Palladium-catalyzed oxidative alkynylation of heterocycles with terminal alkynes under air conditions

Article abstract of DOI:10.1021/ol200154s

Pd-Catalyzed oxidative alkynylation of azoles with terminal alkynes was developed via simultaneous activation of both heterocyclic sp² C-H and alkynyl sp C-H bonds. The choice of palladium catalyst source and external base resulted in being imp

Full text of DOI:10.1021/ol200154s

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1474–1477
Palladium-Catalyzed Oxidative
Alkynylation of Heterocycles with
Terminal Alkynes under Air Conditions
Seok Hwan Kim, Jungho Yoon, and Sukbok Chang*
Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon 305-701, Republic of Korea
sbchang@kaist.ac.kr
Received January 18, 2011
ABSTRACT
Pd-Catalyzed oxidative alkynylation of azoles with terminal alkynes was developed via simultaneous activation of both heterocyclic sp2 C-H and
alkynyl sp C-H bonds. The choice of palladium catalyst source and external base resulted in being important factors for performing the reaction
with high efficiency and selectivity, and air was successfully utilized as an environmental oxidant in the present alkynylation procedure.
In recent years, a promising strategy of C-H bond
activation has been extensively utilized for C-C bond
formation which is one of the most important topics in
organic chemistry.1 This direction of research has been
stimulated mainly due to the advantage of enabling a more
straightforward access to target molecules without requiring
prefunctionalization of starting molecules, thus minimizing
side products in fewer steps. Therefore, although the C-H
bond functionalization often requires relatively harsh reac-
tion conditions, it is considered as an attractive alternative
to the conventional coupling approaches, in which both
reactants are preactivated (Scheme 1, path I).2 With regard
to this aspect, highly efficient C-C bond forming protocols
have been developed from the direct reaction of heteroar-
enes with aryl- or vinyl-(pseudo)halides (path II).3
More recently, a more challenging route to the C-C
bond formation has been scrutinized using two nonacti-
vated reactants (path III). Indeed, the oxidative C-C bond
formation via the activation of C(sp2)-H or C(sp3)-H
bonds has been extensively studied using various metal
catalysts.4,5 On the other hand, while the activation of
C(sp)-H bonds has been examined for the oxidative
couplings,6 synthetic applications of the strategy still re-
main largely unexplored mainly because of the undesired
homocoupling of terminal alkynes under the conditions.
Although Sonogashira reaction is a powerful tool for
(1) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
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A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J.
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Su, W. J. Am. Chem. Soc. 2010, 132, 16377.
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Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
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2010, 46, 677. (e) Gunay, A.; Theopold, K. H. Chem. Rev. 2010, 110,
1060. (f) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008,
130, 16158. (g) Park, E. J.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2008,
130, 17268. (h) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew.
Chem., Int. Ed. 2009, 48, 9127. (i) Kim, J. Y.; Cho, S. H.; Joseph, J.;
Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899. (j) Kim, J.; Chang, S. J.
Am. Chem. Soc. 2010, 132, 10272.
(5) For recent examples of C-C bond formation via C(sp3)-H
activation, see: (a) Lin, S.; Song, C. X.; Cai, G. X.; Wang, W.-H.; Shi,
Z.-J. J. Am. Chem. Soc. 2008, 130, 12901. (b) Li, C.-J. Acc. Chem. Res.
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Chem. Soc. 2009, 131, 18042.
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(b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
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42, 1074.
r
10.1021/ol200154s
Published on Web 02/24/2011
2011 American Chemical Society

