Diversity synthesis via C-H bond functionalization: Concept-guided development of new C-arylation methods for imidazoles

Article abstract of DOI:10.1021/ja036157j

Herein, we have formulated the concept of systematic derivatization of a structural motif via C-H bond functionalization. This concept may not only serve as a blueprint for new strategies in diversity synthesis but also provide systematic guidance for the

Full text of DOI:10.1021/ja036157j

Published on Web 08/09/2003
Diversity Synthesis via C-H Bond Functionalization:
Concept-Guided Development of New C-Arylation Methods for
Imidazoles
Bengu¨ Sezen and Dalibor Sames*
Contribution from the Department of Chemistry, Columbia UniVersity,
3000 Broadway, New York, New York 10027
Received May 14, 2003; E-mail: sames@chem.columbia.edu
This paper was retracted on June 21, 2006 (J. Am. Chem. Soc. 2006, 128, 8364).
Abstract: Herein, we have formulated the concept of systematic derivatization of a structural motif via
C-H bond functionalization. This concept may not only serve as a blueprint for new strategies in diversity
synthesis but also provide systematic guidance for the identification of unsolved and important synthetic
challenges. To illustrate this point, 2-phenylimidazole was selected as the core motif for this study, a choice
inspired by numerous azole-based synthetics, including pharmaceuticals (compound SB 202190), and also
fluorescent and chemiluminescent probes. We were able to show that systematic and comprehensive
arylation of the 2-phenylimidazole core was feasible, and in the context of this study new arylation methods
were developed. The direct 4-arylation of free 2-phenylimidazole was achieved with iodoarenes as the aryl
donors in the presence of palladium catalyst (Pd/Ph3P) and magnesium oxide as the base. A complete
switch from C-4 to C-2′ arylation was accomplished using a ruthenium catalyst [CpRu(Ph3P)2Cl] and Cs2CO3.
The corresponding transformations for (N,2)-diphenylimidazole (C-5 and C-2′ arylation) were accomplished
via the palladium-based method [Pd(OAc)2/Ph3P/Cs2CO3] and a rhodium-catalyzed procedure [Rh(acac)(CO)2/
Cs2CO3], respectively. All of the arylation methods described herein demonstrated broad synthetic scope,
high efficiency, and exclusive selectivity. Furthermore, these new methods proved to be orthogonal to one
another and applicable to sequential arylation schemes. With these methods in hand, arrays of arylated
imidazoles may now be accessed in a direct manner from 2-phenylimidazole. This strategy stands in sharp
contrast to a traditional approach, wherein a distinct and multistep synthesis would be required for each
analogue.
Introduction
Systematic Derivatization of Structural Motifs via C-H
Bond Functionalization: The Concept. The possibility of
direct and selective introduction of a new functionality (or a
new C-C bond) via C-H bond functionalization1 has long
intrigued both developers and practitioners of organic prepara-
tive chemistry.2 The value of such methods is readily apparent
in target-oriented synthesis as multistep synthetic sequences,
often needed for establishing a new group at a preset position,
may substantially be truncated. As a consequence, the possession
of such synthetic ability will inspire new strategies for the
assembly of organic compounds.3
Figure 1. Diversity synthesis via (A) C-H bond functionalization versus
(B) traditional methods.
The impact of C-H bond functionalization may be even
greater in the context of diversity synthesis, where multiple
derivatives of a selected structural core may be generated in a
direct fashion (one step) from the core motif itself (Figure 1A).
This new strategy stands in stark contrast to traditional ap-
proaches, which require multistep and often distinct schemes
(1) In our view, the term “C-H bond activation” carries considerable
mechanistic claim, while “C-H bond functionalization” simply describes
a formal process. Consequently, in the case of unsaturated substrates (e.g.,
arenes, alkenes) or substrates containing relatively acidic C-H bonds (e.g.,
alkynes), the term “C-H activation” should be used thoughtfully, as other
mechanistic modes are readily available (cf. electrophilic metalation of
arenes). Thus, in the absence of a clear mechanistic picture, we prefer the
use of a general term “C-H bond functionalization”.
