Cobalt-catalyzed arylation of azole heteroarenes via direct C-H bond functionalization

Article abstract of DOI:10.1021/ol035313o

(Equation presented) We herein report a new cobalt-catalyzed method for arylation of azole heteroarenes, including thiazole, oxazole, imidazole, benzothiazole, benzoxazole, and benzimidazole. The direct arylation of thiazole and oxazole was achieved both with iodo- and bromoarenes as the aryl donors in the presence of cobalt catalyst [Co(OAc)₂/IMes] and cesium carbonate, while imidazole required the use of zinc oxide as the base. A complete reversal of arylation from C-5 to C-2 was accomplished using the bimetallic Co/Cu/IMes system. A direct comparison of the new cobalt method and the previously developed palladium protocol revealed significant differences, in terms of both chemical yield and selectivity.

Full text of DOI:10.1021/ol035313o

ORGANIC
LETTERS
2
003
Vol. 5, No. 20
607-3610
Cobalt-Catalyzed Arylation of Azole
3
Heteroarenes via Direct C−H Bond
Functionalization
Beng u1 Sezen and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway,
New York, New York 10027
sames@chem.columbia.edu
Received July 16, 2003
This paper was retracted on June 15, 2006 (Org. Lett. 2006, 8, 2899).
ABSTRACT
We herein report a new cobalt-catalyzed method for arylation of azole heteroarenes, including thiazole, oxazole, imidazole, benzothiazole,
benzoxazole, and benzimidazole. The direct arylation of thiazole and oxazole was achieved both with iodo- and bromoarenes as the aryl
donors in the presence of cobalt catalyst [Co(OAc) /IMes] and cesium carbonate, while imidazole required the use of zinc oxide as the base.
2
A complete reversal of arylation from C-5 to C-2 was accomplished using the bimetallic Co/Cu/IMes system. A direct comparison of the new
cobalt method and the previously developed palladium protocol revealed significant differences, in terms of both chemical yield and selectivity.
Heteroarenes represent structural units frequently found in
a broad range of organic compounds, including natural
products, pharmaceuticals, dyes, and other functional syn-
thetics. Consequently, methods for direct functionalization
and expansion of heterocyclic motifs would find enthusiastic
users in various scientific disciplines. Current C-C bond-
forming methods rely on establishing a reactive functionality
alternatives to palladium exist in this context. Out of nearly
unlimited offerings of the periodic table, we focused on the
metals of significantly lower cost compared to palladium.
Thus, we set out to explore a number of low-cost metal
salts, including those of chromium, iron, cobalt, nickel, and
copper, in the context of direct arylation of oxazole, thiazole,
and imidazole. Interestingly, anhydrous Co(OAc) proved
2
(halogenation, metalation) prior to the cross-coupling reac-
to be a notable exception, providing promising early results
tion. In contrast, a more direct approach may not only
eliminate the pre-functionalization step but may also prove
in some cases complementary to traditional methods in terms
of regiochemical outcome.1
while all other salts examined in this study were completely
inactive. It is the aim of this paper to describe our preliminary
results in this area.
The first substrate examined was thiazole 1 which had been
reported to afford only mediocre yields of mono-arylation
and bis-arylation products in the palladium-catalyzed ary-
Direct C-arylation of various heteroarenes has been
2
previously demonstrated; however, these studies, including
3
2
our own, have focused on the use of palladium catalysis.
lation reaction. In our hands, these claims were confirmed,
Although this choice is understandable in light of the
unparalleled versatility of palladium in organic synthesis,
we became interested in the fundamental question of whether
and as shown in Table 1 (entry 5), palladium-catalyzed
arylation with iodobenzene provided a mixture of products
2 and 4 in 42 and 15% yield, respectively. Upon addition of
CuI, previously shown to promote arylation of acidic
methylenes and methines (including the 2-position of thiazole
4
(
1) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580-10585.
(2) (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.
(4) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in Organic
Synthesis; John Wiley & Sons: New York, 1997.
(3) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274-5275.
1
0.1021/ol035313o CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/11/2003