introducing organic groups at the terminal alkynyl carbon,
a recent advance in the direct alkynylation of C(sp2)-H
bonds appears as a promising alternative to the conven-
tional Sonogashira procedure, in which aryl or vinyl
halides are employed.7
(e.g., entry 2). Use of other oxidants such as iodobenzene-
diacetate or tert-butyl hydroperoxide resulted in much lower
product yields (entries 3 and 4, respectively). While Pd(PPh3)4
alone displayed similar catalytic activity compared to that
from combined use of Pd(OAc)2/bipyridyl (entry 5), a higher
product yield was obtained when the reaction was carried
out open to air, a weaker oxidant for oxidizing the phos-
phine ligand, than under an O2 atmosphere (compare entries
5 and 6).
Scheme 1. Strategies of C-C Bond Formation
Table 1. Optimization of the Pd-Catalyzed Alkynylationa
temp yield
entry
catalyst/ligand
oxidant
solvent
(°C)
(%)b
1
Pd(OAc)2/bipyridyl O2
Pd(OAc)2/bipyridyl O2
toluene
toluene
100
100
100
100
100
100
100
100
100
100
100
80
30
2c
3
N.R.
N.R.
<5
Pd(OAc)2/bipyridyl PhI(OAc)2 toluene
Recently, our group has disclosed a Pd-catalyzed alky-
nylation of azoles using 1-haloalkynes, and its efficiency was
observed to be dependent on the ease of C(sp2)-H bond
activation.8 During the course of this study, we found that
a terminal alkyne itself was able to be coupled with azoles
under oxidative catalytic conditions. In fact, oxidative alky-
nylation of arenes with 1-alkynes was developed using Au6h
or Cu6i catalytic systems. In addition, Miura revealed an
elegant protocol of oxidative alkynylation of azoles using a
Ni catalyst.6m Despite these developments, plenty of room
for improvement still remains with regard to reaction effi-
ciency and substrate scope. We herein describe a new proce-
dure for the oxidative alkynylation of azoles using terminal
alkynes under Pd-catalyzed conditions.
5-Methylbenzoxazole (1a) and phenylacetylene (2a)
were chosen as model substrates in order to optimize the
oxidative alkynylation conditions (Table 1).9 We were
pleased to observe that a desired product (3a) was obtained
albeit in moderate yield when a Pd(OAc)2 catalyst was used
in the presence of a 2,20-bipyridine (bipyridyl) ligand under
an O2 atmosphere (entry 1). The reaction efficiency was
highly sensitive to the choice of bases, and LiO-t-Bu pro-
vided the best results among the various bases examined
4
Pd(OAc)2/bipyridyl t-BuOOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
5
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
none
O2
air
air
air
air
air
air
air
air
38
6
50
7d
8e
9
67f
74f
N.R.
<5
10
11
12
13
Pd2(dba)3
Pd(dba)2/PPh3
Pd(PPh3)4
Pd(PPh3)4
44
15
130
<5
a 1a (1.5 equiv), 2a (0.5 mmol), palladium catalyst (5 mol %), ligand
(bidentate: 5.5 mol %; monodentate: 11 mol %), base (2 equiv), oxidant
(O2 and air: 1 atm, others: 2 equiv), solvent (3 mL) for 12 h. b NMR yield.
N.R. indicates no reaction. c KO-t-Bu (2 equiv) was used instead of LiO-
t-Bu. d 1a (2 equiv) and base (3 equiv). e 1a (3 equiv) and base (4 equiv).
f Isolated yield.
A higher product yield was obtained with the larger
equivalent of oxazole and base (entries 7-8). While no
reaction was observed in the absence of the Pd(PPh3)4
species (entry 9), other Pd sources showed lower activity
even in the presence of the PPh3 ligand (entries 10-11).
The reaction proceeded slowly at lower temperature while
decomposition of azole was dominant at higher tempera-
tures (entries 12-13).
Various terminal alkynes were next applied to the opti-
mized conditions in the reaction with 1a (Table 2). Pheny-
lacetylenes bearing a range of substituents were coupled at
the 2-position of 1a to afford the desired products in good
yields (entries 1-8). Steric bulkiness at the aryl part did not
diminish the reaction efficiency as demonstrated in entry 2.10
While the reaction of phenylacetylenes substituted with
electron-donating groups readily took place to provide high
product yields, electron-withdrawing substituents resulted in
slightly lower yields mainly due to dimerization of the
alkynes (entries 6-8). 1-Naphthylacetylene and conjugated
enyne readily reacted with 1a under the optimized conditions
(6) (a) Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem. Soc.,
Dalton Trans. 2001, 2330. (b) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002,
124, 5638. (c) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008,
130, 833. (d) Yin, W.; He, C.; Chen, M.; Zhang, H.; Lei, A. Org. Lett.
2009, 11, 709. (e) Prokhorov, A. M.; Makosza, M.; Chupakhin, O. N.
Tetrahedron Lett. 2009, 50, 1444. (f) Hadi, V.; Yoo, K. S.; Jung, K. W.
Tetrahedron Lett. 2009, 50, 2370. (g) Gao, Y.; Wang, G.; Chen, L.; Xu,
P.; Zhao, Y.; Zhou, Y.; Han, L.-B. J. Am. Chem. Soc. 2009, 131, 7956. (h)
Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512. (i) Wei, Y.;
Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132, 2522.
(j) Chen, M.; Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010,
132, 4101. (k) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262. (l)
Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M. Chem.;
Eur. J. 2010, 16, 1772. (m) Matsuyama, N.; Kitahara, M.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358. (n) Yang, L.; Zhao, L.;
Li, C.-J. Chem. Commun. 2010, 46, 4184.
(7) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2096.
(8) Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868.
(9) For details, see the Supporting Information.
(10) This tendency was observed in the previous Ni-catalyzed reac-
tion (ref 6m).
Org. Lett., Vol. 13, No. 6, 2011
1475

