Palladium-catalyzed oxidative cross-coupling between heterocycles and terminal alkynes with low catalyst loading

Article abstract of DOI:10.1002/anie.201210013

Direct: With [Pd₂(dba)₃] as a catalyst, the direct alkynylation of thiophenes bearing a variety of substituents has been accomplished by using terminal alkynes as alkynylating reagents. This protocol is also applicable to other electron-rich aromatic heterocycles. dba=dibenzylidenacetone. Copyright

Full text of DOI:10.1002/anie.201210013

Angewandte
Chemie
DOI: 10.1002/anie.201210013
Dehydrogenative Coupling
Palladium-Catalyzed Oxidative Cross-Coupling between Heterocycles
and Terminal Alkynes with Low Catalyst Loading**
Xiaoming Jie, Yaping Shang, Peng Hu, and Weiping Su*
Alkynylated (hetero)arenes represent a recurring structural
motif found in bioactive natural products, pharmaceuticals,
and organic materials.[1] These compounds are of great
importance either as building blocks or synthetic intermedi-
ates and have become increasingly attractive for synthetic
organic chemists.
The well-known Sonogashira reaction is one of the most
commonly used methods for installing alkyne moieties into
(hetero)arenes molecules.[2] Recently, the direct alkynylation
Scheme 1. Three examples of useful alkynylated thiophenes: a) 5-(2-
of (hetero)aromatic compounds has appeared as an alter-
Phenylethynyl)-2-b-glucosylmethyl-thiophene, a natural product;[10a]
b) S-3304, a matrix metalloproteinase inhibitor;[10b] c) R=n-C4H9,
native to the Sonogashira reaction by using the alkynyl
reagents prepared from terminal alkynes, such as alkynyl
a liquid-crystalline semiconductor.[10c]
halides,[3]
benziodoxolone-based
hypervalent
iodine
reagents,[4] or arylsulfonylacetylenes.[5] From the viewpoint
of step and atom economy, the oxidative cross-coupling[6]
between (hetero)arenes and terminal alkynes would be
a straightforward and more efficient method for installing
alkynyl groups into the (hetero)arene rings, because the need
for prefunctionalization of the starting materials would be
eliminated. In this context, a few of the seminal examples for
such a transformation were recently reported, including the
gold-catalyzed alkynylation of electron-rich (hetero)arenes
with electron-poor terminal alkynes;[7] the copper-, nickel-, or
palladium-catalyzed alkynylation of C–H acidic polyfluoroar-
enes and azoles;[8] and the palladium-catalyzed alkynylation
of C3-blocked 1-methylindoles.[9] However, these established
alkynylation methods only worked for specific substrates, and
a catalytic method suitable for many important heterocycles
such as thiophenes and furans remains elusive. Owing to the
importance of alkynylated thiophenes in material science,
natural product and medicinal chemistry, as exemplified by
the three alkynylated thiophene molecules illustrated in
Scheme 1,[10] the general method for cross-coupling thio-
phenes and other heterocycles with terminal alkynes would be
highly desirable. Herein, we report a versatile method that
enables the alkynylation of thiophenes bearing various func-
tional groups and other aromatic heterocycles by applying
a low loading of a palladium catalyst and using an array of
terminal alkynes as alkynylating reagents.
Several problems hamper the realization of oxidative
cross-coupling between aromatic heterocycles and terminal
alkynes. The first problem is the undesired terminal alkyne
homocoupling under oxidative conditions.[11] The slow addi-
tion of terminal alkynes to the reaction system indeed
partially overcame the alkyne homocoupling problem but
meanwhile brought about the operational inconve-
nience,[8b,c,9,12] and the use of a large excess of the other
coupling partner was capable of suppressing alkyne homo-
coupling, but sacrificed those reagents.[8a,11b,12] Very recently,
the decrease of the palladium catalyst loading proved to be an
effective means of overcoming alkyne homocoupling in the
Pd-catalyzed cross-coupling of alkynes.[13] Nevertheless, the
low palladium catalyst loading is incompatible with the
general reaction conditions for the C–H functionalization of
aromatic heterocycles, in which relatively high palladium
loadings (5–10 mol% Pd catalyst) are usually required to
obtain satisfying yields. Hence, we speculated that the
establishment of suitable reaction conditions to stabilize the
Pd catalyst and enhance its catalytic activity would allow
using a low catalyst loading and possibly enable selective
cross-coupling reactions of aromatic heterocycles with termi-
nal alkynes.
