Copper-mediated and copper-catalyzed cross-coupling of indoles and 1,3-azoles: Double C-H activation

Article abstract of DOI:10.1002/anie.201201491

A new bronze age: The described copper-mediated cross-coupling with double C-H activation can provide a convergent access to indole-containing biheteroaryls that are of high interest in pharmaceutical and medicinal chemistry. In this strategy an easily attachable and detachable 2-pyrimidyl directing group is used. Moreover, a variant that is catalytic in copper is achieved by using atmospheric oxygen as an ideal co-oxidant (see scheme). Copyright

Full text of DOI:10.1002/anie.201201491

Angewandte
Chemie
DOI: 10.1002/anie.201201491
Synthetic Methods
Copper-Mediated and Copper-Catalyzed Cross-Coupling of Indoles
À
and 1,3-Azoles: Double C H Activation**
Mayuko Nishino, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Since biaryl structures that contain an indole nucleus occur in
many pharmaceuticals, biologically active compounds, and
functional materials, indole–arene cross-coupling reactions
have received great attention from synthetic chemists.[1] In
particular, recent developments in metal-mediated direct
[2]
À
C H functionalization enable a direct cross-coupling of
unactivated indoles and arenes as an ideal and attractive
alternative to the conventional cross-coupling technology
with organic halides or organometallic reagents.[3] However,
reported protocols generally depend on precious palladium
catalysts combined with copper- or silver-based terminal
oxidants. Thus, further developments for new reactions
mediated by other transition metals are strongly desired,
since they can provide a complementary and unique selectiv-
ity as well as higher efficiency and versatility toward the
Scheme 1. Cu-promoted intermolecular direct biaryl coupling.
dehydrogenative synthesis of indole–arene conjugates. Mean-
DG=directing group.
while, significant attention has been recently focused on
copper salts and catalysts as an inexpensive and potentially
more effective alternative to the above palladium catalysts,
result of a control experiment with N-(4-pyridyl)indole (1a-
4Py) indicates a pivotal role of the directing effect of nitrogen
to the copper center (Table 1, entry 5). Pleasingly, a more
easily attachable and detachable 2-pyrimidyl group[8b,c]
showed a comparable efficiency as the N-(2-pyridyl)indole
1a-2Py (Table 1, entries 6 and 4). With the N-(2-pyrimi-
dyl)indole 1a as the optimized indole substrate, other
reaction parameters were screened next. Anhydrous Cu-
(OAc)2 slightly improved the yield (Table 1, entry 7), whereas
the use of CuCl2 or Cu(OTf)2 instead of Cu(OAc)2·OH2
completely shut down the reaction (Table 1, entries 8 and
9). Investigation of the reaction stoichiometry and the use of
some additives revealed that the desired heteroarylated
indole 3aa was isolated in 94% yield when anhydrous
Cu(OAc)2 and AcOH were employed (Table 1, entry 11).
Even in the absence of AcOH, the reaction proceeded, but
the yield was somewhat lower (Table 1, entry 12). Notably the
Cu-based cross-coupling occurred exclusively at the indole
C2-position; this selectivity is complementary to the prece-
dent Pd-based methodology.[3f]
À
and copper-promoted C H arylations of some (hetero)arenes
with aryl (pseudo)halides[4] and aryl metals[5] now become
possible. Moreover, our group also succeeded in the cross-
coupling with unfunctionalized arenes (Scheme 1a).[6]
Herein, we introduce a copper salt as a new promising
promoter in the direct coupling between indoles and 1,3-
azoles. The key to our success is the installation of a suitable 2-
pyrimidyl director on the indole nitrogen atom; this group is
readily removable after the coupling event. Moreover, the use
of atmospheric oxygen is found to render the reaction
catalytic in copper (Scheme 1b).
Our study commenced by an identification of an appro-
priate substituent on the indole nitrogen atom under Cu-
(OAc)2·OH2/PivOH-mediated conditions based on the pre-
vious work[6] (Table 1). While indoles that bear Me, Ph, and
(2-pyridyl)sulfonyl[7] groups completely failed to couple with
benzoxazole (2a; Table 1, entries 1–3), an N-(2-pyridyl)in-
dole (1a-2Py)[8] was a promising candidate (entry 4). The
By using the conditions indicated in entry 11 of Table 1,
we evaluated the scope of the direct indole/1,3-azole coupling.
