Highly efficient and versatile pd-catalyzed direct alkynylation of both azoles and azolines

Article abstract of DOI:10.1021/ol100488v

A highly efficient and versatile Pd-catalyzed direct alkynylation reaction of heterocycles with 1-bromoalkynes was developed. The substrate scope of the reaction was very broad to include not only azoles but also azolines for the first time, thus offering an important advance in the direct functionalization of heterocycles.

Full text of DOI:10.1021/ol100488v

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1868-1871
Highly Efficient and Versatile
Pd-Catalyzed Direct Alkynylation of Both
Azoles and Azolines
Seok Hwan Kim and Sukbok Chang*
Department of Chemistry and Molecular-LeVel Interface Research Center, Korea
AdVanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
sbchang@kaist.ac.kr
Received February 26, 2010
ABSTRACT
A highly efficient and versatile Pd-catalyzed direct alkynylation reaction of heterocycles with 1-bromoalkynes was developed. The substrate
scope of the reaction was very broad to include not only azoles but also azolines for the first time, thus offering an important advance in the
direct functionalization of heterocycles.
The functionalization of heterocyclic compounds has
emerged as one of the most important topics in the field
of metal-catalyzed C-H bond activation due to the fact
that products are an important synthetic motif in organic
synthesis, the pharmaceutical industry, and materials
science.1 Therefore, a vast amount of effort has been made
to develop more efficient and versatile methods to
functionalize C-H bonds of various heterocycles, thus
leading to a range of catalytic systems of Pd, Rh, Cu, or
Ni.2 The recent advances have been directed mainly
toward the introduction of aryl, vinyl, or albeit in rare
cases, alkyl groups.3 On the other hand, the installation
of an alkynyl moiety at a proper position of heterocycles
has been less studied,4 although Yamaguchi reported an
ortho-selective alkynylation of benzene derivatives using
GaCl3.5 Recently, Miura4d and Piguel4e revealed that the
C-2 position of azoles was selectively alkynylated using
bromoalkynes under Ni and Cu catalysts, respectively.
Gevorgyan also reported an elegant protocol of the Pd-
catalyzed alkynylation of N-fused heterocycles.4a In
addition, Tobisu and Chatani developed a Pd-catalyzed
ortho-alkynylation of aromatic C-H bonds of anilides.6
(3) (a) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A.
Org. Lett. 2004, 6, 35. (b) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek,
A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. (c) Wiedemann, S. H.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 1685. (d) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (e) Do, H.-
Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (f) Lebrasseur, N.;
Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (g) Campeau, L.-C.;
Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.; Gorelsky, S.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 3276. (h) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848. (i) Besselie`vre, F.; Piguel,
S.; Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008, 10, 4029. (j)
Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737.
(k) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009,
48, 201. (l) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem., Int. Ed. 2009,
48, 3644.
(1) (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995. (b) Fisk, J. S.; Mosey,
R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36, 1432. (c) Carson, C. A.; Kerr,
M. A. Chem. Soc. ReV. 2009, 38, 3051.
(4) For alkynylations of N-fused rings or indole, see: (a) Seregin, I. V.;
Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (b) Gu,
Y.; Wang, X.-M. Tetrahedron Lett. 2009, 50, 763. (c) Brand, J. P.;
Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48, 9346. For
alkynylations of azoles, see: (d) Matsuyama, N.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 4156. (e) Besselie`vre, F.; Piguel, S. Angew.
Chem., Int. Ed. 2009, 48, 9553. (f) Kawano, T.; Matsuyama, N.; Hirano,
K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75, 1764. (g) Dudnik, A. S.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096.
(2) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (c) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (d) Lewis, J. C.; Bergman,
R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (e) Daugulis, O.; Do,
H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. For relevant works
from this laboratory, see: (f) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem.
Soc. ReV. 2004, 33, 302. (g) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am.
Chem. Soc. 2008, 130, 9254. (h) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am.
Chem. Soc. 2008, 130, 16158. (i) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang,
S. Angew. Chem., Int. Ed. 2009, 48, 9127. (j) Kim, M.; Kwak, J.; Chang,
S. Angew. Chem., Int. Ed. 2009, 48, 8935.
(5) (a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc.
2002, 124, 8528. (b) Amemiya, R.; Fujii, A.; Yamaguchi, M. Tetrahedron
Lett. 2004, 45, 4333.
10.1021/ol100488v  2010 American Chemical Society
Published on Web 03/25/2010