À
Elegant studies on C H bond functionalization of (het-
ero)arenes[14,15] and recent advances in metal-catalyzed oxi-
dative cross-coupling reactions involving terminal alkynes[16]
provided useful starting points for our investigation of this
direct alkynylation of thiophenes. The reaction of phenyl-
acetylene (1a) with 2-acetylthiophene (2a) was chosen as
a model system for optimization studies (Table 1). Initially,
the reaction that was carried out in 1,2-dimethoxyethane
(DME) at 908C for 4 h in the presence of Pd(OAc)2 (5 mol%)
as a catalyst and Ag2CO3 (1.5 equiv) as an oxidant did not give
the desired product 3a, but instead formed a large amount of
[*] Dr. X. Jie, Y. Shang, P. Hu, Prof. Dr. W. Su
State Key Laboratory of Structural Chemistry
Fujian Institute of Research on the Structure of Matter
Chinese Academy of Sciences
Yangqiao west road 155#, Fuzhou, Fujian 350002 (China)
E-mail: wpsu@fjirsm.ac.cn
[**] Financial support from the 973 Program (2011CB932404,
2001CBA00501), NSFC (20925102) is greatly appreciated.
unwanted alkyne homocoupling by-product
entry 1). Although the addition of K2CO3 or pivalic acid as
4 (Table 1,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210013.
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Table 1: Selected screening results for Pd-catalyzed oxidative cross-
coupling of phenylacetylene and 2-acetylthiophene.[a]
Entry
[Pd] (mol%)
Additive (equiv)
Yield [%][b]
3a/4
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
[PdCl2(PhCN)2] (5)
PdCl2 (5)
[Pd2(dba)3] (2.5)
[Pd2(dba)3] (0.2)
–
[Pd2(dba)3] (0.2)
[Pd2(dba)3] (0.2)
[Pd2(dba)3] (0.2)
–
–/48
–/54
–/34
35/20
23/26
48/20
–/21
K2CO3 (1)
PivOH (1)
K2CO3 (1), PivOH (2)
Na2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), AcOH (2)
PivOCs (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Cs2CO3 (1), PivOH (2)
Et3N (0.5)
8/47
9
46/24
36/28
51/28
53/22
56/10
–/–
10
11
12
13[c]
14[c]
15[d]
16[d,e]
17[d,e]
69/9
80/5
85(81)[f]/4
[a] Reaction conditions: 1a (0.3 mmol), 2a (3 equiv), Pd catalyst,
additive, Ag2CO3 (1.5 equiv), DME (1.5 mL). [b] Yield determined with
GC by using dodecane as an internal standard. [c] Phenylacetylene
(0.6 mmol) and DME (3 mL) were used. [d] Phenylacetylene (0.6 mmol)
and DME (1.5 mL) were used. [e] Ag2O (1.5 equiv) was used instead of
Ag2CO3. [f] Yield of isolated product.
additives to the reaction system also failed to afford 3a, the
presence of pivalic acid was observed to diminish the alkyne
dimerization (entries 2–3). When simultaneously adding
K2CO3 (1 equiv) and PivOH (2 equiv) as additives, we were
pleased to find that 3a was obtained in 35% yield (entry 4).