(Table 1, entry 1). In the absence of the IMes ligand (or in
the presence of triphenylphoshine), cobalt(II) acetate gave
only a trace amount of the desired product (Table 1, entry
Table 1. Cobalt-Catalyzed Arylation of Thiazole:
A Comparison with Palladium-Based Methods
2
). A complete switch from C-5 to C-2 selectivity was
achieved by the addition of CuI, furnishing compound 3
exclusively in 84% yield. In addition to the IMes ligand,
SALEN [ethylenebis-(salicylimine)] proved equally effective
in this case (Table 1, entries 3 and 4). A control experiment
examining cuprous iodide and cesium carbonate in the
absence of cobalt and the ligand, produced C-2 arylation
product, however, in low yield (11%, Table 1, entry 7),
demonstrating the necessity of the bimetallic system. Note-
worthy is the fact that bromobenzene also gave the corre-
sponding arylated products, albeit at reduced yields in
comparison to iodobenzene.
We were pleased that an attractive alternative to palladium
was found. Furthermore, a direct comparison with the
palladium method showed that the cobalt-based system
proved superior both in terms of yield and selectivity. The
cost of Co(OAc)
lower in comparison to $89.14 per gram of Pd(OAc)
2
is $8.36 per gram which is significantly
10
2
. The
availability and low cost of SALEN and IMes ligands further
adds to the attractiveness of this protocol.
The conditions developed for thiazole were subsequently
applied to oxazole. As in the previous case, palladium-
catalyzed arylation was unselective yielding a mixture of
three products 6, 7, and 8, the last being the major one (Table
2
). Although addition of CuI increased the yield of C-2
Table 2. Cobalt-catalyzed Arylation of Oxazole:
5
A Comparison with Palladium-Based Methods
and N-methylimidazole), a different mixture was obtained,
containing products 3 and 4, corresponding to mono- and
bis-arylation at positions 2 and 5.6
We were encouraged to find that, in contrast to the
palladium-based procedure, the cobalt-catalyzed method
proved superior in terms of both yield and selectivity.
Systematic optimization focused on the choice of cobalt
source and ligand in addition to the usual parameters such
as base, solvent, and temperature. 1,3-Bis-mesitylimidazolyl
7,8
carbene (IMes) proved to be the ligand of choice, together
with anhydrous cobalt(II) acetate and cesium carbonate.
9
Using these conditions, the arylation reaction was selective,
affording compound 2 as a single product in 64% yield
(
5) (a) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J.
Org. Chem. 1993, 58, 4716-4721 and references therein. (b) See also ref
a. (c) A discussion on possible roles of Cu(I) in Pd/Cu catalytic systems:
Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364.
6) (a) Mori et al. have recently reported the use of fluoride salts in the
2
(
Pd/Cu-catalyzed arylation of thiazole. Selective phenylation of 2-position
was achieved at mild temperatures. Mori, A.; Sekiguchi, A.; Masui, K.;
Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am.
Chem. Soc. 2003, 125, 1700-1701. (b) For solid-phase-assisted selective
arylation of azoles: Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000,
arylation, bis-arylation was still predominant, affording
compound 8 in 42% yield as the major product along with
1
3% of compound 7. Note that CuI itself provided C-2
2
, 3111-3113.
7) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1291-1309.
b) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.; Nolan,
S. P. J. Organomet. Chem. 2002, 653, 69-82.
8) 1,3-Bis-mesitylimidazolium chloride is commercially available from
(
(9) In a typical procedure, anhydrous cobalt(II) acetate and the ligand
(
were stirred at room temperature to form the active catalyst system, prior
to the addition of the other reagents. This sequence of addition of ingredients
proved to be important for the success of the method. For more detailed
experimental procedures, see the Supporting Information.
(10) These prices are quoted from the Aldrich Catalog, Aldrich,
Milwaukee, WI, 2003.
(
Strem. It can also be prepared according to the procedure described in
Arduengo, A. J., III (E. I. Du Pont de Nemours & Company), US 5.077.414
A2, 1992; WO 91/14678.
3608
Org. Lett., Vol. 5, No. 20, 2003