Although these achievements are promising, new catalytic
systems are still desired to further improve the reaction
efficiency and scope, thus making this approach more
attractive. In particular, a similar range of high efficiency is
required not only for various azoles which are the most
representatively employed substrate type in the precedent
catalyst systems4 but also for other types of partially saturated
heterocycles such as azolines which are an important building
motif in organic synthesis. Herein, we report a highly
efficient Pd-catalyzed direct alkynylation of both azoles and
azolines with 1-bromoalkynes.
product yield (entry 7), that of the 1-chloro derivative11 was
much more sluggish (entry 8).
The above optimized conditions were subsequently applied
to a range of 1-bromoalkynes in the reaction with 1a, and
the reaction proceeded well with various substrates including
previously reported ones4d,e (Table 2).12 Linear or cyclic
Table 2. Direct Alkynylation of 1a with 1-Bromoalkynesa
Optimization of the alkynylation reaction was first tried
using 5-methylbenzoxazole (1a) and 1-bromophenylacety-
lene under Pd catalyst systems (Table 1).7 It was found
entry
bromoalkyne (R)
time (h)
product
yieldb (%)
1
2
3
4
5
6
7
8
CH3(CH2)4CH2
cyclohexyl
Cl(CH2)3CH2
1-cyclohexenyl
Ph
(4-Me)C6H4
(4-Cl)C6H4
(4-Br)C6H4
(2-Br)C6H4
(4-CF3)C6H4
(4-MeO)C6H4
Si(i-Pr)3
4
2
2
4
2
4
4
4
2
4
4
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
75
85
69
97
99
92
95
80
87
80
89
79
Table 1. Optimization of the Pd-Catalyzed Alkynylation of 1a
with 1-Halophenylacetylenea
9
entry
X
ligand
solvent
toluene
toluene
toluene
toluene
base
yieldb (%)
10
11
12
3j
3k
3l
1
2
3
4
Br SPhos
Br SPhos
Br SPhos
Br none
Br Xantphos toluene
Br Xantphos 1,4-dioxane LiO-t-Bu
K2CO3
CsOAc
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
<5
18
82
17
79
99 (99)
79
a Reaction conditions: 1a (1.2 equiv), 2 (0.5 mmol), Pd(OAc)2 (2.5 mol
%), Xantphos (2.8 mol %) and LiOtBu (2 equiv) in 1,4-dioxane under 100 °C.
b Isolated yield.
5
6c
7c
8c
I
Cl
Xantphos 1,4-dioxane LiO-t-Bu
Xantphos 1,4-dioxane LiO-t-Bu
16
aliphatic 1-bromoalkynes (entries 1 and 2) or that bearing a
functional group (entry 3) were readily alkynylated at the
C-2 position of 1a. A bromoalkyne conjugated to the vinyl
group was also easily reacted under the conditions (entry
4). Arylacetylenes bearing various substituents were smoothly
installed at the C-2 position of 1a to afford the corresponding
2-alkynylheteroarenes in good to excellent yields (entries
5-11). It should be noted that the electronic and/or steric
variation on the phenyl substituents displayed negligible
effects on the reaction efficiency. In addition, the reaction
was completely chemoselective in that the bromo substituent
on the arylacetylenes was completely intact (entries 8 and
9). Significantly, bromosilylacetylene, a precursor of terminal
alkyne, was also readily reacted to afford the corresponding
silyl group-protected alkynylbenzoxazole (3l) in 79% yield
(entry 12).
a Reaction conditions: 1a (1.5 equiv), 2 (0.5 mmol), Pd(OAc)2 (5 mol
%), ligand (11 mol % for SPhos, 5.5 mol % for Xantphos), base (2 equiv).
b NMR yield and the number in parentheses is the isolated yield. c 1a (1.2
equiv), Pd(OAc)2 (2.5 mol %), and ligand (2.8 mol %) were used for 2 h.
that alkynylation at the C-2 position of benzoxazole took
place with low efficiency when Pd(OAc)2 was used with
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos)
and CsOAc (entry 2). In this case, most of the bro-
moalkyne was transformed to 1,4-diphenylbutadiyne (40%),
implying that dimerization is a major side reaction
competing with the desired reaction. As observed in the
previous examples of the azole couplings,3j,8 the reaction
efficiency was significantly improved when LiO-t-Bu was
employed as a base (entry 3). While only poor yield was
obtained in the absence of the ligand (entry 4), 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)
turned out to be the most effective ligand in 1,4-dioxane at
100 °C(entry 6). It should be noted that the homocoupling
of 1-bromoalkyne was completely inhibited under these
conditions.9 On the other hand, while the reaction of
1-iodophenylacetylene10 resulted in a slight decrease of
Next, we investigated the scope of azole heterocycles
under the reaction conditions (Table 3). The C-2 position of
parent oxazole was selectively alkynylated in high yields
(entries 1-2). Reactions of oxazoles bearing electronically
different aryl groups at the C-5 position took place with high
(10) For the preparation of 1-iodophenylacetylene, see: Xu, W.; Chen,
Q.-Y. J. Org. Chem. 2002, 67, 9421.
(6) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250.
(7) For details, see the Supporting Information.
(8) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11,
(11) For the preparation of 1-chlorophenylacetylene, see: Sud, D.;
Wigglesworth, T. J.; Branda, N. R. Angew. Chem., Int. Ed. 2007, 46, 8017.
(12) For the preparation of 1-bromoalkynes, see: (a) Li, L.-S.; Wu, Y.-
L. Tetrahedron Lett. 2002, 43, 2427. (b) Abou, A.; Foubelo, F.; Yus, M.
Tetrahedron 2007, 63, 6625. (c) Kim, J. Y.; Kim, S. H.; Chang, S.
Tetrahedron Lett. 2008, 49, 1745.
1733
.
(9) For an example of increased product yield by decreasing the amount
of catalyst, see: Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
Org. Lett., Vol. 12, No. 8, 2010
1869

