Palladium-catalyzed direct arylation of heteroarenes with aryl mesylates

Article abstract of DOI:10.1002/chem.201002354

Not so challenging after all! The first general examples of the direct arylation of heteroarenes by using challenging aryl mesylates as electrophiles are disclosed. These easy reaction conditions also allow the functionalization of other heterocycles, such as caffeine, triazole and benzathiazole (see scheme). Copyright

Full text of DOI:10.1002/chem.201002354

COMMUNICATION
DOI: 10.1002/chem.201002354
Palladium-Catalyzed Direct Arylation of Heteroarenes with Aryl Mesylates
Chau Ming So, Chak Po Lau, and Fuk Yee Kwong*[a]
Dedicated to Professor Albert S. C. Chan on the occasion of his 60th birthday
The palladium-catalyzed cross-coupling repertoire has
been successful in modular organic synthesis for connecting
two different fragments together through the formation of
carbon–carbon and/or carbon–heteroatom bonds.[1] To con-
struct useful biaryl motifs,[2] coupling methods such as
Kumada coupling, Negishi coupling, Stille coupling, and
Suzuki–Miyaura coupling have been found to be versatile in
recent decades.[1] Although these reactions are effective,
possible drawbacks still exist in that corresponding organo-
metallic nucleophiles need to be prepared in situ (e.g., Ar–
MgCl, Ar–ZnCl) or require isolation prior to the catalysis
(e.g., Ar–B(OH)2). Indeed, the assembly and subsequent
disposal of stoichiometric organometallic agents are undesir-
different or unique substituted groups in the aromatic ring,
in which the corresponding aryl halides are not commonly
available or require additional synthetic steps to manipulate
the pattern of complementary substitution. Although it pos-
sesses unique scope, the direct arylation of heteroaromatics
with aryl sulfonates has attracted less attention. In most
cases, only expensive aryl triflates were used as electro-
philes.[9,10] Indeed, aryl tosylates or mesylates are excellent
substitution for the corresponding aryl triflates as electro-
philes in cross-coupling reactions. Although they have sever-
al beneficial features, their superior stability reflects their in-
ferior reactivity in palladium-catalysed coupling process-
es.[11,12] Consequently, the general palladium-catalysed cross-
coupling reactions of aryl tosylates[13] and mesylates[14] with
organometallic nucleophiles were only developed very re-
cently. In 2009, Ackermann et al. reported the first palladi-
um-catalyzed direct arylation of heteroarenes with aryl tosyl-
À
able. Recently, C H activation and direct arylation of
hetero
N
new methodologies serve as attractive alternatives to con-
ventional coupling protocols in terms of better atom econo-
my, environmental friendliness and streamlined chemical
synthesis.[3,4]
AHCTUNGTREGaNNNU tes and two examples of activated aryl mesylates that em-
ployed Buchwaldꢀs biaryl-type X-Phos/Pd system[15] in the
present of sub-stoichiometric amounts of tBuCO2H addi-
tive.[16] In fact, the use of aryl mesylates in the coupling reac-
tions is more atom economical than the corresponding aryl
tosylates due to their significantly lower molecular weight.
Nevertheless, there has been a long-standing problem for
Reports by Fagnou et al., Itami et al., Lautens et al.,
Miura et al., Sames et al., Sanford et al. and others on the
arylation of heteroarenes were achieved by using aryl io-
dides and bromides.[5] In fact, direct arylation by using non-
activated aryl chlorides remains less explored.[5r,6] Stoichio-
metric amounts of copper salt additives are necessary to fa-
cilitate some heterocycle arylations.[7] Recently, Daugulis
et al. reported a general protocol for the direct arylation of
heteroarenes with ArCl by using a Pd/nBuP(Ad)2 catalytic
system at 1258C.[8] Apart from aryl halides, it is worth devel-
oping methods for phenolic compounds (pseudo-halides) to
serve as electrophiles. In fact, these compounds usually offer
À
applying aryl mesylates in C H bond functionalisation be-
cause they are even more inactive than aryl tosylates in pal-
À
ladium catalysis. This is because the inherent CAr OSO2Me
bond strength in aryl mesylate is stronger than that of the
corresponding aryl tosylate.[17] Excluding the difficulties of
activating the aryl mesylates, we believe that direct arylation
by using aryl mesylates is highly favourable, especially given
that the reaction conditions do not require extra additives.
Herein, we uncover our efforts to establish a general and
additive-free palladium-catalyzed direct arylation of benzox-
azole and their derivatives with aryl mesylates.
[a] Dr. C. M. So, Prof. Dr. C. P. Lau, Prof. Dr. F. Y. Kwong
State Key Laboratory of Chirosciences and
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
To probe the feasibility of direct arylation of heteroarenes
with aryl mesylates, a series of initial screenings were car-
ried out (Table 1). Benzoxazole and electronically neutral
phenyl mesylate were used as model substrates, and 5 mol%
Hung Hom, Kowloon, Hong Kong (Hong Kong)
Fax : (+852)-2364-9932
E-mail: bcfyk@inet.polyu.edu.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002354.
of PdACTHNUTRGNE(NUG OAc)2 with CM-phos ligand was used as the initial
Chem. Eur. J. 2011, 17, 761 – 765
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761

