Pd(ii)-catalyzed direct C5-arylation of azole-4-carboxylates through double C-H bond cleavage

Article abstract of DOI:10.1039/c2cc00081d

The first palladium-catalyzed direct C5-arylation of azole-4-carboxylates with simple unactivated arenes through double C-H bond cleavage is realized. This protocol provided a straightforward access to diverse 5-arylsubstituted azole-4-carboxylic derivatives with good functional group tolerance. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc00081d

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COMMUNICATION
Pd(II)-catalyzed direct C5-arylation of azole-4-carboxylates through
double C–H bond cleavagew
Ziyuan Li, Ling Ma, Jinyi Xu, Lingyi Kong, Xiaoming Wu and Hequan Yao*
Received 5th January 2012, Accepted 20th February 2012
DOI: 10.1039/c2cc00081d
The first palladium-catalyzed direct C5-arylation of azole-4-
carboxylates with simple unactivated arenes through double C–H
bond cleavage is realized. This protocol provided a straightforward
access to diverse 5-arylsubstituted azole-4-carboxylic derivatives
with good functional group tolerance.
interest in the direct cross-coupling of azole-4-carboxylic
derivatives at the 5-position, we observed that direct
C5-arylation of methyl 2-benzylthiazole-4-carboxylate with
p-xylene in DMF/DMSO with Pd(OAc)2 could take place,
albeit in fairly low yield.18 In order to pursue a general
procedure, we focused our interest on the direct C5 arylation
of azole-4-carboxylates with simple unactivated arenes. We
herein report our results.
Azole moieties, such as thiazole and oxazole, are prevalent scaffolds
found in a variety of natural products and pharmacophores, many
of which possess interesting bioactivities.1 For example, 5-arylated
thiazole-4-carboxylic derivatives serve as good orexin receptor
blockers for treating obesity2 and 5-arylated oxazole-4-carboxylic
derivatives are potent Cdc25 phosphatase antagonists as anticancer
agents.3
Our initial investigation focused on the coupling of methyl
2-phenylthiazole-4-carboxylate (1a) with benzene as summarized
in Table 1. Preliminary attempts using Pd(OAc)2 as a catalyst
and AgOAc as an oxidant in benzene at 80 1C led to the
formation of the desired C5-arylated product 2a in 44% yield,
along with the homocoupled product 3a in 38% yield (entry 1).
To date, lots of efforts have been spent on developing
practical methods for the transition-metal-catalyzed arylation
of azoles at C2,4 C45 and C5 positions.6–15 Conventional C5
arylation of azoles relies on the use of stoichiometric organo-
metallic compounds, such as ArSnR3 and ArB(OH)2, as
nucleophilic components.6,7 Recently, several groups8–14 have
independently reported pioneering palladium-catalyzed cross-
coupling reactions to synthesize various 5-arylated azoles between
aryl halides or arene tosylates/mesylates15 and 5-unsubstituted
azoles through single C–H bond cleavage. Although most of the
above approaches could generate 5-arylated azoles in good yields,
they required prefunctionalization of one or both of the coupling
components. In the past several decades, transition-metal-catalyzed
arylation of azoles has been extensively explored, however, to
the best of our knowledge direct C5 arylation of azoles or
azole-4-carboxylates with unactivated arenes through double
C–H bond cleavage has never been reported so far. Over the
past few years, significant breakthrough has been made in
palladium(II)-catalyzed oxidative cross-couplings of unpreactivated
heteroaryls and unactivated arenes through double C–H
cleavage.16,17 These methodologies represent an ideal strategy for
the synthesis of biaryl compounds since they could avoid the need
for preactivation of any coupling partner. During our continuing
Table 1 Optimization of reaction conditionsa
Oxidant
(2 quiv.)
Additive
(equiv.)
Yieldb (%)
(2a/3a/1a)
Entry
Catalyst
1c
2d
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2(CH3CN)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
Ag2O
p-BQ
Cu(OAc)2
IOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
44/38/trace
59/27/trace
21/67/0
62/25/0
46/39/7
Trace/92/0
0/26/68
6/42/44
0/trace/56
36/40/15
54/16/12
69/11/5
0/82/5
0/84/9
0/35/53
38/19/33
31/27/32
66/18/6
77/15/5
79/13/6
77/16/0
—
DMSOe
—
—
—
—
—
—
—
—
—
K2CO3 (1)
Cs2CO3 (1)
KOAc (2)
TFA (1)
TsOH (1)
AcOH (1)
PivOH (1)
PivOH (2)
PivOH (2)
State Key Laboratory of Natural Medicines and Department of
Medicinal Chemistry, China Pharmaceutical University, Nanjing,
210009, P. R. China. E-mail: hyao@cpu.edu.cn;
a
Reaction conditions: methyl 2-phenylthiazole-4-carboxylate 1a
(0.5 mmol), Pd catalyst (0.05 mmol), oxidant (1 mmol) and additive in
Fax: +86 25-83301606; Tel: +86 25-83271042
b
c
d
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all title compounds. See DOI:
10.1039/c2cc00081d
benzene (1.5 mL) at 120 1C for 12 h. Isolated yields. 80 1C. 100 1C.