Next, we tested the effect of the metal ions of the base, which
revealed that Cs2CO3 was the base of choice (entries 5–6). In
contrast, the use of acetic acid in place of pivalic acid was
ineffective for this reaction (entry 7). Notably, the combina-
tion of Cs2CO3 (1 equiv) and PivOH (2 equiv) was not merely
the equivalent of cesium pivalate (PivOCs), because the use
of PivOCs (2 equiv) as base dramatically lowered the yield
and increased the alkyne dimerization (entry 8). The attempts
to use cheaper copper oxidants or a catalytic amount of silver
with nonmetallic stoichiometric oxidants were unsuccess-
ful.[17] Further screening of the palladium sources showed that
[Pd2(dba)3] (dba = dibenzylidenacetone) gave better result
(entries 9–12). Interestingly, 0.2 mol% of [Pd2(dba)3] could
be used without comprising the yield of 3a (entry 13). And
a control experiment revealed that palladium was indispen-
sable in this reaction (entry 14). Further experiments showed
that both doubling the reaction concentration and replacing
Ag2CO3 with Ag2O enhanced the yield of 3a (entries 15–16).
Finally, when Et3N (0.5 equiv) was added to the reaction
system, the product was isolated in 81% yield (entry 17).
We used the reaction conditions of entry 17 in Table 1 to
first examine the substrate scope of this reaction with respect
to thiophenes. As shown in Scheme 2, this reaction was
Scheme 2. The scope of heterocycles. Reaction conditions:
1 (0.6 mmol), 2 (3 equiv), [Pd2(dba)3] (0.2 mol%), Cs2CO3 (1 equiv),
PivOH (2 equiv), Ag2O (1.5 equiv), Et3N (0.5 equiv), DME (1.5 mL),
908C, 4–10 h. Yields of isolated products are reported. [a] 2.5 equiv
Ag2O were used. [b] Without Et3N. [c] Pd(TFA)2 (0.5 mol%) and DMF
(1.5 mL) were used. See the Supporting Information for details.
compatible with keto, bromo, chloro, iodo, aldehyde, ester,
alkenyl, and trifluoroacetyl substituents, and furnished the
desired product in good yields (3a–3l). Notably, the iodo
group is extremely reactive in the Sonogashira reaction, and
its tolerance is seldom reported in Pd-catalyzed C–H/C–H
cross-coupling reactions. Benzothiophene also smoothly
underwent this reaction to generate the corresponding
products in good yields (3m). In the reaction with 2,2’-
bithiophene, which has two nucleophilic positions available,
monoalkynylation took place in good yield with a small
amount of dialkynylated product formed (3n and 3n’). Thus,
the unsymmetrical bisalkynylated product 3o could be
obtained by starting from 3n. Gratifyingly, in addition to
thiophenes, our reaction conditions were also applicable to
2
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various other heterocycles. Among them, furans were alky-
nylated in synthetically useful yields (3p and 3q). In the cases
of N-methyl pyrrole and indole, dimerizations of both alkyne
and heterocycle led to a decrease in the yield of the cross-
coupling product (3r and 3s). Notably, thiazoles and an
oxazole afforded the corresponding alkynylated product at
the C5-position in good yields (3t–3v). Finally, N-methylpyr-
azole and N-fused imidazo[1,2-a]pyridine were also alkyny-
lated in reasonable yields (3w and 3x).
Subsequently, we evaluated the substrate scope with
respect to terminal alkynes (Scheme 3). Both electron-
donating (5a–5c) and electron-withdrawing (5d–5i) groups
were compatible on the aryl alkynes, generating highly
Scheme 4. A possible reaction pathway for the Pd-catalyzed oxidative
cross-coupling between heterocycles and terminal alkynes.
intermediate B and final reductive elimination of the cross-
coupling product from B. The low catalyst loading
(0.2 mol%) in this reaction may be associated with the
in situ generated insoluble alkynylsilver derivative, which is
[19]
ꢀ
a coordinating polymer (RC CAg)n and serves as a solid
support to prevent the Pd catalyst from agglomeration of Pd0
to inactive Pd black. Additionally, because of its insolubility,
the alkynylsilver derivative slowly liberates the alkynyl group
into the reaction system and therefore suppresses the
undesired homocoupling of terminal alkynes.[17]
In summary, we have developed a Pd-catalyzed method
for the direct alkynylation of heterocycles with terminal
alkynes. Most of the aromatic heterocycles described herein,
such as thiophenes and furans, were for the first time observed
to undergo direct alkynylation with terminal alkynes. Because
of the low catalyst loading (0.2 mol%), the simple operational
process, and excellent functional group tolerance, we believe
this protocol will find applications in synthetic chemistry.