Representative products are illustrated in Scheme 2. In
addition to the simple benzoxazole 2a, some 5-substituted
benzoxazoles could couple with 1a (3ab–ad). Various mono-
cyclic 5-aryloxazoles also could be employed to form the
corresponding biheteroaryls 4aa–af at synthetically useful
levels. Notably, electron-donating methyl and methoxy as well
as electron-withdrawing chloro, nitro, and cyano groups were
tolerated during the reaction. On the other hand, benzothia-
zole and N-methylbenzimidazole in place of the oxazoles
could be reacted, albeit with lower efficiency (5 and 6). Other
[*] M. Nishino, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry
Faculty of Engineering
Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from the Ministry
of Education, Culture, Sports, Science, and Technology (Japan).
M.M. acknowledges Kansai Research Foundation for technology
promotion.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201491.
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Table 1: Optimization studies for cross-coupling of indole 1 and benzoxazole 2a.[a]
electron-deficient arenes, such as pentafluoroben-
zene and pyridine N-oxide, resulted in no formation
of the corresponding biaryls (data not shown). The
generality of the indole substrate was subsequently
investigated. While 3-methylindole resulted in
a moderate yield of 3ba even at higher temperature,
its cyano analogue underwent the coupling very
smoothly to afford 3ca in a good yield. The Cu-based
reaction tolerated the methoxy and chloro substitu-
ents on the benzene ring (3da–fa). Moreover,
a pyrrole nucleus was also available for use: the
cross-coupling with benzoxazole and 5-phenyloxa-
zole took place without any difficulty to make the
pyrrole–oxazole linkage directly in 67 and 75%
yields, respectively (7a and 7b).
Although the above protocol, which uses stoi-
chiometric amounts of Cu, deserves significant
attention owing to some benefits associated with
inexpensiveness and relatively low toxicity of copper
salts, the development of catalytic variants is quite
appealing from the economical and synthetic points
of view. After an extensive survey of terminal co-
oxidants, we were pleased to find that the most
Entry
R (1)
Cu salt/additive
3, Yield [%][b]
1
2
3
4
5
6
7
8
Me (1a-Me)
Ph (1a-Ph)
Cu(OAc)2·OH2/PivOH
Cu(OAc)2·OH2/PivOH
Cu(OAc)2·OH2/PivOH
Cu(OAc)2·OH2/PivOH
Cu(OAc)2·OH2/PivOH
Cu(OAc)2·OH2/PivOH
Cu(OAc)2/PivOH
CuCl2/PivOH
Cu(OTf)2/PivOH
Cu(OAc)2/PivOH
Cu(OAc)2/AcOH
3aa-Me, 0
3aa-Ph, 0
3aa-SO2Py, 0
3aa-2Py, 56
3aa-4Py, 0
3aa, 55
3aa, 69
3aa, 0
3aa, 0
3aa, 82
SO2(2-pyridyl) (1a-SO2Py)
2-pyridyl (1a-2Py)
4-pyridyl (1a-4Py)
2-pyrimidyl (1a)
2-pyrimidyl (1a)
2-pyrimidyl (1a)
2-pyrimidyl (1a)
2-pyrimidyl (1a)
2-pyrimidyl (1a)
2-pyrimidyl (1a)
9
10[c]
11[c]
12
3aa, (94)
3aa, 83
Cu(OAc)2/none
[a] Reaction conditions: Cu salt (0.50 mmol), additive (0.25 mmol), indole
(0.25 mmol), 2a (0.50 mmol), o-xylene (1.5 mL), 1508C, N2. [b] Yield estimated by
GC method. Yield of isolated product given in parenthesis. [c] With Cu(OAc)2
(0.75 mmol). OTf=trifluoromethanesulfonate, Piv=tert-butylcarbonyl.
attractive and ideal co-oxidant atmospheric oxygen could
make the reaction catalytic in copper. Our preliminary but
intriguing results are shown in Scheme 3. In a typical experi-
ment, treatment of N-(2-pyrimidyl)indole 1a (0.25 mmol)
with benzoxazole 2a in the presence of Cu(OAc)2 (20 mol%)
and AcOH (4.0 equiv) in boiling o-xylene under atmospheric
conditions produced 3aa in 59% yield. The copper catalysis
could be applied to various combinations of substituted
indoles and benzoxazoles (3). Particularly notable is the
satisfying formation of the 2-chloroindole derivative 3ga,
which is otherwise difficult to obtain under the stoichiometric
conditions in Scheme 2, because of the competitive dechlori-
nation. Moreover, some 5-aryloxazoles could be employed
with good efficiencies (4). The conjugated pyrrole–oxazole
cores were also readily accessible even under catalytic
conditions (7). In some cases, homocoupling products of
oxazoles were observed (ca. 2–8% based on 1,3-azoles; GC).