DMSO (0.15 mL).
e
c
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Chem. Commun., 2012, 48, 3763–3765 3763

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In the subsequent screening of reaction temperature, we found
that the yield of 2a was raised to 62% when the temperature
was increased to 120 1C (entries 2–4). Very interestingly, most
of 1a was converted to 3a when DMSO (10%, v/v) was used as
co-solvent (entry 3), resulting in low yield of 2a. Following the
above results, we then performed the systematic screening on
oxidants, catalysts, and additives. Oxidant screening showed
that Ag2CO3 was less effective, whereas the use of Ag2O or
cheaper oxidants, such as p-BQ, Cu(OAc)2 or IOAc, was
entirely unsuccessful (entries 5–9). Catalyst screening revealed
that PdCl2 could give a similar result, while Pd(CH3CN)2Cl2 or
Pd(TFA)2 was less effective (entries 10–12). Further screening
using bases or acids as an additive (entry 13–21) indicated that
PivOH (2 equiv.) exhibited good performance in reactivity.19
Finally, we found that the combination of Pd(OAc)2 and
PivOH was the best system for fully consuming 1a (entry 21),
facilitating the purification of 2a by flash chromatography.20
With the optimized conditions established, we first explored
the effect of substituents at the C2 position on azoles (Table 2).21,22
We were pleased to find that a range of substituents were
tolerated under these conditions. For 2-phenyl-substituted
thiazole substrates with electron-donating substitution on
the phenyl ring, the reactions gave the desired products in
moderate yields (2b, 2c). On the other hand, the substrates
with electron-withdrawing or halogen (F, Cl) substitutions on
the phenyl ring could generate 5-arylated products in good
yields (2d–2i). It is noteworthy that a 4-bromo-substituted
substrate could also smoothly react with benzene to give the
corresponding product 2h in 64% yield when DMSO was used
as an additive.23 The tolerance of chloro and bromo substituents
might provide an opportunity for further synthetic functionaliza-
tion. In addition, 2-alkyl- or 2-carbonyl-substituted substrates
could be arylated to achieve the desired cross-coupling products
in moderate yields (2j, 2k). Similarly to the thiazoles, all oxazole
substrates could be smoothly converted to the corresponding
products in good yields under the optimized conditions (2l–2q).
Next, the effective conditions were extended to a variety of
unactivated arenes as illustrated in Table 3. Generally, the
coupling preferentially occurred at the less sterically hindered
position on arenes. For instance, when azoles coupled with
toluene, it provided a mixture of 1,4- and 1,3-substituted products
in moderate yields, and no 1,2-product was acquired (4a, 4b). The
good yields could be maintained when 1,2-disubstituted
benzenes were used as an arene to couple with azoles (4c–4h).
Most of these reactions furnished the 1,2,4-substituted product,
along with no or a small amount of the 1,2,3-substituted isomer.
With regard to more sterically hindered 1,3-disubstituted
benzenes, the yields of the desired products slightly dropped
and the 1,3,5-substituted product was found to be a major
product (4i, 4j). In contrast, the use of 1,4-disubstituted
benzene as a simple arene for these arylations led to fairly
poor yields of the desired arylated products (4k,4l) under the
optimized conditions. To our delight, the coupling yields for
p-xylene could be remarkably improved by substituting
DMSO for PivOH as an additive (4k, 4l) although the role
of DMSO was not clear.23 It should also be noted that
electron-deficient benzene (nitrobenzene) could also couple
Table 3 Scope of unactivated arenesa,b
Table 2 Scope of azole-4-carboxylatesa,b
a
a
Reaction conditions: azole-4-carboxylate (0.5 mmol), Pd(OAc)2
(0.05 mmol, 10 mol%), oxidant (1 mmol) and PivOH (1 mmol) in
Reaction conditions: azole-4-carboxylate (0.5 mmol), Pd(OAc)2
(0.05 mmol), oxidant (1 mmol) and PivOH (1 mmol) in arene
b
c
b
c
benzene (1.5 mL) at 120 1C for 12 h. Isolated yield. DMSO
(0.15 mL) was used instead of PivOH at 100 1C for 12 h.
(1.5 mL) at 120 1C for 12 h. Isolated yield. Determined by HPLC.