Scheme 3. The scope of terminal alkynes. Reaction conditions: See
Scheme 2 for details of the reaction conditions. [a] Ag2CO3 (1.5 equiv)
was used instead of Ag2O. [b] Carried out at 1008C. [c] Without Cs2CO3
and Et3N. See the Supporting Information for details.
Received: December 14, 2012
Published online: && &&, &&&&
Keywords: C–H functionalization · cross-coupling ·
.
heterocycles · palladium · terminal alkynes
functionalized products in generally good yields. The hetero-
cyclic alkynes also served as suitable coupling partners as
exemplified by (pyridin-3-yl)acetylene (for 5j). Notably, the
silyl-protected (triisopropylsilyl)acetylene afforded alkyny-
lated thiophene in synthetically useful yield (5k), which could
be easily converted into free acetylene products or used as
a precursor for further functionalization.[4a] Unfortunately,
only a trace of product was observed for aliphatic alkynes.[18]
A possible reaction pathway is proposed to rationalize the
direct alkynylation reaction (Scheme 4). First, the alkynylsil-
ver derivative generated in situ undergoes transmetalation
with a PdII species to form the alkynyl–palladium intermedi-
ate A. Then, the intermediate A attacks the heterocycles
through concerted metalation–deprotonation to generate the
intermediate B, which delivers the desired alkynylated
product through reductive elimination. The oxidation of Pd0
to PdII by a AgI species finishes the catalytic cycle. Alter-
natively, the reaction may proceed through the initial
palladation of the heterocycle to form the intermediate C
and subsequent transmetalation from Ag to Pd to give
[1] Acetylene Chemistry: Chemistry, Biology and Material Science
(Eds.: F. Diederich, P. J. Stang, R. R. Tykwinski), Wiley-VCH,
Weinheim, 2005.
[2] For recent reviews, see: a) H. Doucet, J.-C. Hierso, Angew.
Chem. 2007, 119, 850 – 888; Angew. Chem. Int. Ed. 2007, 46, 834 –
871; b) R. Chinchilla, C. Nꢀjera, Chem. Soc. Rev. 2011, 40, 5084 –
5121.
[3] a) A. S. Dudnik, V. Gevorgyan, Angew. Chem. 2010, 122, 2140 –
2142; Angew. Chem. Int. Ed. 2010, 49, 2096 – 2098; b) K.
Kobayashi, M. Arisawa, M. Yamaguchi, J. Am. Chem. Soc.
2002, 124, 8528 – 8529; c) N. Matsuyama, K. Hirano, T. Satoh, M.
Miura, Org. Lett. 2009, 11, 4156 – 4159; d) T. Kawano, N.
Matsuyama, K. Hirano, T. Satoh, M. Miura, J. Org. Chem.
2010, 75, 1764 – 1766; e) M. Tobisu, Y. Ano, N. Chatani, Org.
Lett. 2009, 11, 3250 – 3252; f) I. V. Seregin, V. Ryabova, V.
Gevorgyan, J. Am. Chem. Soc. 2007, 129, 7742 – 7743; g) F.
Besseliꢁvre, S. Piguel, Angew. Chem. 2009, 121, 9717 – 9720;
Angew. Chem. Int. Ed. 2009, 48, 9553 – 9556; h) S. H. Kim, S.
Chang, Org. Lett. 2010, 12, 1868 – 1871.
