Palladium-catalyzed dehydrogenative cross-couplings of benzazoles with azoles

Article abstract of DOI:10.1002/anie.201006208

Different enough: Palladium-catalyzed cross-couplings of benzazoles with imidazoles, oxazoles, and thiazoles furnish unsymmetrical 2,2′- bisheteroaryls in high yield (see scheme). These oxidative Ci-C bond formations use the selective cleavage of the Ci-H bond at C2 in the two coupling partners and are robust enough to be conducted under normal air atmosphere.

Full text of DOI:10.1002/anie.201006208

Communications
DOI: 10.1002/anie.201006208
À
C H Functionalization
Palladium-Catalyzed Dehydrogenative Cross-Couplings of Benzazoles
with Azoles**
Wei Han, Peter Mayer, and Armin R. Ofial*
Biaryl compounds play an important role in nature and many
functional materials.[1] Classical transition-metal-catalyzed
methods for the synthesis of biaryls, such as Kumada, Negishi,
Stille, Suzuki, and Hiyama–Denmark reactions, require
functionalized arenes for the selective linkage of two arenes
[2]
À
through a C C bond. Recently, catalytic direct arylations
have emerged which avoid the introduction of functional
groups in at least one of the two coupling partners prior to
cross-coupling by C H bond activation. The development
of direct selective intermolecular heteroarylations of hetero-
arenes appears particularly beneficial because prefunctional-
[3]
Scheme 1.
À
izations of heteroarenes are often difficult. From the view-
luciferin emits light in the range of 530–640 nm (bioluminis-
cence).[10]
À
point of atom economy, twofold C H bond activation is the
À
ideal strategy for interconnecting two heteroarenes, and the
Herein we report a method for the selective C C coupling
groups of Fagnou and DeBoef showed independently that
between the nonfunctionalized C2 positions of azoles through
À
À
À
palladium(II) catalysis can be used for oxidative C H/C H
cross-couplings of heteroarenes with carbocyclic arenes.[4] The
Pd(OAc)2-catalyzed oxidative cross-coupling of electron-
deficient polyfluoroarenes with thiophenes, furans, and imi-
dazoles was achieved by Zhang and co-workers by using
Ag2CO3 in the presence of 1 equivalent of acetic acid.[5] Hu,
You, and co-workers reported on Pd(OAc)2-catalyzed
the cleavage of two C H bonds which provides access to a
class of widely unexplored unsymmetrical 2,2’-bishetero-
aryls.[11]
We chose the reaction between 1 and 2a to optimize the
conditions for the palladium-catalyzed cross-coupling reac-
tion (Table 1). In a first series of experiments, the reactions
Table 1: Pd(OAc)2-catalyzed cross-coupling of 1 with 2a.[a]
À
À
copper-salt-activated C H/C H cross-couplings of xanthines,
azoles, and electron-poor pyridine N-oxides with thiophenes
and furans.[6] However, to date, efficient C H/C H cross-
couplings between very similar partners, such as different
azoles, remains a challenge because of their tendency to
À
À
undergo homocoupling.[7] Hence, decarboxylative C H ary-
À
Entry
CuX2
Additives
Yield[b] [%]
lations were employed by Zhang and Greaney to link
differently substituted azoles in moderate to good yield, but
homocoupling was not fully suppressed and remained a
limiting factor.[8]
1[c]
2[c]
3[c]
4[c]
5
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
–
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuF2
Cu(OAc)2·H2O
–
–
–
trace[d]
93
AgF (2 equiv)
KF (2 equiv)
AgF (2 equiv)
AgF (2 equiv)
KF/AgNO3 (3+1.5 equiv)
AgOAc (1.5 equiv)
KF/AgNO3 (3+1.5 equiv)
KF/AgOAc (3+1.5 equiv)
KF/AgOAc (3+3 equiv)
KOAc/AgF (2+2 equiv)
KF/AgNO3 (3+1.5 equiv)
KF/AgNO3 (3+1.5 equiv)
KF/AgNO3 (3+1.5 equiv)
22[d]
trace[e]
92[f]
91 (63)[g]
87
Though numerous natural products with important bio-
logical activities contain directly linked azoles, the 2,2’-
linkage of azoles is a rare motif in nature.[9] The only
prominent example is d-luciferin, which is used by firefly
beetles to generate oxyluciferin in an electronically excited
state (Scheme 1). Upon its return to the ground state oxy-
6
7
8[h]
9
31[h]
35
71
10
11
12
13
14
CuBr
CuCl2
CuBr2
Cu(OTf)2
84
trace
trace
31
[*] W. Han, Dr. P. Mayer, Dr. A. R. Ofial
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-9977715
[a] A mixture of 1 (0.25 mmol), 2a (0.38 mmol), Pd(OAc)2 (5 mol%),
CuX2 (0.50 mmol), and additives in DMF (2.5 mL) was stirred at 1208C
for 22 h under air. [b] Yield of isolated 3a (homocoupling of either 1 or 2a
gave yields <5% if not mentioned otherwise). [c] Under oxygen
atmosphere. [d] Homocoupling consumed some 2a by formation of
1,1’-dimethyl-2,2’-biimidazole (21% yield for entry 1; 15% yield for
entry 3). [e] Almost quantitative recovery of the starting materials. [f] The
same yield of 3a was obtained when TEMPO (20 mol%) was added as a
radical scavenger. [g] Under an atmosphere of dry nitrogen. [h] Without
Pd(OAc)2; 1 was recovered with 63% yield.