(2) (a) Lo¨ffler, K.; Kober, S. Ber. 1909, 42, 3431-3438. (b) Barton, D. H. R.;
Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083-4089. (c) Corey, E. J.;
Felix, A. M. J. Am. Chem. Soc. 1965, 87, 2518-2519. (d) Moritani, I.;
Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119-1122. (e) Breslow, R.;
Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu, S.; Washburn, W. J. Am. Chem.
Soc. 1973, 95, 3251-3262.
(3) (a) Taber, D. F.; Stiriba, S.-E. Chem. Eur. J. 1998, 4, 990-992. (b) Dangel,
B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149-
8150. (c) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124,
6900-6903. (d) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames,
D. J. Am. Chem. Soc. 2002, 124, 11856-11857. (e) Davies, H. M. L.;
Venkataramani, C.; Hansen, T.; Hopper, D. W. J. Am. Chem. Soc. 2003,
125, 6462-6468.
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Diversity Synthesis via C−H Bond Functionalization
A R T I C L E S
Figure 2. A pharmaceutical lead (SB 202190) inspired the selection of
the 2-phenylimidazole motif.
for each derivative (Figure 1B). In addition to significant
practical consequences, the concept of comprehensive elabora-
tion of structural motifs serves to systematically expose unsolved
and important synthetic challenges.
Systematic Arylation of the 2-Phenylimidazole Core.
Heteroaromatics constitute an important class of structural units
frequently found in natural products, pharmaceuticals, and other
functional synthetics. Recently, we reported a palladium-
catalyzed C-arylation of free (NH)-azoles, and this work led us
to further explore direct arylation methods with tunable selec-
tivities at the heteroarene core.4 The selection of 2-phenyl-
imidazole as the structural motif for this study was primarily
inspired by compound SB 202190, a synthetic inhibitor of p38
kinase and a clinical candidate for the treatment of inflammatory
and immunological disorders.5 Furthermore, many fluorescent
and chemiluminescent probes contain the arylated azole motif.6
Encouraged by our recent results in the arylation of free azoles
and guided by the concept described above, we formulated the
challenge of comprehensive arylation of 2-phenylimidazole
(Figure 2). Note that this task required the selective targeting
of four different C-H bonds in the presence of a free amine
functionality, an intriguing chemical challenge, indeed.
This goal stimulated the development of new arylation
methods for imidazole substrates, which is the main subject of
this report. The direct arylation of positions C-4 and C-2′ in
2-phenylimidazole and positions C-5 and C-2′ in (N,2)-di-
phenylimidazole was accomplished with complete control of
regiochemistry. Moreover, these new methods proved to be
orthogonal to one another and applicable to sequential arylation
schemes. In addition, arylation of positions C-3′ and C-4′ was
accomplished via a two-step sequence, yielding a separable
mixture of compounds 5 and 6 as the main products (Figure
3). Remarkably, complete and systematic arylation of the
2-phenylimidazole core was achieved, providing a specific
example of the general concept introduced earlier. Consequently,
diverse arylimidazole compounds may be synthesized directly
from the common core, eliminating the need for multistep
syntheses of each analogue.
Figure 3. Programmable and comprehensive arylation of the 2-phenyl-
imidazole core.
Cs2CO3].7 Thus, we set out to explore the possibility for selective
C-arylation of free (NH)-azole, a challenge attainable via
selective targeting of C-H bonds in the presence of free N-H
functionality. We hypothesized that the failure of the alkali bases
(e.g., NaOMe, KOtBu, Cs2CO3) was due to formation of a
solvated azolyl anion, which in turn inhibited the palladium
catalyst via formation of a phenylpalladium-azolyl complex.4
Facing this challenge, we proposed that a salt possessing a strong
metal-nitrogen bond may not only protect the amino function
but also increase the nucleophilicity of the annular carbon
centers of the heteroarene. Led by this hypothesis, we found
that MgO proved to be the base of choice when used in
combination with Pd(OAc)2 and triphenylphosphine. Exclusive
C-arylation was achieved under these conditions with a number
of free azoles, including pyrrole, indole, pyrazole, and imidazole.