[4] a) J. P. Brand, J. Waser, Angew. Chem. 2010, 122, 7462 – 7465;
Angew. Chem. Int. Ed. 2010, 49, 7304 – 7307; b) J. P. Brand, J.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Charpentier, J. Waser, Angew. Chem. 2009, 121, 9510 – 9513;
Angew. Chem. Int. Ed. 2009, 48, 9346 – 9349; c) J. P. Brand, C.
Chevalley, R. Scopelliti, J. Waser, Chem. Eur. J. 2012, 18, 5655 –
5666; d) J. P. Brand, J. Waser, Org. Lett. 2012, 14, 744 – 747; e) X.
Liu, Z. Wang, X. Cheng, C. Li, J. Am. Chem. Soc. 2012, 134,
14330 – 14333.
[14] a) K. Ueda, S. Yanagisawa, J. Yamaguchi, K. Itami, Angew.
Chem. 2010, 122, 9130 – 9133; Angew. Chem. Int. Ed. 2010, 49,
8946 – 8949; b) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C.
Hu, J. You, J. Am. Chem. Soc. 2010, 132, 1822 – 1824; c) C.-Y. He,
S. Fan, X. Zhang, J. Am. Chem. Soc. 2010, 132, 12850 – 12852;
d) S. Yanagisawa, K. Ueda, H. Sekizawa, K. Itami, J. Am. Chem.
Soc. 2009, 131, 14622 – 14623; e) H.-Q. Do, R. M. Kashif Khan,
O. Daugulis, J. Am. Chem. Soc. 2008, 130, 15185 – 15192; f) S.
Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer, K. Itami,
Angew. Chem. 2011, 123, 2435 – 2439; Angew. Chem. Int. Ed.
2011, 50, 2387 – 2391; g) P. Hu, M. Zhang, X. Jie, W. Su, Angew.
Chem. 2012, 124, 231 – 235; Angew. Chem. Int. Ed. 2012, 51, 227 –
231; h) N. Kuhl, M. N. Hopkinson, F. Glorius, Angew. Chem.
2012, 124, 8354 – 8358; Angew. Chem. Int. Ed. 2012, 51, 8230 –
8234; i) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2011, 133,
13577 – 13586.
[5] a) J. L. Garcꢂa Ruano, J. Alemꢀn, L. Marzo, C. Alvarado, M.
Tortosa, S. Dꢂaz-Tendero, A. Fraile, Angew. Chem. 2012, 124,
2766 – 2770; Angew. Chem. Int. Ed. 2012, 51, 2712 – 2716; For
other selected examples of transition-metal-free alkynylation
reactions, see: b) M. S. Maji, S. Murarka, A. Studer, Org. Lett.
2010, 12, 3878 – 3881; c) S. Protti, M. Fagnoni, A. Albini, Angew.
Chem. 2005, 117, 5821 – 5824; Angew. Chem. Int. Ed. 2005, 44,
5675 – 5678; d) P. L. DeRoy, S. Surprenant, M. Bertrand-
Laperle, C. Yoakim, Org. Lett. 2007, 9, 2741 – 2743; e) T.
Truong, O. Daugulis, Org. Lett. 2011, 13, 4172 – 4175.
[15] a) F. Zhang, M. F. Greaney, Angew. Chem. 2010, 122, 2828 –
2831; Angew. Chem. Int. Ed. 2010, 49, 2768 – 2771; b) A.
Garcꢂa-Rubia, R. G. Arrayꢀs, J. C. Carretero, Angew. Chem.
2009, 121, 6633 – 6637; Angew. Chem. Int. Ed. 2009, 48, 6511 –
6515; c) Z. Wang, K. Li, D. Zhao, J. Lan, J. You, Angew. Chem.
2011, 123, 5477 – 5481; Angew. Chem. Int. Ed. 2011, 50, 5365 –
5369; d) J. Ryu, S. H. Cho, S. Chang, Angew. Chem. 2012, 124,
3737 – 3741; Angew. Chem. Int. Ed. 2012, 51, 3677 – 3681; e) S. J.