Table 2. Pd-Catalyzed Oxidative Alkynylation of 1a with Var-
ious Terminal Alkynesa
Scheme 2. Pd-Catalyzed Oxidative Alkynylation of Hetero-
cycles with Terminal Alkynesa
entry
R
product
yield (%)b
1
(4-Me)C6H4
(2-Me)C6H4
(4-MeO)C6H4
(4-PhO)C6H4
(4-Me2N)C6H4
(4-CF3)C6H4
(4-Cl)C6H4
3b
3c
3d
3e
3f
75
88
67
73
82
50
64
52
63
67
75
36
41
31
2
3
4
5
6c
7
3g
3h
3i
8
(4-F)C6H4
9
1-Naphthyl
1-Cyclohexenyl
3-Thiophene
3-Pyridyl
3j
10
11
12
13d
14d
3k
3l
3m
3n
3o
Cyclohexyl
Triisopropylsilyl
a 1a (3 equiv), 2 (0.5 mmol), Pd(PPh3)4 (5 mol %), LiO-t-Bu (4 equiv),
toluene (3 mL) for 12 h. b Isolation yield. c Alkyne was slowly added.
d The reaction was performed at 130 °C in xylene (3 mL) solvent.
a Conditions: 1 (3 equiv), 2 (0.5 mmol), Pd(PPh3)4 (5 mol %), LiO-t-
Bu (4 equiv), toluene (3 mL) for 12 h (yield of isolated products). bCoCl2
(5 mol %) was used as an additive. TIPS indicates triisopropylsilyl.
(entries 9 and 10, respectively). While alkynylation of 1a with
thiophenacetylene occurred with high efficiency (entry 11),
the presence of a pyridyl moiety decreased the product yield
(entry 12). Importantly, an aliphatic alkyne was introduced
under the conditions albeit in a rather moderate yield (entry
13). However, the reaction with linear derivatives such as
1-octyne was very sluggish only affording less than 5%
product yield under the applied conditions. A silyl protected
acetylene was alkynylated at the 2-position of 1a to afford
the corresponding product 3o which would be a precursor of
terminal acetylene upon desilylation (entry 14).
Alkynylation of various heterocycles was subsequently
investigated under the optimized conditions (Scheme 2).
Unsubstituted benzoxazole smoothly underwent the alky-
nylation reaction with phenylacetylene to afford 4a in 74%
yield. While the reaction of 5-substituted benzoxazoles2i
produced the corresponding products in moderate to good
yields (4b-4d), higher reactivity was observed with substrates
bearing electron-donating groups (e.g., 4d). Importantly,
oxazoles in addition to benzoxazoles were also alkynylated
selectively at the 2-position. For instance, the reaction of
4-phenyloxazole with phenylacetylene proceeded to give
2-alkynyl-4-phenyloxazole (4e) albeit in lower yield. Interest-
ingly, electronic effects of substituents were observed in the
reaction of 4-aryloxazoles.11 Electron-withdrawing substitu-
ents on those substrates provided higher product yields (com-
pare 4h and 4g). On the other hand, benzothiazole underwent
the alkynylation in rather modest efficiency, and a moderate
product yield was obtained in the presence of a cobalt salt
while the desired product (4i) was formed in low yield (<5%)
in the absence of the cobalt additive.12,13 However, only a
poor product yield (4j) resulted from the reaction of a
partially saturated oxazoline.
In order to gain insight into the present oxidative
alkynylation reaction, kinetic isotope effects (KIE) were
studied with regard to the C-H/D bonds of 5-methylben-
zoxazole and phenylacetylene (Scheme 3). No significant
KIE values were observed in both cases, thereby indicating
that the C-H bond breaking is not involved in the rate-
determining step in the present alkynylation reaction.14,15
Scheme 3. Kinetic Isotope Effect Study
Although more comprehensive studies are required to
describe the mechanistic details, a plausible pathway of the
(11) For the synthesis of 4-aryloxazoles, see: (a) Whitney, S. E.;
Winters, M.; Rickborn, B. J. Org. Chem. 1990, 55, 929. (b) Lafontaine,
J. A.; Day, R. F.; Dibrino, J.; Hadcock, J. R.; Hargrove, D. M.;
Linhares, M.; Martin, K. A.; Maurer, T. S.; Nardone, N. A.; Tess,
D. A.; DaSilva-Jardine, P. Bioorg. Med. Chem. Lett. 2007, 17, 5245.
(12) When CoCl2 (5 mol %) was applied without palladium, 5% (GC
yield) of the desired product was formed.
(13) For a review on cooperative effects of multicatalytic systems, see:
Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302.
1476
Org. Lett., Vol. 13, No. 6, 2011