Importantly, 2-phenylimidazole 1 afforded C-4 arylation product
2 in 82% yield (Scheme 1).
The Pd/Ph3P/MgO system was then investigated in the context
of 2-phenylimidazole with respect to the substitution on the aryl
donor. This method was found to be compatible with both
electron-donating and electron-withdrawing substituents in the
4-position of aromatic iodide. While electron-releasing groups
(Me, OMe) had no effect on efficiency of this reaction, electron-
withdrawing substituents (F, CF3, COMe) resulted in minor
reduction of the yields (76-80%, Scheme 1). Regarding the
bromide donors, Ph-Br provided the lower yield of product 2
(60%) in comparison to Ph-I (82%), while 4-bromopyridine
proved to be an excellent donor, furnishing compound 12 in
80% isolated yield. 2-Iodotoluene also led to exclusive 4-aryl-
ation, albeit at a slower rate, furnishing product 13 in 72% yield.
A notable exception to an otherwise broad scope was found
when a dimethylamino group was placed in the para position
of the aryl donor. Both 4-(dimethylamino)iodobenzene and the
corresponding bromide decomposed during the reaction, yielding
no desired product 8 (Scheme 1). The exclusive formation of
the C-4 arylated products is noteworthy, as neither N-arylation
Results and Discussion
Selective C-4 Arylation of 2-Phenylimidazole. In the course
of our investigations, we found that known arylation conditions
were not applicable to free (NH)-azoles, including methods
developed for oxazole and thiazole substrates [Ar-X/Pd(OAc)2/
(7) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 467-473. (b) A review on arylation of arenes:
Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211-241. (c) A recent
example of selective and low-temperature arylation of thiazole: Mori, A.;
Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto,
M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700-1701.
(4) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274-5275.
(5) Jackson, P. F.; Bullington, J. L. Curr. Top. Med. Chem. 2002, 2, 1011-
1020 and references therein.
(6) Nakashima, K.; Fukuzaki, Y.; Nomura, R.; Shimoda, R.; Nakamura, Y.;
Kuroda, N.; Akiyama, S.; Irgum, K. Dyes Pigments 1998, 38, 127-136.
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A R T I C L E S
Sezen and Sames
Scheme 2. Selective 2′-Arylation of 2-Phenylimidazolea
Scheme 1. Selective 4-Arylation of 2-Phenylimidazolea
a Conditions: (a) Ar-X (1.8 equiv), CpRu(Ph3P)2Cl (5 mol %), Cs2CO3
(1.2 equiv), DMF, 130 °C. (b) The same as conditions a except that 2.4
equiv of 2-Me-C6H4-I was used.
Scheme 3. C-3′ and C-4′ Arylation of 2-Phenylimidazolea
a Conditions: (a) Ar-X (1.2 equiv), Pd(OAc)2 (5 mol %), Ph3P (20 mol
%), MgO (1.2 equiv), dioxane, 150 °C. (b) The same as conditions a except
that 1.8 equiv of 2-Me-C6H4-I was used.
nor bis-arylation products were detected even in the presence
of an excess of the haloarene donor.
Selective C-2′ Arylation of 2-Phenylimidazole. As the
N-arylation of imidazoles has previously been established by
other groups,8-10 the next challenge involved the selective
arylation of position C-2′. N-Directed arylation of 2-phenyl-
pyridine and arylalkylimines has previously been demonstrated
with aryl halide and stannane donors.11 However, these methods
suffered from poor selectivity, as 2′,6′-bis-arylation products
were formed in significant amounts in addition to the desired
monoarylated compounds.12 Furthermore, selective 2′-arylation
of free 2-phenylimidazole has not been previously reported, and
once again the issue of targeting a C-H bond in the presence
of a free amine group presented itself. Consequently, we
undertook a systematic study focusing on Ru and Rh metal
complexes as potential catalysts (see Supporting Information
for complete screening results).13 To our delight, we found that
exclusive C-2′ arylation was attainable, CpRu(Ph3P)2Cl being
the most efficient catalyst. Thus, heating 2-phenylimidazole 1
a Conditions. Step 1: HBPin (1.2 equiv), [IrCl(COD)]2 (1.5 mol %),
bipyridine (3 mol %), NaOMe (6 mol %), hexane, 80 °C. Step 2: Ph-I (1
equiv), Pd(PPh3)4 (5 mol %), K2CO3 (1 equiv), DMF, 100 °C. 4-Arylation
product 2 was also formed in 6% yield.