Table 1. Initial screening of direct arylation with non-activated ArOMs.[a]
tained (Table 1, entry 9). The Pd/XPhos system gave a poor
yield in the direct arylation with aryl mesylate (Table 1,
entry 10). Bellerꢀs ligands CataCXiumꢂ A[18] and Cata-
CXiumꢂ PInCy[19] and our previously reported amino-phos-
phine L1[20] were inferior (Table 1, entries 11–13). Control
experiment revealed that no reactions were observed either
in the absence of palladium salt or without the supporting
phosphine ligand (Table 1, entries 14, 15).
Entry Solvent
Ligand
Base
Yield[b] [%]
To test the effectiveness of the Pd/CM-phos catalytic
system, the direct arylation of benzoxazole with a range of
aryl mesylates was examined by using the preliminary opti-
mized reaction conditions (Table 2). Electronically neutral
aryl mesylates were effective substrates for the direct aryla-
tion of benzoxazole and gave the corresponding products in
good to excellent yields (Table 2, entries 1–4). It is worth
1
tBuOH
K2CO3
53
2
3
4
5
6
7
8
9
DMF
THF
toluene
CM-phos
CM-phos
CM-phos
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
45
3
2
11
86
13
tBuOH/dioxane (1:2) CM-phos
tBuOH/DMF (1:2)
tBuOH/DMF (1:2)
tBuOH/DMF (1:2)
tBuOH/DMF (1:2)
CM-phos
CM-phos
CM-phos
CM-phos
Na2CO3 24
K3PO4
Table 2. Direct arylation of benzoxazole with aryl mesylates.[a]
3
10
tBuOH/DMF (1:2)
K2CO3
25
Entry Heteroarene ArOMs
Product
Yield[b]
[%]
1
2
86
83
11
12
tBuOH/DMF (1:2)
tBuOH/DMF (1:2)
0
2
K2CO3
K2CO3
3
92
4
5
81
46
13
tBuOH/DMF (1:2)
2
14[c]
15
tBuOH/DMF (1:2)
tBuOH/DMF (1:2)
CM-phos
–
K2CO3
K2CO3
0
0
6
82
51
[a] Reaction conditions: benzoxazole (0.5 mmol), ArOMs (1.0 mmol),
7[c]
base (2.0 mmol), Pd
3.0 mL), at 1108C under N2 for 20 h. [b] Isolated yields. [c] Performed in
the absence of Pd(OAc)2 salt.
ACHTUNGTRENNUNG(OAc)2 (5 mol%), Pd/L=1:4, solvent (total volume=
ACHTUNGTRENNUNG
8
9
41
69
catalytic system for our prototypical investigations. Of the
commonly used organic solvents examined, tBuOH and
DMF gave moderate yields whereas THF and toluene pro-
vided only poor conversions (Table 1, entries 1–4). Gratify-
ingly, tBuOH/DMF solvent mixtures afforded the best yield
for the direct arylation (Table 1, entry 6). Of the commonly
used inorganic bases, K2CO3 was found to be the most suita-
ble base for the direct arylation reaction (Table 1, entry 6).
Na2CO3 and KOAc were found to be inferior in the reaction
(Table 1, entries 7, 8). If K3PO4 was used in this reaction,
phenolic side products (from the hydrolysis of sulfonate)
10
11
82
82
[a] Reaction conditions: benzoxazole (0.5 mmol), ArOMs (1.0 mmol),
K2CO3 (2.0 mmol), Pd(OAc)2 (5 mol%), Pd/CM-phos=1:4, tBuOH
(1.0 mL)/DMF (2.0 mL), at 1108C under N2 for 24 h (reaction times were
AHCTUNGTRENNUNG
were observed and only poor product yield could be ob- not optimized for each substrate). [b] Isolated yields. [c] 1008C under N2.
762
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Chem. Eur. J. 2011, 17, 761 – 765

