d) 5.0 mol % Pd(OAc)2, 7.5 mol
3
% P(n-Bu)Ad2, 1.2 equiv of 2-bromonaphthalene, 2.0 equiv of K2CO3, DMA (0.5 M), 120 °C, 18 h (82% yield). Yields are an average of two separate
isolated yields.
Programmable Synthesis of Complex 1-Alkyl-triarylimida-
zoles. The gathered results substantiate a general strategy for the
synthesis of a broad range of mono-, di-, and triarylimidazoles
from the parent imidazole as well as substituted imidazoles. For
example, 2,5-diarylimidazoles can be accessed by either C5-C2
or C2-C5 sequential arylation reactions. Further, 2,4,5-triaryl-
imidazoles can be rapidly prepared by the SEM-switch and
C5-arylation of the diarylimidazoles. If the goal is to prepare
free (NH)-imidazoles, SEM deprotection can be carried out
under either acidic or basic (fluoride) conditions.
However, when N-alkyl-triarylimidazoles are desired,
trans-N-alkylation followed by the final C5-arylation repre-
sents a good synthetic plan. This approach was implemented
in a five-step synthesis of 44 (Scheme 4). In detail, the C5-
arylation of imidazole 1 afforded compound 41, from which
diarylimidazole 42 was derived by C2-arylation with 4-bro-
mo-1-trifluoromethylbenzene. The N-methylation and the
SEM-group deprotection provided 1-methylimidazole 43,
which was subsequently subjected to the final coupling with
2-bromonaphthalene to furnish fully substituted product 44.
In this synthesis, all four substituents including the N-alkyl
group were introduced to the bare imidazole core in a
programmable manner. This general approach based on
sequential C-arylation and N-alkylation of SEM-protected
imidazoles provides rapid access to complex aryl imidazoles,
and it is quite apparent how series of derivatives (with
different substitutions at one or more positions) can be
synthesized in short order in this manner.
the parent imidazole or advanced imidazole derivatives (accessed
from ring-forming or substituent-modifying reactions). Our
approach and the new C-H arylation protocols will thus
complement transition-metal-catalyzed cross-coupling reac-
tions, including the Suzuki reaction19,38 and the catalytic
N-arylation of imidazoles,39,40 as well as the C-H arylation
reactions developed by others.19,20,28 The particular strength of
our strategy is the flexibility with which the N-alkyl groups can
be introduced in a regioselective manner at various stages of the
arylation sequence. Another important advance this paper
brings is that both C5- and C2-arylation reactions can be carried
out with low-cost and readily available aryl chloride donors.
Experimental Section
General Procedure for the C2-Arylation of SEM-Imidazoles.
The imidazole (0.50 mmol) was weighed into a 4-mL glass vial
equipped with a magnetic stir bar. Through a Teflon-lined cap, the
vial was purged with argon. The aryl halide (0.75 mmol) and
toluene (0.25 mL) were added to the vial under a positive pressure
of argon. The reaction vial was moved to a glovebox. Pd(OAc)2
(5.6 mg, 0.025 mmol), P(n-Bu)Ad2 (13.4 mg, 0.038 mmol), and
NaOt-Bu (96 mg, 1.0 mmol), which were stored under argon in the
glovebox, were then added to the reaction mixture. The cap was
replaced with a new Teflon-lined solid cap. The reaction vial was
removed from the glovebox and then moved to a preheated
reactionblock(100°C). After stirring for 24 h, the reaction mixture
was cooled to room temperature and was directly loaded to a silica
gel column. Purification by flash column chromatography pro-
vided the desired 2-arylimidazole. For a procedure that does not
require the use of a glovebox, see Supporting Information.
2-(3-Methoxyphenyl)-5-phenyl-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-imidazole (13). Purification by flash column chroma-
tography (hexanes/EtOAc = 3:1) provided 13 as a colorless oil:
IR (film) 2952, 2894, 2836, 1605, 1482, 1359, 1286, 1250, 1170,
1083 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63-7.58 (m, 2H),
7.49-7.43 (m, 4H), 7.42-7.35 (m, 2H), 7.22 (s, 1H), 7.02-6.97
(m, 1H), 5.14 (s, 2H), 3.87 (s, 3H), 3.45 (t, J = 8.4 Hz, 2H), 0.97 (t,
Conclusions
Imidazoles are an important group of the azole family of
heterocycles frequently found in pharmaceuticals, drug can-
didates, ligands for transition metal catalysts, and other
molecular functional materials. Owing to their wide applica-
tion in academia and industry, a great deal of work has been
dedicated to the generation of functionalized imidazole
derivatives. In contrast to conventional condensation meth-
ods, catalytic C-H bond functionalization reactions enable
derivatization and elaboration of the existing imidazole rings
and provide new possibilities for the synthesis of complex
imidazoles.
We here described a general and comprehensive approach
for the synthesis of complex aryl imidazoles, where all three
C-H bonds of the imidazole core can be arylated in a regio-
selective and sequential manner. The synthesis of individual
compounds or compound libraries can commence from either
(38) (a) Primas, N.; Mahatsekake, C.; Bouillon, A.; Lancelot, J.-C.;
Santos, J. S. O.; Lohier, J.-F.; Rault, S. Tetrahedron 2008, 64, 4596–4601.
(b) Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. J.
Med. Chem. 1998, 41, 2019–2028.
(39) Catalytic N-arylation of imidazoles with aryl halides: (a) Altman,
R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190–6199 and
references therein. (b) Zhu, L.; Li, G.; Luo, L.; Guo, P.; Lan, J.; You, J.
J. Org. Chem. 2009, 74, 2200–2202.
(40) Catalytic N-arylation of imidazoles with aryl boronic acids: (a) Lam,
P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944. (b) Collman,
J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528–1531.
(c) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G. Chem. Commun.
2004, 188–189.
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Joo et al.
JOCFeatured Article
J = 8.4 Hz, 2H), 0.00 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 159.6, 149.8, 135.4, 131.8, 129.9, 129.4, 128.7, 128.6, 128.0,
127.4, 121.0, 115.3, 113.7, 73.1, 65.3, 55.2, 17.9, -1.6; HRMS
(FAB) calcd for C22H29N2O2Si [M þ H]þ 381.1998, found
381.1991.
of General Medical Sciences (GM60326) for support of
this work and NSERC Canada for a postdoctoral fellowship
(B.B.T.).
Supporting Information Available: Detailed experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. This article is dedicated to the memory
of Professor Keith Fagnou. We thank the National Institute
4920 J. Org. Chem. Vol. 75, No. 15, 2010