with PhI (1.8 equiv) in the presence of CpRu(Ph3P)2Cl (5 mol
%) and Cs2CO3 (1.2 equiv) yielded desired compound 4 in 84%
yield (Scheme 2). The use of bromobenzene afforded 69% yield
of 4 under identical conditions.
The scope of the ruthenium-catalyzed C-2′ arylation meth-
odology was subsequently explored in terms of the aryl halide
substitution. This method also showed broad utility, and tolerated
both electron-donating and electron-withdrawing substituents
at the 4-position, furnishing C-2′-arylated products in good to
excellent yields (77-84%). 2-Iodotoluene and 4-(dimethyl-
amino)iodobenzene were less efficient donors, but nevertheless,
desired compounds 20 and 15 were obtained in 64 and 52%
yields, respectively (Scheme 2).
Although the mechanism of this reaction remains speculative,
the oxidative addition of aryl halide to the ruthenium metal and
the cyclometalation represent two key events of the catalytic
cycle. While the order of these two steps is not certain, the
N-directed metalation must presumably be responsible for the
observed C-2′ selectivity.
The exclusive formation of 2′-arylated products was found
in all studied cases under the optimized conditions. It is
remarkable that no arylation of the imidazole ring was observed
even in the presence of excess aryl halide and at elevated
temperatures (>1.8 equiv of ArI or >130 °C). Only under such
forceful conditions were the 2′,6′-diarylated products detected.
(8) Palladium-catalyzed N-arylation of imidazoles has not been reported. For
N-arylation of other heterocycles: (a) Mann, G.; Hartwig, J. F.; Driver,
M. S.; Ferna´ndez-Rivas, C. J. Am. Chem. Soc. 1998, 120, 827-828. (b)
Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (c) Old, D. W.; Harris,
M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403-1406. (d) Grasa, G. A.;
Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001, 66, 7729-7737.
(9) Copper-promoted N-arylation of imidazoles with aryl boronic acids and
aryl siloxanes: (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. Org. Lett. 2000, 2, 1233-1236.
(c) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong,
P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600-7601. (d) Lam, P. Y.
S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.
2001, 42, 3415-3418.
(10) Copper-catalyzed N-arylation of nitrogen heterocycles (including imid-
azoles) with aryl halides: Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7727-7729.
(11) (a) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439-2440. (b)
Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org.
Lett. 2001, 3, 2579-2581. (c) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org.
Lett. 2002, 4, 1783-1785.
(12) Recent example of ruthenium-catalyzed arylation of aromatic ketones also
suffered from fast bis-arylation unless sterically bulky substrates were used
(e.g., pivaloylarenes). Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 1698-1699.
(13) Examples of other heteroatom-directed and catalytic C-C bond-forming
reactions at the arene ring: (a) Kakiuchi, F.; Murai, S. In ActiVation of
UnreactiVe Bonds and Organic Synthesis; Murai, S., Ed.; Springer: Berlin,
1999; pp 47-79. (b) Jun, C.-H.; Hong, J.-B.; Kim, Y.-H.; Chung, K.-Y.
Angew. Chem., Int. Ed. 2000, 39, 3440-3442. (c) Thalji, R. K.; Ahrendt,
K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692-
9693.
