Catalytic C-H arylation of SEM-protected azoles with palladium complexes of NHCs and phosphines

Article abstract of DOI:10.1021/ol053021c

The synthesis and catalytic evaluation of palladium complexes containing imidazolyl carbene ligand of varying steric and electronic properties is reported. These complexes catalyze the efficient C-H arylation of SEM-protected azole heteroarenes and thus provide a good method for preparation of a wide range of arylated free (NH)-azoles including pyrroles, indoles, imidazoles, and imidazo[1,2-a]pyridines. The reaction is operationally simple; the complexes are insensitive to moisture.

Full text of DOI:10.1021/ol053021c

ORGANIC
LETTERS
2006
Vol. 8, No. 10
1979-1982
Catalytic C−H Arylation of
SEM-Protected Azoles with Palladium
Complexes of NHCs and Phosphines
B. Barry Toure´, Benjamin S. Lane, and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway,
New York, New York 10027
sames@chem.columbia.edu
Received December 13, 2005
ABSTRACT
The synthesis and catalytic evaluation of palladium complexes containing imidazolyl carbene ligand of varying steric and electronic properties
is reported. These complexes catalyze the efficient C H arylation of SEM-protected azole heteroarenes and thus provide a good method for
−
preparation of a wide range of arylated free (NH)-azoles including pyrroles, indoles, imidazoles, and imidazo[1,2-a]pyridines. The reaction is
operationally simple; the complexes are insensitive to moisture.
Azoles are ubiquitous features of natural products, pharma-
ceuticals, and fluorescent dyes, as well as many other
synthetics. This broad range of uses of azoles and related
heteroarenes warrants the development of efficient and cost-
effective methods for their elaboration. The recent advances
in transition metal catalysis have unlocked many exciting
opportunities in this arena. New synthetic strategies such as
the direct functionalization of sp2 C-H bonds are now
emerging as viable alternatives to traditional cross-coupling
reactions.1 In these instances, the need for preactivating one
of the reaction components as its halide, tin, silicon, or boron
derivative is thus circumvented. The current repertoire
includes catalytic systems for arylation of 1-alkyl/aryl azoles
and binuclear azoles.2,3 However, the direct arylation of free
(NH)-azoles still remains a significant synthetic challenge.
Currently, there are two approaches to this problem: (1)
arylation of azole magnesium4 and zinc salts5 formed in situ
and (2) direct rhodium-catalyzed arylation of free (NH)-
pyrroles and indoles.6 While the former method suffers from
significant moisture sensitivity, the latter one is limited in
scope, most notably it is not applicable to imidazoles and
pyrrazoles.6 A new method for C-2 arylation of benzimida-
zole and related systems has been reported.7
We have recently reported a practical palladium-catalyzed
arylation of 1-alkyl indoles.2 A major drawback of this
procedure was the formation of biphenyl byproducts, which
was marginalized by using low catalyst loading. Although
satisfactory in the context of simple alkyl indoles, many
attractive but less reactive substrates such as SEM-protected
(1) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211-241.
(2) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897-2900.
(3) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn 1998, 71, 467-473. (b) Li, W. J.; Nelson, D. P.;
Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org.
Lett. 2003, 4835-4837. (c) Park, C.-H.; Ryabova, V.; Seregin, I. V.;
Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159-1162. (d) Bellina,
F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. J. Org. Chem. 2005,
70, 3997-4005.
(4) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050-8057.
(5) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett.
2004, 6, 3981-3983.
(6) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127,
4996-4997.
(7) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 35-38.
10.1021/ol053021c CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/12/2006