E-mail: ofial@lmu.de
Homepage: http://www.cup.lmu.de/oc/ofial
[**] We thank Dr. David S. Stephenson for helpful discussions and
Marianne Rotter for the XRD measurements, as well as the China
Scholarship Council (fellowship to W.H.) and Prof. Herbert Mayr for
generous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006208.
2178
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Angew. Chem. Int. Ed. 2011, 50, 2178 –2182

Table 2: Pd(OAc)2-catalyzed C2 arylation of 1 with azoles 2.[a]
were carried out under an atmosphere of O2 (1 atm) in N,N-
dimethylformamide (DMF) which gives heterogeneous reac-
tion mixtures (Table 1, entries 1–4). Whereas the presence of
2 equiv of the additive Cu(OAc)2·H2O was not sufficient to
afford 3a, the combination Cu(OAc)2·H2O (2 equiv)/AgF
(2 equiv) led to the formation of 3a in excellent yield
(93%).[12] Replacing AgF by KF diminished the yield of 3a
considerably (Table 1, entry 3). The cross-coupling failed
completely when the reaction was carried out in the presence
of AgF but without Cu(OAc)2·H2O (Table 1, entry 4). We
were delighted to find that oxygen atmosphere was not
necessary to achieve the cross-coupling, and 3a was obtained
in high yield when 1 and 2a reacted under ambient air
atmosphere without exclusion of moisture (92%, Table 1,
entry 5). The reliability of this coupling method was con-
firmed by the successful generation of 3a on a 1 mmol scale
(see the Experimental Section). The combinations Cu-
(OAc)2·H2O/KF/AgNO3 and CuF2/AgOAc were as efficient
as Cu(OAc)2·H2O/AgF in mediating the formation of 3a
(Table 1, entries 5–7). These results show that the sources of
Cu2+, Ag+, and AcOÀ ions are not crucial for the success of
the cross-coupling. Different polar aprotic solvents (e.g.,
DMSO, NMP) could be employed to achieve high yields of
3a, whereas the use of protic and apolar solvents was less
effective.[13]
Entry Azole 2
Conditions Product 3
Yield[b]
[%]
1
A
91
95
2
3
B
B
91
4
5
A
B
87
86
The reaction of 1 with 2a was significantly attenuated in
the absence of the Pd(OAc)2 catalyst (Table 1, entry 8).
Whereas the low degree of conversion in the absence of Cu2+
could be partially compensated by using 3 equivalents of Ag+
or providing CuBr (Table 1, entries 9–11),[6,14] combining Cu2+
and Ag+ salts is more economical and gives superior results
(Table 1, entries 5–7).
6
B
71
7
8
9
A
A
A
65
67
92
To gain further insight into the fate of the Cu2+ and Ag+
ions during the cross-coupling reaction, the precipitates
isolated by filtration at the end of the reactions in entries 5
and 6 of Table 1 were analyzed by X-ray powder diffraction.