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A R T I C L E S
Scheme 4. Sequential Arylation of 2-Phenylimidazole Core with Highly Selective and Orthogonal Methodsa
a Conditions: (a) Ar-I (1.8 equiv), CpRu(Ph3P)2Cl (5 mol %), Cs2CO3 (1.2 equiv), DMF, 130 °C. (b) Ar-I (1.2 equiv), Pd(OAc)2 (5 mol %), Ph3P (20
mol %), MgO (1.2 equiv), dioxane, 150 °C. (c) Ar-I (1.2 equiv), Pd(OAc)2 (5 mol %), Ph3P (20 mol %), MgO (1.2 equiv), K3PO4 (1.2 equiv), dioxane/
DMF, 150 °C.
The selective formation of 2′-arylation versus 2′,6′-diarylation
product merits additional comment. The slower rate of the
second arylation step may be ascribed to stereo-electronic effects
associated with the conformational change (disfavoring co-
planarity between the phenyl ring in the 2-position and the
imidazole) exerted by the arene ring in the 2′-position (for
arylation rates with 1 vs 4, see Supporting Information).
Importantly, the new catalytic system developed herein
[CpRu(Ph3P)2Cl/Cs2CO3] showed higher selectivity for substrate
1 in comparison to previously reported methods.11 Thus,
formation of bis-arylation products may be completely avoided
while achieving high yields of the desired monoarylation
products (approximate reaction time, 10 h). Apparently, the Cp
ligand provides the favorable tuning of the ruthenium catalyst.
C-3′ and C-4′ Arylation of 2-Phenylimidazole. To complete
the systematic arylation of the 2-phenylimidazole core, a
selective targeting of positions C-3′ and C-4′ remained. This
task posed a considerable challenge as meta and para positions
of an electron-deficient benzene ring were to be functionalized
selectively, in the presence of the free imidazole ring. Although
presently there are no direct arylation methods capable of such
fine chemoselectivity, we considered the application of a two-
step procedure, consisting of direct borylation, followed by
Suzuki coupling (Scheme 3). The iridium-catalyzed borylation
of arenes, a remarkable methodology recently reported by others,
was indeed shown to target meta and para positions of
substituted benzene substrates.14 However, the issues regarding
the selectivity and degree of borylation remained unclear since
both arenes and heteroarenes have been shown to undergo facile
borylation.15
Thus, compound 1 was submitted to a two-step sequence,
including the borylation protocol developed in the Miyaura and
Hartwig laboratories, followed by Suzuki coupling. After some
optimization, a 2:1 mixture of compounds 5 and 6, products of
C-3′ and C-4′ arylation, respectively, was formed in 46%
combined yield. A small amount of C-4 arylation product 2
(6%) was also isolated. Compounds 5 and 6 were prepared in
a pure form following separation by flash chromatography. We
were not able to improve the yields of this sequence, as the
addition of excess pinacolborane resulted in the formation of
bis-borylation products. The ability to control the extent of
borylation remains to be achieved in this methodology, par-
ticularly in the context of complex arenes wherein the use of
an excess of the arene substrate is impractical. Regardless of
the low yields, these results serve to demonstrate the feasibility
of selectively targeting relatively unreactive C-H bonds.
In summary, comprehensive arylation of 2-phenylimidazole
was achieved affording all five isomers 2-6 in a direct fashion
from the same starting material (Figure 3). With the exception
of positions C-3′ and C-4′ where a mixture of the corresponding
products was formed, arylation of positions C-4, N-1, and C-2′
may now be carried out with complete control of regioselec-
tivity.
Sequential Arylation of 2-Phenylimidazole via Fully
Orthogonal Arylation Methods. The monoarylation of 2-
phenylimidazole was accomplished with excellent selectivity
at C-4 and C-2′ positions, employing the methods discussed
above. The next key question centered on the possibility of
performing two arylation reactions sequentially, thus providing
a direct route to diarylated derivatives.
We were gratified to find that both arylation methods were
fully orthogonal and applicable to sequential functionalization
(Scheme 4). To demonstrate this point, regioisomers 21 and 22
were prepared in two steps from the same starting material 1.