The competitive reaction can inform us about the reaction
mechanism (see below). To our knowledge, this is the first
example of the copper-catalyzed intermolecular direct biaryl
cross-coupling.[9]
To get some insights into the reaction mechanism, some
deuterium-labeling experiments were conducted. The expo-
sure of 2-deuteriobenzoxazole [D1]-2a alone to the catalytic
conditions induced the rapid H/D scrambling after one hour
[Eq. (1)]. In the absence of Cu(OAc)2, no H/D scrambling of
[D1]-2a was observed. In contrast, the exposure of 2-
deuterioindole [D1]-1a to catalytic conditions resulted in
only a minor drop of the deuterium content, while the
addition of benzoxazole 2a accelerated the H/D exchange
reaction of [D1]-1a [Eq. (2); the values 91% and 83% are the
amounts of isolated recovered material].
Based on these outcomes, we propose the reaction
mechanism for the catalytic coupling of 1a with 2a as follows
Scheme 2. Products of copper-mediated cross-coupling of N-(2-pyrimi-
dyl)indoles or -pyrroles and 1,3-azoles. The reaction was performed by
using the conditions in Table 1, entry 11. The yields are of the isolated
products. [a] At 1708C for six hours.
(Scheme 4). An initial carboxylate-ligand-assisted cupration
[10]
À
of the relatively acidic C H bond of 2a generates hetero-
2
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Scheme 4. Plausible reaction mechanism. L=AcOH, O2, or solvent.
irreversible reductive elimination[13] provides the product 3aa
along with regeneration of the starting copper complex to
complete the catalytic cycle. The postulated metalation order
(1,3-azole then indole) can account for the observation that
the loss of deuterium of [D1]-1a was accelerated by addition
of 2a in Eq. (2). The highly electron-withdrawing nature of
the benzoxazole ligand in 8 might facilitate a coordination of
the pyrimidyl nitrogen atom to the copper center to trigger
À
the second C H metalation. At this stage, we speculate that
this highly electron-deficient nature of the 1,3-azolyl ligand
on 8 is key to the preference for cross-coupling over homo-
coupling. Although the minor but significant H/D exchange at
the indole C2-position interfered with calculation of a correct
kinetic isotope effect (KIE) value, comparison of production
rates of 3aa in a set of the following three experiments
informs us about the rate-determining step of the reaction
(Scheme 5): the introduction of deuterium into benzoxazole
2a had little influence on the yield of 3aa, whereas the use of
Scheme 3. Copper-catalyzed cross-coupling of N-(2-pyrimidyl)indoles
or -pyrrole and 1,3-azoles. Reaction conditions: Cu(OAc)2
(0.050 mmol), AcOH (1.0 mmol), indole (0.25 mmol), 1,3-azole
(0.50 mmol), o-xylene (1.5 mL), 1508C, air. The yields are of the
isolated products. [a] Contaminated with a trace amount of the
product from dechlorination.
Scheme 5. Comparison of production rates of 3aa with deuterium-
labeled 1a or 2a. Conditions: Cu(OAc)2 (0.75 mmol), AcOH
(0.25 mmol), 1a or [D1]-1a (0.25 mmol), 2a or [D1]-2a (0.50 mmol), o-
xylene (1.5 mL), 1508C, N2, one hour.
[D1]-1a instead of unlabeled 1a induced a large drop in the
yield even under otherwise identical conditions. Thus, the
arylcopper intermediate 8.[11] The formation of homocoupling
byproducts of 1,3-azoles that were observed during the
reaction shown in Scheme 3 can be consistent with the
proposed intermediate.[12] The competitive cupration of the
second benzoxazole generates a bis(benzoxazole)copper, en
route to the homocoupling product. Subsequent chelation-
À
C H bond cleavage of 1a would be the most plausible rate-
limiting step.[14] However, at the present, we cannot com-
pletely exclude an alternative pathway that includes 1) for-
mation of an indolylcopper species through a chelation-
À
=
assisted C H cupration of indoles, 2) insertion of the C N
À
À
assisted C H metalation of 1a occurs to form the bis(het-
double bond of 1,3-azoles to the C Cu bond, and 3) oxidation
eroaryl)copper species 9 as a key intermediate. The phenom-
leading to rearomatization of azole cores.[15] Additional
efforts are essential for clarification of the detailed mecha-
nism; studies are ongoing in our laboratory.[16]
enon seen in Eqs. (1) and (2) is highly suggestive of reversible
À
C H bond cleavage of each substrate. Final O2-promoted
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À
Keywords: C H activation · copper · cross-coupling · indoles ·
synthetic methods
.