arylation product 7 exclusively, however, in low yield (27%,
entry 6, Table 2). Although the Co(OAc) /IMes system was
more selective, the yield was significantly lower than in the
product, namely compound 11 in 78% yield. While both
palladium and cobalt systems proved highly selective for
imidazole arylation (note that no N-arylation was detected
in either case), the palladium method proved more efficient
for C-4(5) phenylation (Table 3).
2
case of thiazole: C-5 arylation product 6 was obtained in
34% yield together with 6% of isomer 7. Importantly, the
C-2 selective method (Co/Cu/IMes) was quite successful,
furnishing compound 7 exclusively in 73% yield. Currently,
this appears to be the method of choice for the direct C-2
arylation of oxazole. Thus, although the cobalt method was
more selective, further optimization will be required to
improve the yield of these reactions.
Finally, we explored benzothiazole, benzoxazole, and
benzimidazole as substrates for the arylation conditions
described above. We were pleased that the Co/Cu/IMes
system converted benzothiazole 13 and benzoxazole 15 to
the corresponding C-2 arylation products 14 and 16 in 90
and 92% yield, respectively (Scheme 1). Also, selective
11
Subsequently, we posed the question of whether cobalt
salts would be applicable to arylation of azole heterocyclic
compounds containing a free N-H group. Recently, we
developed a palladium-catalyzed method to effect direct
C-arylation of free (NH)-azoles (e.g., pyrrole, indole, pyra-
Scheme 1. Cobalt-Catalyzed Arylation of Benzazoles
3
zole, and imidazole). The use of magnesium oxide (or zinc
oxide) as the base was essential for the success of this
method, and according to our proposal, the formation of
magnesium N-azolyl salts takes place in situ. The salt not
only protects the nitrogen but also promotes the reactivity
of the heteroarene nucleus. In the case of imidazole, C-4(5)
and C-2 arylation was carried out with excellent control of
regioselectivity; namely, the Pd/Ph
3
P/MgO system provided
72% yield of compound 10 as the exclusive product while
the same protocol in the presence of CuI resulted in exclusive
C-2 arylation, furnishing compound 11 in 83% yield (Table
3, entries 3 and 4). Next, we addressed the issue of whether
Table 3. C-Arylation of Imidazole: A Comparison of Cobalt-
and Palladium-Based Methods
C-arylation of benzimidazole 17 was achieved by the
protocol developed for imidazole, furnishing compound 18
as the sole product in 78% yield. In the case of benzothiazole
and benzoxazole, the cobalt and palladium methods gave
practically identical yields while the palladium system was
more efficient in the arylation of benzimidazole (90% vs
7
8%, see the Supporting Information).
Although the mechanism of the cobalt-catalyzed arylation
remains uncertain at this point, we wish to make a few points
in the context of related cobalt-mediated/catalyzed pro-
1
2
cesses. Intramolecular Heck-type coupling of alkyl- and
aryl iodides to alkenes have been promoted by stoichiometric
13
amounts of Co(I) complexes [e.g., Na[Co(SALEN)]]. These
reactions are usually formulated as free-radical reactions, and
there is good evidence to support these claims.14 More
recently, cross-coupling of alkenyl, aryl, and alkyl halides
with alkenes, Grignard compounds, and organozinc com-
the cobalt system would be compatible with the magnesium
azolyl salts. Although the Co(OAc) /IMes pair performed
2
poorly in the presence of MgO (<20%), the use of zinc oxide
led to a major improvement, affording a 41% yield of C-4(5)
arylation product 10. As in the previous cases, the addition
of CuI resulted in the exclusive formation of the C-2 arylation
1
5
pounds have been catalyzed by Co(II) salts. Co(I)/Co(III)
(12) The mechanistic picture for the palladium-catalyzed arylation of
heteroarenes has not been elucidated either. For discussion and references
on this topic, see ref 3.
(
11) The indirect methods require lithiation and transmetalation to zinc
(13) Bhandal, H.; Patel, V. F.; Pattenden, G.; Russell, J. J. J. Chem.
Soc., Perkin Trans. 1 1990, 2691-2701.
(14) Clark, A. J.; Jones, K. Tetrahedron Lett. 1989, 40, 5485-5488.
(
to prevent oxazole ring cleavage) prior to cross-coupling. Anderson, B.
A.; Harn, N. K. Synthesis 1996, 583-585.
Org. Lett., Vol. 5, No. 20, 2003
3609