Hwang, S. H. Cho, S. Chang, J. Am. Chem. Soc. 2008, 130,
16158 – 16159; f) P. Gandeepan, C. H. Cheng, J. Am. Chem. Soc.
2012, 134, 5738 – 5741; g) S. Yang, C. Sun, B. Li, Y. Li, Z. Shi,
Angew. Chem. 2008, 120, 1495 – 1498; Angew. Chem. Int. Ed.
2008, 47, 1473 – 1476; h) B. Xiao, Y. Fu, J. Xu, T.-J. Gong, J.-J.
Dai, J. Yi, L. Liu, J. Am. Chem. Soc. 2010, 132, 468 – 469; i) S.
Ding, N. Jiao, J. Am. Chem. Soc. 2011, 133, 12374 – 12377; j) M.
Nishino, K. Hirano, T. Satoh, M. Miura, Angew. Chem. 2012, 124,
7099 – 7103; Angew. Chem. Int. Ed. 2012, 51, 6993 – 6997; k) K.
Funaki, T. Sato, S. Qi, Org. Lett. 2012, 14, 6186 – 6189.
[6] For selected reviews, see: a) T. Satoh, M. Miura, Chem. Lett.
2007, 36, 200 – 205; b) X. Chen, K. M. Engle, D.-H. Wang, J.-Q.
Yu, Angew. Chem. 2009, 121, 5196 – 5217; Angew. Chem. Int. Ed.
2009, 48, 5094 – 5115; c) C.-J. Li, Acc. Chem. Res. 2009, 42, 335 –
344; d) O. Daugulis, H.-D. Do, D. Shabashov, Acc. Chem. Res.
2009, 42, 1074 – 1086; e) L. Ackermann, R. Vicente, A. R. Kapdi,
Angew. Chem. 2009, 121, 9976 – 10011; Angew. Chem. Int. Ed.
2009, 48, 9792 – 9826; f) T. W. Lyons, M. S. Sanford, Chem. Rev.
2010, 110, 1147 – 1169; g) C. S. Yeung, V. M. Dong, Chem. Rev.
2011, 111, 1215 – 1292; h) X. Bugaut, F. Glorius, Angew. Chem.
2011, 123, 7618 – 7620; Angew. Chem. Int. Ed. 2011, 50, 7479 –
7481; i) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111,
1780 – 1824; j) D.-G. Yu, B.-J. Li, Z.-J. Shi, Tetrahedron 2012, 68,
5130 – 5136; k) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F.
Glorius, Angew. Chem. 2012, 124, 10382 – 10401; Angew. Chem.
Int. Ed. 2012, 51, 10236 – 10254; l) J. Yamaguchi, A. D. Yama-
guchi, K. Itami, Angew. Chem. 2012, 124, 9092 – 9142; Angew.
Chem. Int. Ed. 2012, 51, 8960 – 9009.
[16] a) C. Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638 – 5639;
b) Y. Gao, G. Wang, L. Chen, P. Xu, Y. Zhao, Y. Zhou, L.-B. Han,
J. Am. Chem. Soc. 2009, 131, 7956 – 7957; c) M. Chen, X. Zheng,
W. Li, J. He, A. Lei, J. Am. Chem. Soc. 2010, 132, 4101 – 4103;
d) L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2010, 132, 7262 – 7263;
e) L. Zhou, F. Ye, J. Ma, Y. Zhang, J. Wang, Angew. Chem. 2011,
123, 3572 – 3576; Angew. Chem. Int. Ed. 2011, 50, 3510 – 3514;
f) C. Zhang, N. Jiao, J. Am. Chem. Soc. 2010, 132, 28 – 29; g) S.
Xiang, L.-H. Zhang, N. Jiao, Chem. Commun. 2009, 6487 – 6489;
h) J. A. Souto, P. Becker, ꢃ. Iglesias, K. MuÇiz, J. Am. Chem.