The diffraction patterns of the two samples were almost
identical and showed significant peaks which were assigned to
Ag0 (see the Supporting Information). Hence, Ag+ ions can
be considered as terminal oxidants in these reactions.[15] The
role of the Cu2+ ions is less clear at present. We assume that, in
analogy to the Wacker process,[16] Cu2+ ions catalyze the
oxidation of Pd0 by O2 when substoichiometric amounts of
Ag+ ions are applied (Table 1, entries 6 and 7). Moreover, it
has been reported that Pd(OAc)2 and Cu(OAc)2·H2O can
form polymetallic acetate-bridged clusters in acetic acid.[17,18]
It seems possible, therefore, that catalytically active Cu–Pd
species are generated in situ also under our reaction
conditions.[4b,d,19] To test this hypothesis, we varied the
counterion X in the copper salt CuX2 in the presence of KF/
AgNO3 and catalytic amounts of Pd(OAc)2. The poor results
obtained with CuCl2, CuBr2, and Cu(OTf)2 (Table 1,
entries 12–14) confirmed the crucial role of acetate ions for
achieving high yields of 3a.
[a] A mixture of 1 (0.25 mmol), 2 (0.38 mmol, 1.5 equiv), Pd(OAc)2 (5 or
10 mol%), Cu(OAc)2·H2O (0.50 mmol), and additives (KF/AgNO3 or
AgF) in DMF (2.5 mL) was stirred at 1208C for the given time under air.
[b] Yield of isolated product after column chromatography.
furnished 3b in excellent yield (Table 2, entry 2). Interest-
ingly, the N-(2,3,5,6-tetrafluorophenyl)-substituted imidazole
2c, which has sites for C H activation at both rings, reacted
with 1 regioselectively at C2 of the imidazole moiety to give
3c (Table 2, entry 3). As the C H bond at the tetrafluorinated
phenyl ring in 2c did not react in the arylation of 1,
subsequent direct functionalizations of 3c are possible.[5,20]
The reaction of 1 with 2d delivered 3d carrying an N-vinyl
group, which could be useful for incorporating the bishetero-
aryl unit into functional (co)polymers.
À
À
We explored various azoles as coupling partners for 1 by
employing the two equally efficient additive combinations,
that is, Cu(OAc)2·H2O with either KF/AgNO3 or AgF, in the
presence of 5 to 10 mol% Pd(OAc)2 as catalyst (Table 2). The
cross-coupling of 1 with 5-chloro-1-methylimidazole (2b)
Further reactions of 1 with differently substituted oxa-
zoles and thiazoles (Table 2, entries 5–9) show the versatility
À
À
of this direct oxidative C H/C H cross-coupling method-
ology. Since the aryl bromide 2 f is compatible with the
reaction conditions of the cross-coupling, the bisheteroaryl–
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2179

Communications
aryl scaffold of 3 f can be extended by subsequent classical
palladium-catalyzed aryl couplings.
The scope of the catalytic method presented here could be
extended to C2 heteroarylations of a series of benzimidazoles
4 with imidazoles, oxazoles, and thiazoles to furnish the
bisheteroaryls 5a–i (Scheme 2).
Scheme 4. Competition between 2a and 6 for benzothiazole (1).
We investigated the effect of the Ag+ salt on the ratio of
cross- and homocoupling products by studying the reaction of
benzothiazole (1) with 4,5-dimethylthiazole (2i). Scheme 5
shows that the formation of homocoupling products was
suppressed by the presence of Ag+ ions and that cross-
coupling (to 3i) is favored under these conditions. This pivotal
effect of silver(I) is presently not well understood and
requires further investigation.
Scheme 2. Direct C2 arylation of benzimidazoles 4 with azoles 2
(yields of isolated product after column chromatography are given).
Scheme 5. Products of the reaction of benzothiazole (1) with 4,5-
dimethylthiazole (2i) in the presence (Table 2, entry 9) and the absence
of Ag+ ions. [a] Yield of isolated product based on 2i. [b] Estimated
based on GC—MS analysis.
To understand the parameters that determine the selec-
tivity for cross-coupling we compared the homocoupling
reactions of 1 and 2a. These azoles behaved differently under
the reaction conditions of entry 6 in Table 1. After 9 h, GC–
MS analysis showed that less than 10% of 1 had been
converted, while the reaction of 2a achieved a greater than
90% conversion.