Furthermore, both compounds may be accessed via two alterna-
(14) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R.,
III. Science 2002, 295, 305-308. (b) Ishiyama, T.; Takagi, J.; Ishida, K.;
Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
390-391.
(15) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron
Lett. 2002, 43, 5649-5651.
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Sezen and Sames
Scheme 5. (N,2)-Diphenylimidazole Core: Development of the
2′-Arylation Method
nitrogen atom, whereas the C-2′′ arylation would require the
involvement of the more crowded nitrogen atom (we assume
that compounds 7 and 9 exist as two tautomeric forms in
equilibrium). Thus, even in the presence of an electron-rich aryl
ring at C-4 position (cf. 7), exclusive arylation of the electron-
poor ring was observed.
These two examples demonstrated the full orthogonality of
the new arylation methods, which bears significant consequences
for the synthesis of imidazole-based arrays. The power of direct
C-H bond functionalization thus becomes apparent in this
context as diverse libraries of diarylated analogues may be
synthesized from the same starting material, in two steps and
via the same methodology for each analogue.
tive routes. For instance, compound 21 was synthesized via two
routes, which differed in the order of the arylation steps. The
left route (Scheme 4) involved the C-2′ arylation first, followed
by the C-4 arylation. The ruthenium-catalyzed C-2′ arylation
was conducted in the presence of 4-methoxy-iodobenzene as
the arene donor under the conditions developed earlier, furnish-
ing compound 14 in 83% yield. Subsequent palladium-catalyzed
arylation with 4-trifluoromethyl-iodobenzene produced the
desired compound 21 as the exclusive product in 76% yield.
Alternatively, compound 21 was synthesized via the right route
wherein the C-4 arylation was carried out first, followed by the
C-2′ arylation. Both routes afforded compound 21 with identical
overall efficiency (63% yield). Similarly, regioisomer 22 was
prepared via two alternative routes with essentially identical
yields (61-62%).
A minor modification of the original C-4 selective protocol
was required for the biphenylimidazole substrates (cf. 14 and
16). In these cases, addition of the second base (K3PO4) was
required to obtain good yields (Scheme 4, conditions c).
Noteworthy is the fact that compounds 7 and 9 contain two
arene rings, both of which are poised for potential directed ortho
arylation (C-2′ vs C-2′′), raising a selectivity issue not previously
encountered in substrate 1. Remarkably, exclusive arylation of
the 2′-position was observed, providing the desired products
21 and 22 in 79 and 76% yields, respectively. We rationalized
this finding by a simple steric argument. The C-2′ selectivity
may be explained by the directing effect of the less hindered
Sequential Arylation of (N,2)-Diphenylimidazole. As the
N-arylated imidazoles are readily available, we proceeded to
examine (N,2)-diphenylimidazole substrate 3. As expected, the
methodology developed for substrate 1 proved to be hardly
applicable to 3, a finding that prompted the development of
new methods suitable for the N-aryl-imidazole substrates.
The ruthenium-catalyzed C-2′ arylation method, developed
for substrate 1, provided low yields of desired product 23
(<50%). Consequently, we submitted substance 3 to a system-
atic study, focusing primarily on ruthenium and rhodium metal
complexes as the potential catalysts (for screening results, see
Supporting Information). This effort led to the development of
new conditions suitable for substrate 3 (Scheme 5). Efficient
C-2′ arylation of this substrate using bromobenzene occurred
in the presence of Rh(acac)(CO)2 as the catalyst and Cs2CO3
as the base, affording compound 23 as the only detectable
product in 81% yield. In this instance, bromobenzene proved
to be a superior arene donor in comparison to iodobenzene, and
Rh(acac)(CO)2 outperformed the other Ru(II), Ru(III), and Rh(I)
complexes examined in this study (Supporting Information).