azoles were ineffective. SEM (2-(trimethylsilyl)ethoxy-
methyl) represents a versatile and robust protecting group
for azoles that can readily be removed under a variety of
reaction conditions.8 Herein, we disclose a catalytic system
that allowed the efficient arylation of SEM-protected azoles,
which in turn enables rapid preparation of a wide range of
arylated free (NH)-azoles.
Design of new catalyst precursors was founded on the
premise that one robust ligand (permanent ligand) should
be attached to the palladium center to improve its stability,
modulate its reactivity, and disfavor biphenyl formation.
Also, a labile ligand (i.e., Ph3P) should improve the stability
of the entire complex while in the reaction mixture it would
be readily displaced by the substrate.
Led by the above criteria, L1L2PdX2 palladium complexes
wherein L1 ) N-heterocyclic carbene (NHCs) and L2 )
phosphine9 were identified as promising leads. Accordingly,
we initiated the synthesis of a series of these catalysts with
particular emphasis on the steric and electronic properties
of the carbene ligand. The requirement for sufficient steric
demand of the carbene ligand became rapidly apparent,
which led to selection of four complexes 1a-d for further
examination (Figure 1).10 With the exception of 1c,11 these
Figure 2. Relative reactivity of (NR)-indoles.
We next compared 1a to the other catalysts using 1-SEM-
indole (2b) as the model substrate. All four complexes
catalyzed the arylation of 2b, albeit with different efficiency
(Figure 3).
Figure 1. Structure of palladium complexes (catalyst precursors)
investigated in this study.
Figure 3. Direct comparison of catalysts 1a-d, conversion
established by HPLC or GC analysis with benzoic acid and
dodecane, respectively, as internal standards (average of 2-3 runs).
catalysts may be purified by silica gel chromatography. In
addition, they are characterized by a high tolerance to air
and moisture.
The initial results revealed that the direct arylation of
1-SEM-azoles was feasible, suggesting the superior perfor-
mance of 1a in comparison to our previous system.2 As
expected, the less reactive substrates 2c-e failed (Figure 2),
which is consistent with the electrophilic metalation hypoth-
esis proposed for these reactions.3,4
Interestingly, the activity of the bulky and more electron-
rich complex 1b mirrored that of the electron-deficient
analogue 1a, implying the predominant role for sterics.
Related systems 1c and 1d, containing the popular IMes
ligand, also performed well. 1d was clearly superior in terms
of both rate and conversion.
As our objective was to develop an operationally simple
arylation procedure, we chose 1a for the exploration of the
substrate scope, reserving the use of 1d for difficult cases.
The synthesis of 1d is currently low yielding. In contrast,
N-carbamoyl-substituted carbene ligand is readily available
from the common reagent CDI (carbonyldiimidazole) and
complex 1a can be obtained in good yield on a benchtop
(Supporting Information).
(8) (a) Muchowski, J. M.; Solas, D. R. J. Org. Chem. 1984, 49, 203-
205. (b) Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. J. Org. Chem.
1986, 51, 1891-1894.
(9) (a) Herrmann, W. A.; Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.;
Grosche, M.; Reisinger, C.-P.; Weskamp, T. J. Organomet. Chem. 2001,
617-618, 616-628. (b) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett.
2002, 4, 1411-1414.
(10) A detailed report on the chemistry of these carbenes will be given
in due course.
(11) Konnick, M. M.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004,
126, 10212-10213..
Subsequently, the scope of the system was explored with
emphasis on SEM-protected azoles that cannot be currently
1980
Org. Lett., Vol. 8, No. 10, 2006