Benzothiazole (1) underwent direct arylation with [trans-
PhPdI(PPh3)2] (6) to form 7 under the reaction conditions of
entry 5 in Table 1, (Scheme 3).[21]
Palladium-catalyzed cross-couplings under oxidative con-
ditions may, in principle, proceed through a Pd0/PdII or a PdII/
PdIV cycle. As diaryliodonium salts are known to oxidize PdII
to PdIV species,[3 s,22] the failure of [Ph2I]+[PF6]À (2 equiv) to
transfer a phenyl group to benzothiazole (1) or N-methyl-
imidazole (2a) in the presence of Pd(OAc)2 as the catalyst
(5 mol%) suggests that the contribution of an arylpalladi-
um(IV) intermediate to the reaction pathway is unlikely,
though we apply oxidative conditions.
Addition
of
2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO, 20 mol%) as a radical trap to the palladium-
catalyzed reaction between 1 and 2a did not affect the yield of
3a (Table 1, entry 5). This finding indicates that radical
species do not play a decisive role in the cross-coupling
process.[22c, 23]
Scheme 3.
Despite the presently rather fragmentary information on
Further, a competition experiment between 1, 2a, and 6
gave only two main products (Scheme 4). Whereas only trace
amounts of the products from homocoupling of 1, homocou-
pling of 2a, and phenylation of 2a by 6 were detectable by
GC–MS in the crude material, the yields of isolated 3a (65%)
and 7 (33%) indicate that the rate of the catalytic hetero-
arylation of 1 with 2a is on the same order of magnitude as
that of the direct phenylation of 1 with the aryl palladium(II)
complex 6.
the mechanism, we propose that the PdII/Pd0 catalytic cycle
À
À
À
follows a C H bond cleavage/C H bond cleavage/C C
À
coupling sequence. After the first C H bond cleavage of
À
the azole HetAr H and the formation of the intermediate
(HetAr)–PdLn, the presence of Ag+ facilitates cleavage of the
À
À
second C H bond selectively at the other azole HetAr’ H.
Thereby the mixed bisheteroaryl–Pd complex (HetAr)–Pd–
(HetAr’) is generated as a key intermediate. A change of the
À
mechanism for the Pd C bond formation may account for the
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change of substrate selectivity between the first and the
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À
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À
as a proton acceptor during the C H bond cleavage.
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benzazoles with N-, O-, and S-containing azoles that is
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À
C H bonds in both substrate molecules without the require-
ment of prefunctionalized azoles, designed ligands, or a huge
excess of one azole over the other.
In the solid state,[12] the small twist angle of 9.39(11)8
between the least-squares planes of the linked heteroaryl
moieties illustrates the planarity of the p system of 3a. As the
2,2’-bisheteroaryls 3 and 5 fluoresce in CHCl3 their rigidity is
retained in solution (at room temperature). The biaryls 3 and
5 may, therefore, find application as versatile ligands, building
blocks in organic synthesis, pharmaceuticals, and functional
materials. Further investigations will concentrate on elucidat-
ing the mechanism of the reaction and extending this catalytic
method to other cross-coupling reactions.
Experimental Section
Synthesis of 3a (1 mmol scale): Under air atmosphere, a round-
bottom flask was charged with Pd(OAc)2 (11.3 mg, 5 mol%), Cu-
(OAc)2·H2O (404 mg, 2.00 mmol), and AgF (256 mg, 2.00 mmol).
Then 1 (116 mL, 1.00 mmol) and 2a (120 mL, 1.50 mmol) were added
by using microliter syringes. After the addition of DMF (2.5 mL) the
mixture was stirred for 10 min at room temperature and then heated
at 1208C for 22 h. After cooling to room temperature, the reaction
mixture was poured into a saturated aqueous NaCl solution (40 mL)
and extracted with EtOAc (3 ꢀ 40 mL). The organic phases were
combined, and the volatile components were removed in a rotary
evaporator. Purification of the crude product by column chromatog-
raphy (silica gel, eluent: n-pentane/EtOAc/NEt3) yielded 3a as a
colorless solid (196 mg, 91%).[12]
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Received: October 4, 2010
Revised: November 8, 2010
Published online: January 18, 2011
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Keywords: azoles · catalysis · cross-coupling · palladium · silver
.
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the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[13] Yields of 3a in different solvents (under conditions analogous to
those of Table 1, entry 6): DMF (91%), DMSO (84%), NMP
(69%), DMA (42%), 1,4-dioxane (26%), toluene (21%),
t-amylalcohol (19%), acetic acid (0%).
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