Soc. 2012, 134, 15505 – 15511; i) Z. Li, C.-J. Li, J. Am. Chem. Soc.
2004, 126, 11810 – 11811; j) H.-P. Bi, L. Zhao, Y.-M. Liang, C.-J.
Li, Angew. Chem. 2009, 121, 806 – 809; Angew. Chem. Int. Ed.
2009, 48, 792 – 795; k) F. Ye, X. Ma, Q. Xiao, H. Li, Y. Zhang, J.
Wang, J. Am. Chem. Soc. 2012, 134, 5742 – 5745; l) H. Wang, C.
Grohmann, C. Nimphius, F. Glorius, J. Am. Chem. Soc. 2012,
134, 19592 – 19595; m) S. Prateeptongkum, K. M. Driller, R.
Jackstell, A. Spannenberg, M. Beller, Chem. Eur. J. 2010, 16,
9606 – 9615.
[7] T. de Haro, C. Nevado, J. Am. Chem. Soc. 2010, 132, 1512 – 1513.
[8] a) Y. Wei, H. Zhao, J. Kan, W. Su, M. Hong, J. Am. Chem. Soc.
2010, 132, 2522 – 2523; b) N. Matsuyama, M. Kitahara, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 2358 – 2361;
c) S. H. Kim, J. Yoon, S. Chang, Org. Lett. 2011, 13, 1474 – 1477;
d) M. Kitahara, K. Hirano, H. Tsurugi, T. Satoh, M. Miura,
Chem. Eur. J. 2010, 16, 1772 – 1775.
[9] L. Yang, L. Zhao, C.-J. Li, Chem. Commun. 2010, 46, 4184 – 4186.
[10] a) R. Wang, Q.-X. Wu, Y.-P. Shi, Planta Med. 2010, 76, 893 – 896;
b) A. P. Spada, U.S. 207569, 2008; c) A. J. J. M. van Breemen,
P. T. Herwig, C. H. T. Chlon, J. Sweelssen, H. F. M. Schoo, S.
Setayesh, W. M. Hardeman, C. A. Martin, D. M. de Leeuw,
J. J. P. Valeton, C. W. M. Bastiaansen, D. J. Broer, A. R. Popa-
Merticaru, S. C. J. Meskers, J. Am. Chem. Soc. 2006, 128, 2336 –
2345.
[11] a) P. Siemsen, R. C. Livingston, F. Diederich, Angew. Chem.
2000, 112, 2740 – 2767; Angew. Chem. Int. Ed. 2000, 39, 2632 –
2657; b) W. Yin, C. He, M. Chen, H. Zhang, A. Lei, Org. Lett.
2009, 11, 709 – 712.
[17] See the Supporting Information for details.
[12] T. Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 833 –
835.
[13] Y. Weng, B. Cheng, C. He, A. Lei, Angew. Chem. 2012, 124,
9685 – 9689; Angew. Chem. Int. Ed. 2012, 51, 9547 – 9551.
[18] Cyclohexylacetylene and 1-octyne were tested.
[19] R. H. Pouwer, C. M. Williams, Silver Alkyls, Alkenyls, Aryls, and
Alkynyls in Organic Synthesis in Silver in Organic Chemistry
(Ed.: M. Harmata), Wiley, Hoboken, 2010.
4
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Dehydrogenative Coupling
X. Jie, Y. Shang, P. Hu,
W. Su*
&&&& — &&&&
Palladium-Catalyzed Oxidative Cross-
Coupling between Heterocycles and
Terminal Alkynes with Low Catalyst
Loading
Direct: With [Pd2(dba)3] as a catalyst, the
direct alkynylation of thiophenes bearing
a variety of substituents has been ac-
complished by using terminal alkynes as
alkynylating reagents. This protocol is
also applicable to other electron-rich
aromatic heterocycles. dba=dibenzyli-
denacetone.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!