DMSO (0.15 mL) was used instead of PivOH.
d
c
3764 Chem. Commun., 2012, 48, 3763–3765
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with azoles to furnish 1,3-substituted products in acceptable
yields (4m–4o).
6 For excellent reviews, see: (a) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174; (b) J. Roger,
A. I. Gottumukkala and H. Doucet, ChemCatChem, 2010, 2, 20.
7 For recent examples, see: (a) B. Liegault, I. Petrov, S. I. Gorelsky
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and K. Fagnou, J. Org. Chem., 2010, 75, 1047; (b) K. J. Hodgetts
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T. Okazawa, T. Satoh, M. Miura and M. Nomura, Tetrahedron,
2003, 59, 5685.
To gain mechanistic insight of this process, we performed
kinetic isotope effect studies (Scheme S2, ESIw).24 By comparing
the initial rates of benzene to those of benzene-d6, the kH/kD
1
values (by H NMR) were determined to be 2.39 and 3.01 for
thiazole and oxazole, respectively. The kH/kD values
1
(by H NMR) of H/D-azoles were determined to be 1.07 and
9 Y. Kondo, T. Komine and T. Sakamoto, Org. Lett., 2000,
2, 3111.
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16 For selected examples, see: (a) K. L. Hull and M. S. Sanford,
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Z. Fang and Z.-J. Shi, Angew. Chem., Int. Ed., 2008, 47, 1115;
1.16 for thiazole and oxazole, respectively. The results suggest
that the second C–H bond cleavage could be a rate-limiting step
of the reaction. Thus, a plausible mechanism for the direct
arylation of azoles is set out in Scheme S2 (ESIw).24 This process
is initiated by palladation of the azole at C5 to give palladium
intermediate A. In the presence of an unactivated arene, the
C5-palladated species A inserts slowly into the arene, and
reductive elimination produces the arylated product, along with
Pd(0) which is reoxidized by Ag(I) to complete the catalytic cycle.
In summary, we have developed the first Pd(II)-catalyzed
direct C5-arylation of azole-4-carboxylates through double
C–H bond cleavage with good functional group tolerance.
This protocol provides a new avenue for synthesizing various
5-arylated azoles (Scheme S3, ESIw),25 which could serve as
useful building blocks for the synthesis of bioactive molecules.
Preliminary studies of the reaction mechanism were also
investigated. Detailed investigation on the reaction mechanism
and application of this methodology to the synthesis of
complex molecules are undertaken in our laboratory.
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´
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This research was supported by State Key Laboratory of
Natural Medicines (JKGZ201110), NSFC-20902111, IRT1193
and Fundamental Research Funds for the Central Universities
(2011BPY001 and JKY2011028 for ZL, JKZ2009002 for HY).
We thank Haipin Zhou in this group for reproducing the
results of 2i, 2l in Table 2, and 4d, 4g in Table 3.
17 For excellent reviews on palladium-catalyzed aryl–aryl bond
formation through double C–H activation, see: (a) C. S. Yeung
and V. M. Dong, Chem. Rev., 2011, 111, 1215; (b) S. L. You and
J. B. Xia, Top. Curr. Chem., 2010, 292, 165; (c) J. A. Ashenhurst,
Chem. Soc. Rev., 2010, 39, 540; (d) G. P. McGlacken and
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J. Xu, X. Wu and H. Yao, Tetrahedron, 2011, 67, 5550.
19 The addition of PivOH into the reaction system produced
Pd(OPiv)2, which was proposed to enable efficient C–H palladation.
See recent reviews: (a) L. Ackermann, Chem. Rev., 2011, 111, 1315;
(b) D. Lapointe and K. Fagnou, Chem. Lett., 2010, 1118.
20 See ESIw for detailed optimization.
21 For the synthesis of azole-4-carboxylic derivatives, see (a) Y. Huang,
H. Gan, S. Li, J. Xu, X. Wu and H. Yao, Tetrahedron Lett., 2010,
51, 1751; (b) Y. Huang, L. Ni, H. Gan, Y. He, J. Xu, X. Wu and
H. Yao, Tetrahedron, 2011, 67, 2066; (c) Y. Wang, Z. Li,
Y. Huang, C. Tang, X. Wu, J. Xu and H. Yao, Tetrahedron,
2011, 67, 7406.
22 The arylation of 4-alkyl or 4-hydrogen substituted azoles under
the optimized conditions was proved to be inefficient, resulting
in the formation of the corresponding homocoupling product in
high yield.
Notes and references
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23 See ESIw for details.
24 See ESIw for mechanism studies.
25 Facile derivation of 5-arylated azole-4-carboxylates demonstrated
that our protocol was capable of being applied to the synthesis of
diverse 5-arylated azole-based molecules. See ESIw for details.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3763–3765 3765