arylated in the free (NH)-form.4-6 Tables 1-3 present a wide
array of substrates, demonstrating a good functional group
tolerance. The arylation of 1-SEM-indole proceeded with
complete conversion and good isolated yield with relatively
low catalyst loading (1.5 mol %). Bromobenzene can also
be used in this process; however, it affords only modest yield
of the product and low regioselectivity. It is worth noting
that both nitro and cyano functionalities are tolerated on the
benzene ring of indole. The reactions with iodo donors
predominantly yielded the 2-arylation products, a regio-
selectivity that is only significantly altered by the use of
ortho-substituted aryl halides (Table 1, entry 5).
The direct arylation of 2- or 3-substituted indoles to
generate 2,3-disubstituted products still remains a major
challenge. We were pleased that the prototype substrate
3-methylindole (Table 1, entry 6) was efficiently arylated.
However, electronically deactivated analogues as illustrated
by methyl indole-3-carboxylate only afforded low yields of
the corresponding products (Table 1, entry 7). Nonetheless,
this example demonstrates the feasibility of accessing such
attractive products in a single synthetic operation. The current
methodology also addressed the problematic direct arylation
of electron-deficient pyrroles. 2-Cyanopyrrole was arylated
selectively at the 5-position in moderate yield (entries 8 and
9). In contrast, the arylation of 3-acetylpyrrole afforded a
mixture of products with modest preference for the 5-position
(Table 1, entry 10).
Table 1. Substrate Scope of the Reactiona,b
Heteroarenes bearing a basic nitrogen were also arylated
with good efficiency (Table 2). The arylation of SEM-
Table 2. Arylation of Heteroarenes Bearing Basic Nitrogensa
a All reactions were performed at 1.0-2.0 M concentration of substrate.
Average of two isolated yields. b 3-5% of 2-phenyl side products was also
isolated. c With Ag2CO3 as base.
imidazole afforded the 5-phenyl product in moderate yield
along with 3-5% of C-2, and C2/5 phenylated byproducts,
a significant improvement over the previously reported 2.3:1
ratio for 1-methylimidazole.3a Cesium acetate performed
poorly in the arylation of 2-phenyl-1-SEM-imidazole; silver
carbonate was a superior base in this instance (Table 2, entry
3).
Next, we tested complex 1a against imidazo[1,2-a]-
pyridines. As shown in Table 3, both bromo- and iodo-arene
donors can be used in this transformation, and electron-
draining substituents were tolerated.
a All reactions were performed at 1.0-2.0 M concentration of substrate.
Average of two isolated yields. b PhI afforded a better C2/C3 ratio of the
product than PhBr (10-20:1 versus 3-4:1); small amounts of bisarylation
products are also formed. c 3.5:1 ratio in favor of the 2-regioisomer.
d Product characterized after deprotection (see the Supporting Information).
e Mixture of isomers: 5-phenyl, 2,5-diphenyl, 2-phenyl in 4:2:1 ratio (see
the Supporting Information).
The results presented above outline the applicability and
limits of catalyst 1a. It was of interest to compare the
Org. Lett., Vol. 8, No. 10, 2006
1981

Table 3. Direct Arylation of Imidazo[1,2-a]pyridinesa
Table 4. Direct Comparison of Azoles Arylation Conditionsa
a All reactions were performed at 0.5 M concentration of substrate: (A)
1a (5.0 mol %), CsOAc; (B) 1d (5.0 mol %), CsOAc; (C) 1a (2.5 mol %),
Ag2CO3; (D) 1d (2.5 mol %), Ag2CO3. Entry 1: average of two isolated
yields. Entry 2: 1H NMR yield with t-BuOH as internal standard.
a All reactions were performed at 1.0-2.0 M concentration of substrate.
Average of two isolated yields.
performance of this system with 1d against some difficult
arylation substrates (Table 4). With the indole substrate, the
catalysts were comparable (Table 4, entry 1). In contrast, in
the context of 1-SEM-2-phenylimidazole, complex 1a out-
performed 1d. These results forecast that fine-tuning of the
coordination sphere of the catalyst will be required for each
azole ring type, especially with less reactive analogues. A
notable example of unsuccessful substrates was methyl
1-SEM-pyrrole-2-carboxylate, which gave no arylation prod-
uct.
In summary, we have reported a new catalytic system that
provides a direct access to a wide range of SEM-protected
azoles. Simple deprotection of these products lead to free
(NH)-azoles, many of which cannot currently be accessed
via direct arylation. Future investigations will focus on
shedding light on the mechanism of these processes, includ-
ing the subtle interplay between the steric and electronic
properties of the ligand.
Acknowledgment. This work is supported by NIGMS,
NSF, Merck Research Laboratories, and GlaxoSmithKline.
D.S. is a recipient of the Bristol Myers Squibb Unrestricted
Grants in Synthetic Organic Chemistry Award, Pfizer Award
for Creativity in Organic Chemistry. B.B.T. thanks NSERC
Canada for a postdoctoral fellowship. We thank Dr. Xiang
Wang for valuable discussions.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL053021C
1982
Org. Lett., Vol. 8, No. 10, 2006