C2, C5, and C4 azole N-oxide direct arylation including room-temperature reactions

Article abstract of DOI:10.1021/ja7107068

The N-oxide group imparts a dramatic increase in reactivity at all positions of the azole ring of thiazoles and imidazoles and changes the weak bias for C5 > C2 arylation to a reliable C2 > C5 > C4 reactivity profile. Use of this cross-coupling strategy enables high yielding and room-temperature C2 arylations, mild reactions at C5, and the first examples of C4 arylation-providing a unique opportunity for exhaustive functionalization of the azole core with complete control of regioselectivity. A correlation of reactivity with the relative contributions of each carbon atom to the HOMO is observed and discussed. Copyright

Full text of DOI:10.1021/ja7107068

Published on Web 02/27/2008
C2, C5, and C4 Azole N-Oxide Direct Arylation Including Room-Temperature
Reactions
Louis-Charles Campeau, Me´gan Bertrand-Laperle, Jean-Philippe Leclerc, Elisia Villemure,
Serge Gorelsky, and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received November 29, 2007; E-mail: keith.fagnou@uottawa.ca
Scheme 1. Stepwise C2-C5-C4 Thiazole Arylationa
Because of their importance in medicinal chemistry and in
materials science1 methods for the derivatization of heterocyclic
aromatics such as palladium-catalyzed cross-coupling reactions find
broad academic and industrial use.2,3 Recently, processes capable
of forming similar products while avoiding the use of stoichiometric
organometallic reagents, such as direct arylation, are emerging as
attractive alternatives.4
An underlying challenge associated with direct arylation is that,
in the absence of preactivating groups, the reactivity is governed
by the inherent properties of the heterocycle itself. In nonideal cases,
this can complicate regioselectivity and/or necessitate the use of
very forcing reaction conditions. Methods to manipulate the
reactivity of heterocyclic substrates are thus invaluable, especially
if new or improved reactivity/regiocontrol can be achieved. Azole
direct arylation reactions, which are believed to be facilitated by
azole π-nucleophilicity at C5 and C-H acidity at C2, are illustrative.
a Conditions: Step A: ArI, thiazole N-oxide (1.1 equiv), Pd(OAc)2 (5
In most cases, arylation at C5 is preferred,5 although the formation
mol %), ligand 1 (10 mol %), Cs2CO3 (1.5 equiv), PivOH (20 mol %),
CuBr (10 mol %), PhMe (0.2 M), 25 °C; Step B: ArBr, thiazole N-oxide
of C5/C2 double arylation side products is commonplace.6 C2
arylation has been achieved through the use of copper additives
with palladium catalysis,7 but a broadly applicable process remains
to be identified. Typically, very high reaction temperatures are
required, and a high yielding C4 arylation has not been described.
We have been investigating the use of azine and diazine N-oxide
substrates as alternatives to problematic organometallic reagents
in biaryl synthesis.8 These substrates have proven useful in other
nickel9 and copper10 catalyzed processes as well. Herein, we
demonstrate that the N-oxide group not only imparts a dramatic
increase in reactivity in direct arylation at all positions of the azole
ring but also changes the weak azole bias for C5 > C2 arylation to
a reliable C2 > C5 > C4 reactivity profile (Scheme 1). This permits
high yielding, regioselective, and room temperature arylation at C2,
high yielding arylation at C5, and the first examples of arylation at
C4sproviding a unique opportunity for exhaustive functionalization
of the azole core. A correlation of reactivity with relative HOMO
populations at the different carbon atoms is observed and discussed
(Scheme 2).
The thiazole N-oxides were easily prepared by treatment with
mCPBA or with H2O2 in the presence of catalytic MeReO3.11
Preliminary investigations on the direct arylation of thiazole N-oxide
revealed a strong bias for reaction at C2. Further optimizations lead
to the establishment of high yielding C2 direct arylations under
very mild conditions (Scheme 3). For example, treatment of an
aryl halide with 1.1 equiv of a thiazole N-oxide in the presence
of Pd(OAc)2 (5 mol %), 2-(diphenylphosphino-2′-(N,N-dimethyl-
amino)biphenyl 1 (10 mol %), acid12 (20 mol %), and K2CO3 (1.5
equiv) in toluene at 25 °C results in C2 arylation as the exclusive
product (Schemes 1 and 3).13 These are rare examples of direct
arylation occurring under such mild conditions.14 If the C2 position
is blocked, the thiazole N-oxide can then undergo a highly selective
(1.5 equiv), Pd(OAc)2 (5 mol %), tBu3PHBF4 (5 mol %), K2CO3 (1.5 equiv),
PhMe (0.2 M), 70 °C; Step C: ArBr, thiazole N-oxide (1.1 equiv), Pd(OAc)2
(5 mol %), PPh3 (15 mol %), K2CO3 (2 equiv), PhMe, (0.2 M), 110 °C;
Deoxygenation: thiazole N-oxide, zinc powder, NH4Cl(aq), THF. Reported
yields are isolated.
Scheme 2. HOMO for Thiazole and Thiazole N-Oxide Substratesa
a Numbers represent % atomic contributions to the HOMO. C-H bonds
are drawn at the site of direct arylation.
t
C5 arylation when reacted with Pd(OAc)2 (5 mol %), Bu3PHBF4
(5 mol %), and K2CO3 (1.5 equiv) in toluene at 70 °C. Interestingly,
the addition of pivalic acid to C5 arylation reactions reduces the
C5:C4 selectivity compared to a reaction performed in its absence.
We were also pleased to find that the N-oxide moiety will also
enable C4 arylation, the first time that such reactivity has been
obtained. Optimal conditions for C4 arylation were determined to
involve the use of Pd(OAc)2 (5 mol %) in the presence of PPh3
(15 mol %) and 2 equiv of K2CO3 in toluene at 110 °C. The breadth
of products that are readily accessible are illustrated in Scheme 3.
This chemistry has also been validated in a stepwise, exhaustive
arylation of the thiazole core which is highly divergent and may
find application in a diversity oriented evaluation of the biological
and physical properties of these types of molecule (Scheme 1). An
initial evaluation with imidazole N-oxides has also been performed
9
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J. AM. CHEM. SOC. 2008, 130, 3276-3277
10.1021/ja7107068 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Direct Arylation of Thiazole N-Oxidesa
2).15 Since π-nucleophilicity may contribute to reactivity and site
selectivity, the relative contribution of each carbon atom to the
HOMO is informative. The nearly equal distribution at all three
carbons of thiazole (25.2, 29.9, 30.5%) correlates well with the
challenges associated with C5/C2 regioselectivity for that substrate.
In stark contrast, the HOMO of thiazole N-oxide is localized at C2
and has very small density at C4 and C5 (∼3% contribution at
each). This maps well onto the high C2 selectivity and the mild
reaction conditions. Furthermore, the larger density at C5 of
2-phenylthiazole N-oxide corresponds well to the subsequent
preference for reaction at C5. This reactivity should have a broader
impact not only in direct arylation but also in the growing number
of metal-catalyzed heterocycle transformations that could make use
of the N-oxide activation strategy in the rapid functionalization of
these substrates.
Acknowledgment. NSERC, the University of Ottawa, the
Research Corporation, Boehringer Ingelheim (Laval), Merck Frosst
Canada, Merck Inc., and Astra Zeneca Montreal are thanked for
their financial support of this work.
Supporting Information Available: Experimental procedures,
spectroscopic characterization of all new products, and computational
details. This material is available free of charge via the Internet at http://
pubs.acs.org.
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