or Co(0)/Co(II) catalytic cycles are usually invoked wherein
the low-valent cobalt complex serves as an electron donor,
which via single-electron transfer initiates the cleavage of
the carbon-halide bond leading to a carbon-centered radical.
Alternatively, oxidative addition of the organic halide to the
low-valent cobalt may be envisioned, generating a homolysis
prone carbon-cobalt bond. In accepting this view, the
following mechanistic picture may be proposed for the direct
arylation developed herein. Cobalt(II) salts are known to
undergo disproportionation to Co(I) and Co(III) complexes.
The former species may be transformed via oxidative
addition to the aryl-Co(III) complex16 which subsequently
may act as an electrophile or a source of the aryl radical.
The regioselectivity observed herein is not, however, con-
sistent with a radical mechanism as free aryl radicals have
shown preference for the 2-position of thiazole and 1-me-
metalation by an aryl-Co(III) complex, followed by reduc-
tive elimination. Different reactivity characteristics of the
aryl-Co(III) species in comparison to the aryl-Pd(II)
complex may account for higher regioselectivity of the
cobalt-catalyzed arylation of thiazole and oxazole. The high
C-2 selectivity observed in the presence of CuI may be
rationalized by the propensity of Cu(I) salts to metalate acidic
C-H bonds, in this instance, position C-2 of the 1,3-
heteroazoles (followed by Cu-Co transmetalation and
1
9
reductive elimination).
In summary, the use of cobalt acetate represents a
promising advance worthy of further exploration in the
context of direct C-H bond arylation methods and possibly
other C-C bond-forming reactions. Although the present
study revealed clear parallels with established palladium
catalysis, significant differences with respect to the chemical
efficiency and degree of regioselectivity in C-H arylation
reactions were observed. For example, in the case of thiazole,
cobalt was clearly superior to the palladium system both in
terms of yields and selectivity. Similarly, in the arylation of
oxazole, the cobalt catalytic system proved more selective,
although further optimization will be required to improve
the yields of this process. Finally, although the cobalt-
catalyzed arylation of imidazole and benzimidazole was
highly selective, in this instance chemical yields were lower
in comparison to the palladium system. Studies aimed at
elucidation of the mechanism and scope of these reactions
are currently underway in our laboratories.
1
7
thylimidazole. It may be argued that the presence of metal
salts may strongly affect the regiochemical outcome. How-
ever, under acidic conditions, the C-2 preference of aryl
radicals was even more pronounced; the same trend may be
18
expected in the presence of Lewis acidic metal salts. Thus,
based on the observed regiochemistry, we propose that the
heteroarene ring undergoes base promoted electrophilic
(
15) (a) Iyer, S. J. Organomet. Chem. 1995, 490, C27-C28. (b) Cahiez,
G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159-6162. (c) Avedissian,
H.; B e´ rillon, L.; Cahiez, G.; Knochel, P. Tetrahedron Lett. 1998, 39, 6163-
6
166. (d) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2
001, 123, 5374-5375. (e) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2002, 41, 4137-4139. Kneisel, F. F.; Monguchi, Y.; Knapp,
K. M.; Zipse, H.; Knochel, P. Tetrahedron Lett. 2002, 43, 4875-4879.
(16) Ph-Co(III) complexes have been prepared via this route. Lampeka,
Acknowledgment. Generous support for this work was
provided by the National Institutes of Health (NIGMS),
GlaxoSmithKline, Johnson & Johnson Pharmaceutical R &
D, and Merck. D.S. is a recipient of the Alfred P. Sloan
Fellowship and the Camille Dreyfus Teacher-Scholar
Award. We thank Dr. J. B. Schwarz for editorial assistance.
J. D.; J a¨ ger, E.-G.; M u¨ ller, K.; Schade, W. Z. Chem. 1988, 28, 70.
17) (a) Metzger, J. V. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Pergamon: New York, 1984; Vol. 6, pp 263-266.
b) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Pergamon: New York, 1984; Vol. 5, pp 418-419.
18) The effect of cobalt on the regiochemical course of intramolecular
(
(
(
coupling between an aryl bromide and the pyridine ring has been observed.
Harrowven, D. C.; Nunn, M. I. T.; Blumire, N. J.; Fenwick, D. R.
Tetrahedron Lett. 2000, 41, 6681-6683.
Supporting Information Available: Experimental details
and compound spectral characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) A metal-carbene intermediate should also be considered. For
interesting reading on related topics, see: (a) Tan, K. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 3202-3203. (b) Gr u¨ ndemann,
S.; Kovacevic, A.; Albrecht, M.; Faller, J. W.; Crabtree, R. H. J. Am. Chem.
Soc. 2002, 124, 10473-10481.
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Org. Lett., Vol. 5, No. 20, 2003