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Scheme 6. Removal of 2-pyrimidyl director.
Finally, we attempted to remove the directing group from
the coupling products (Scheme 6). Upon treatment of benz-
oxazole-substituted 3aa and 3ca with NaOMe in dimethyl-
sulfoxide (DMSO) at 1008C,[8b] the corresponding N-H
indoles 3aa’ and 3ca’ were obtained in 68 and 67% yields,
respectively. The free N-H indole/oxazole/benzene-conju-
gated aromatic cores 4aa’ and 4ca’ were also available by
using the same procedure. For the removal of the 2-pyrimidyl
director from the pyrrole ring, the use of KOMe instead of
NaOMe was found to be more effective (7b’).
In conclusion, we have developed a copper-mediated
intermolecular cross-coupling of indoles and 1,3-azoles with
the chelation assistance of a 2-pyrimidyl group. Moreover,
a catalytic variant also has been achieved by using atmos-
pheric oxygen as the sole oxidant. The process can be
regarded as one of the most environmentally benign, ideal
cross-couplings with the liberation of H2O as the sole
byproduct. The Cu/O2 catalysis can provide a new opportu-
nity to a direct, catalytic dehydrogenative biaryl coupling
À
through dual C H bond cleavage and additionally contribute
to the synthetic utility of copper complexes in the field of
À
C H functionalization. Further studies seek to uncover the
detailed reaction mechanism, improve the turnover number,
and expand the scope of arene coupling partners.
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Experimental Section
Copper-catalyzed cross-coupling of 1-(pyrimidin-2-yl)-1H-indole
(1a) and benzoxazole (2a; Scheme 2) to give 3aa: Cu(OAc)2
(9.0 mg, 0.050 mmol), acetic acid (60 mg, 1.0 mmol), 1-(pyrimidin-2-
yl)-1H-indole (1a, 49 mg, 0.25 mmol), benzoxazole (2a, 60 mg,
0.50 mmol), o-xylene (1.5 mL), and 1-methylnaphthalene (ca.
20 mg, internal standard) were placed in a 20 mL two-necked reaction
flask equipped with a reflux condenser and a drying tube lined with
calcium chloride. The solution was stirred at 1508C for four hours in
air. The consumption of 1a was confirmed by GC analysis, and the
resulting mixture was then quenched with water. The mixture was
extracted with ethyl acetate, and the combined organic layers were
dried over sodium sulfate. Concentration in vacuo followed by silica
gel column chromatography with hexane/ethyl acetate (2:1, v/v) gave
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2-{1-(pyrimidin-2-yl)-1H-indol-2-yl}benzoxazole
0.15 mmol) in 59% yield.
(3aa,
46 mg,
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Received: February 23, 2012
Revised: May 8, 2012
Published online: && &&, &&&&
4
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À
[14] The exact mechanism of C H bond cleavage of 1a still remained
obscure, but the major impact of deuterium incorporation on the
production rate of 3aa (Scheme 5) and the positive effect of the
electron-withdrawing CN group (Scheme 2, 3ba vs. 3ca) can
support the concerted metalation–deprotonation system.
[15] Recently, a relevant mechanism was proposed in the copper/O2-
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[16] When the reaction was carried out in the presence of [D4]-
AcOH, the deuterium incorporation occurred selectively at the
indole C2-position (see the following scheme). Thus, a migration
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involved in the reaction; see: N. P. Grimster, C. Gauntlett,
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prior to the reductive elimination. In the case of the stoichio-
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and CuIII can be alternative; a) L. M. Huffman, S. S. Stahl, J. Am.
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Angewandte
Communications
Communications
Synthetic Methods
M. Nishino, K. Hirano,* T. Satoh,
M. Miura*
&&&& — &&&&
Copper-Mediated and Copper-Catalyzed
Cross-Coupling of Indoles and 1,3-
A new bronze age: The described copper-
an easily attachable and detachable 2-
pyrimidyl directing group is used. More-
over, a variant that is catalytic in copper is
achieved by using atmospheric oxygen as
an ideal co-oxidant (see scheme).
À
À
Azoles: Double C H Activation
mediated cross-coupling with double C
H activation can provide a convergent
access to indole-containing biheteroaryls
that are of high interest in pharmaceutical
and medicinal chemistry. In this strategy
6
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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