the 2-alkynylazole product and Pd(0) species which is
reoxidizedunder the aerobic conditions in accordancewith
the precedent literature.17
Scheme 4. Proposed Mechanism for the Pd-Catalyzed Oxidative
Alkynylation of Heterocycle
Scheme 5. Proton and Deuterium Exchange Experiment in the
Absence of Palladium Species
However, the order of transmetalation into a palladium-
(II) species between two lithiated substrates of azoles and
1-alkynes is not clear at the moment. In fact, a noticeable
degree of proton/deuterium exchange takes place between
5-methylbenzoxazole and deuterated phenylacetylene in
the absence of a palladium species (Scheme 5).
In conclusion, we have described the first example of a
palladium-catalyzed oxidative alkynylation of azole het-
erocycles. Terminal alkynes are directly employed under
aerobic conditions to afford 2-alkynylazoles in moderate
to good yields. Detailed mechanistic studies and synthetic
applications are currently ongoing.
oxidative alkynylation of azoles is shown in Scheme 4
based on the above KIE results and precedent literature.6i
It is postulated that an initial deprotonation of an azole
C(2)-H bond takes place by the action of an alkoxide base
leading to a lithium azolate that is subsequently transme-
talated into an in situ generated Pd(II) species to afford an
azolyl complex of palladium(II) (A).16 At this stage, a
dimerization pathway of azoles is envisioned to be mini-
mized since the formation of a palladium acetylide species
B will be highly facile. Reductive elimination of the key
intermediate (B) is assumed to subsequently occur to give
Acknowledgment. This research was supported by a
grant (AC3-101) from the Carbon Dioxide Reduction &
Sequestration Research Center, one of the 21st Century
Frontier Programs funded by the Ministry of Science and
Technology of Korean government.
(14) For a discussion on the kinetic isotope effect study for C-H
activation, see: (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed.
2005, 44, 2112. (b) Garcia-Cuadrado, D.; Barga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (c) Chiong, H. A.;
Daugulis, O. Org. Lett. 2007, 9, 1449. (d) Garcia-Cuadrado, D.; de
Mendoza, P.; Barga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am.
Chem. Soc. 2007, 129, 6880.
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For the oxidative addition of a terminal alkyne to an iridium
complex, see: Chin, C. S.; Yoon, J.; Song, J. Inorg. Chem. 1993, 32, 5901.
(16) (a) L’Helgoual’ch, J.-M.; Seggio, A.; Chevallier, F.; Yonehara,
M.; Jeanneau, E.; Uchiyama, M.; Mongin, F. J. Org. Chem. 2008, 73,
177. (b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185. (c) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org.
Lett. 2009, 11, 1733.
(17) For representative references regarding the in situ aerobic oxida-
tion of Pd(0) to Pd(II) species, see: (a) Schott, G. W. H.; Heimbach, P.
Angew. Chem., Int. Ed. 1967, 6, 92. (b) Popp, B. V.; Stahl, S. S. Chem.;
Eur. J. 2009, 15, 2915. (c) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43,
3400. (d) Adamo, C.; Amatore, C.; Ciofin, I.; Jutand, A.; Lakmini, H. J.
Am. Chem. Soc. 2006, 128, 6829.
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