The selective C-5 arylation of 3 was achieved under optimized
conditions originally reported for 2-phenyloxazole, 2-methyl-
thiazole, and (N,2)-dimethylimidazole by Miura et al.7 The use
Scheme 6. Sequential Arylation of (N,2)-Diphenylimidazole Core with Highly Selective and Orthogonal Methodsa
a Conditions: (a) Ar-Br (1.2 equiv), Rh(acac)(CO)2 (5 mol %), Cs2CO3 (1.2 equiv), DMF, 150 °C. (b) Ar-I (1.2 equiv), Pd(OAc)2 (5 mol %), Ph3P (20
mol %), Cs2CO3 (1.2 equiv), DMF, 150 °C. (c) The same as conditions b except that 1.5 equiv of Ar-I was used.
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Scheme 7. Direct C-H Bond Arylation versus Traditional Syntheses of Imidazole Analog Arrays
of Cs2CO3 as the base, in addition to aryliodide and Pd(OAc)2,
was crucial for the success of this transformation (Scheme 6).
This method proved to be highly selective, yielding 1,2,5-
triarylated products exclusively and in good yields. The high
selectivity for substitution at the sterically hindered C-5 position
may be rationalized by invoking an electrophilic metalation of
the imidazole ring with the phenylpalladium halide.
Importantly, these two methods were compatible with the
sequential functionalization strategy (Scheme 6). In analogy to
the previous case, compounds 26 and 29 were prepared in two
steps from the same starting material 3, via two alternative
pathways for each compound, highlighting the orthogonality of
these arylation methods. In the case of 26, both pathways gave
good yields of the final product; however, the left route,
consisting of C-2′ arylation as the first step followed by C-5
arylation, was more efficient in comparison to the right route
(71 vs 61%, Scheme 6). For substance 29, the C-2′fC-5
arylation sequence (the left route) was also superior; however,
there seemed to be less difference between the two pathways
(68 vs 63%, Scheme 6).
We have shown that systematic and comprehensive arylation
of the 2-phenylimidazole core was feasible, and in the context
of this study, new arylation methods were developed. The direct
arylation of positions C-4 and C-2′ in 2-phenylimidazole and
positions C-5 and C-2′ in (N,2)-diphenylimidazole was ac-
complished with complete control of regiochemistry. Further-
more, the new methods proved to be orthogonal to one another
and applicable to sequential arylation schemes.
With this methodology in hand, arrays of arylated imidazoles
may be accessed in a direct manner from 2-phenylimidazole.
For instance, two analogue series, namely, the triarylimidazole
array and the tetraarylimidazole array, represented by structures
30 and 31, may be synthesized from the same starting material
1 in two or three steps, respectively. This strategy stands in
sharp contrast to the traditional approach, where a distinct and
multistep synthesis would be required for each series (Scheme
7). The development of new methods for direct functionalization
of other heteroarenes is currently underway in our laboratories.
Acknowledgment. Funding was provided by the National
Institutes of Health (NIGMS: R01 GM60326), GlaxoSmith-
Kline, Johnson & Johnson, and Merck. D.S. is a recipient of
an Alfred P. Sloan Fellowship and the Camille Dreyfus
Teacher-Scholar Award. We thank Dr. J. B. Schwarz (Pfizer,
editorial assistance), Dr. David A. Claremon (Merck, stimu-
lating discussion), and Vitas Votier Chmelar (intellectual
contribution).
Conclusion
The introduction of a new bond via direct C-H bond
functionalization has significant consequences in both target-
oriented synthesis and diversity synthesis. In the context of the
latter, we formulated the concept of systematic derivatization
of a structural motif via C-H bond functionalization. This
concept may play two major intellectual roles. First, it may serve
as a blueprint for new strategies in diversity synthesis; second,
it may provide systematic guidance for identification of unsolved
and important synthetic challenges. To illustrate this point, we
selected 2-phenylimidazole as the core motif for this study, a
choice inspired by numerous azole-based synthetics, including
pharmaceuticals (compound SB 202190) and fluorescent and
chemiluminescent probes.
Supporting Information Available: Experimental procedures
and spectral data for all products. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA036157J
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J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003 10585