Palladium-Catalyzed Direct Arylation
COMMUNICATION
noting that the use of common additives for the C H activa-
tion reaction, such as copper salts and organic acids, to im-
prove the product yield are not necessary in our catalytic
system. m-Methoxyphenyl mesylate was also an effective
substrate for the direct arylation of benzoxazole, whereas
the more electron-rich p-methoxyphenyl mesylate was con-
verted to the desired product in moderate yield (Table 2, en-
tries 5, 6). Thus, deactivated aryl mesylates are more de-
manding substrates for this direct arylation reaction.[21]
Functionalized aryl mesylates and heteroaryl mesylates,
such as quinolyl mesylate, were smoothly transformed into
their desired products (Table 2, entries 7–9).[22] Furthermore,
substituted benzoxazoles were converted to the products in
good yields (Table 2, entries 10, 11).
agents,[27] and 1,2,3-triazole moieties are emerging as highly
À
useful and powerful pharmacophores.[28]
With an effective catalytic system in hand, we attempted
to explore the scope of the direct arylation reaction for
these important heteroarenes with neutral aryl mesylates.
Caffeine, 1-(4-methoxyphenyl)-1,2,3-triazole and benzothia-
zole were used as model substrates to represent each set of
heteroarenes for direct arylation with 3,5-dimethylphenyl
mesylate (Scheme 3). Caffeine, 1-(4-methoxyphenyl)-1,2,3-
The selective stepwise arylation at the C2 and C5 posi-
tions of the benzoxazoles with different aryl rings can be ap-
plied to synthesize a series of important biological active
compounds.[23] To demonstrate a possible pathway to synthe-
sise these compounds, stepwise regioselective arylation of 5-
chlorobenzoxazole has been attempted by using Pd/CM-
phos-catalyzed Suzuki coupling at C5 of 5-chlorobenzoxa-
zole with arylboronic acids followed by regioselective C2
direct arylation of the benzoxazole derivative with aryl me-
sylates (Scheme 1). 5-Chlorobenzoxazole was selectively
coupled with arylboronic acids at the C5 chloro-position.
The Suzuki-coupled products then underwent selective
direct arylation with phenyl or 3,5-dimethylphenyl mesylates
at the C2 position in good yields (Scheme 2).
Scheme 3. Direct arylation of various heteroarenes with electronically
neutral aryl mesylates.
triazole, and benzothiazole were effectively functionalized
to give moderate to good yields. In particular, the direct ary-
lation of 1-(4-methoxyphenyl)-1,2,3-triazole with 3,5-dimeth-
AHCTUNGTREGyNNUN lphenyl mesylate occured in a highly regioselective manner
and thus only the 5-substituted product was obtained.
In summary, we have uncovered an effective system that
enables the first general palladium-catalyzed direct arylation
of heteroarenes with aryl mesylates. Particularly worth
noting is that the palladium catalyst with CM-phos can
smoothly catalyse the direct arylation reaction without the
addition of supplementary acid or copper salt additives. Be-
cause the substitution patterns between the phenolic com-
pounds and aryl halides are usually different, this protocol
potentially offers facile access to a variety of arylated heter-
oarenes that are not easily accessible from aryl halides. The
viability of using challenging aryl mesylates in this direct ar-
ylation could potentially open up a versatile foundation for
Scheme 1. Stepwise arylation of 5-chlorobenzoxazole.
Apart from benzoxazoles, benzothiazoles, 1,2,3-triazoles
and xanthines (e.g., caffeine, theophyline and theobromine)
are all possess a series of biological properties.[24] For exam-
ple, heteroaryl-substituted xanthines are highly potent and
selective antagonists for human A2B adenosine receptors[25]
and highly effective luminescence/fluorescent frameworks
for cancer imaging.[26] Additionally, benzothiazoles are
widely used as Ca2+ channel antagonists and antitumor
À
future frontier C H functionalization/arylation explorations
with relevant difficult sulfonate electrophiles.
Acknowledgements
We thank the Research Grants Council of Hong Kong (project no.
CERG: PolyU5008/07P) for financial support, and are grateful to PolyU
funding (SEG 01 PolyU) for NMR instrumental support.
À
Keywords: aryl mesylates
arylation · heterocycles · palladium
·
C H activation
·
direct
763
Scheme 2. Suzuki coupling and direct arylation of benzoxazole (yields in
scheme represent the direct arylation step).
Chem. Eur. J. 2011, 17, 761 – 765
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www.chemeurj.org

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Chem. Eur. J. 2011, 17, 761 – 765

Palladium-Catalyzed Direct Arylation
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Received: August 16, 2010
Published online: December 16, 2010
Chem. Eur. J. 2011, 17, 761 – 765
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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