Table 3. Direct Alkynylation of Azoles with 1-Bromoalkynesa
Table 4. Direct Alkynylation of Oxazolinesa
a Reaction conditions: 5 (1.5 equiv), 2 (0.5 mmol), Pd(OAc)2 (2.5 mol
%), Xantphos (2.8 mol %), and LiO-t-Bu (2 equiv) in 1,4-dioxane at 100
°C. TIPS indicates triisopropylsilyl. b Isolated yield. c Reaction was run for
16 h.
a Reaction conditions: 1 (1.2 equiv), 2 (0.5 mmol), Pd(OAc)2 (2.5 mol
%), Xantphos (2.8 mol %) and LiO-t-Bu (2 equiv) in 1,4-dioxane at 100
°C. b Isolated yield. c 1 (1.5 equiv) was used. d 1 (1.5 equiv), Pd(OAc)2 (5
mol %), and Xantphos (5.5 mol %) were used. e CuI (5 mol %) was used
as an additive. f GC yield of the product without CuI.
organic synthesis,14 the application of the direct alkynylation
protocol to oxazolines would draw intense interests for the
derivatization of those heterocyclic compounds.
Using 4,4-dimethyloxazoline as a test substrate, it was
observed that the alkynylation reaction proceeded smoothly
to afford the desired products in high yields (entries 1-4).
Notably, bromoalkynes substituted with silyl, conjugated
alkenyl, and alkyl groups were readily reacted with 4,4-
dimethyloxazoline (entries 5, 6, and 7, respectively), although
the last reaction provided just a moderate yield.15 The fact
that 4-phenyloxazoline was alkynylated only at the C-2
position in good yield demonstrates again that the reaction
is highly regioselective (entry 8). When 4,5-indanediylox-
azoline, prepared according to the Meyers’ procedure,16 was
subjected to the present conditions, the desired product was
obtained in synthetically acceptable yield (entry 9).
efficiency to give the corresponding 2-alkynyloxazoles
(entries 3-8).
It is highly noteworthy that the present alkynylation
protocol can also be applied to other types of heteroarenes,
although with slightly lower efficiency when compared to
(benz)oxazoles. For instance, derivatives of benzothiazole
(entries 9 and 10), benzimidazole (entry 11), or imidazole
(entry 12) were found to be included as reactive substrates
to afford the corresponding C-2 alkynylazoles. Interestingly,
the product yield was significantly improved by the addition
of catalytic amount of CuI in the reaction of benzothiazole
with 1-bromophenylacetylene, presumably due to the ben-
eficial effects of the copper additive.4e,13
Gratifyingly, it was found that the alkynylation reaction
was readily extended for the first time, to the best of our
knowledge, to partially saturated oxazolines and their
analogues under the optimal conditions (Table 4). Since
oxazoline moieties are highly versatile building blocks in
Meanwhile, it was observed that no racemization took
place during the course of the alkynylation reaction with the
(13) For examples of CuI additive effects on the Pd-catalyzed direct
arylation of azoles, see: (a) Satoh, T.; Kokubo, K.; Miura, M.; Nomura, M.
Organometallics 1994, 13, 4431. (b) Pivsa-Art, S.; Satoh, T.; Kawamura,
(15) For examples of the possible side reactions of initially produced
2-alkyloxazolines, see: (a) The Chemistry of Heterocycles; Eicher, T.,
Hauptmann, S., Eds.; Wiley-VCH: Weinheim, 2003. (b) Capriati, V.;
Degennaro, L.; Florio, S.; Luisi, R. Tetrahedron Lett. 2007, 48, 8651.
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467
.
(14) (a) Meyers, A. I.; Temple, D. L., Jr. J. Am. Chem. Soc. 1970, 92,
6644. (b) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837
.
1870
Org. Lett., Vol. 12, No. 8, 2010

use of an optically active 4-benzyloxazoline (eq 1). Since
chiral oxazolines have been widely used as ligands or
versatile precursors in asymmetric synthesis,17 a direct
alkynylation of chiral oxazolines would offer a new and
convenient opportunity for the functionalization of those
compounds.
intermediate (B).20 As the final step of the catalytic cycle,
reductive elimination of B produces 2-alkynyl heterocycles
upon the regeneration of Pd(0) species.
While a precise description of the reaction paths of the
present Pd-catalyzed direct alkynylation of heterocycles still
requires comprehensive mechanistic studies, a proposal is
presented in Scheme 1 on the basis of preliminarily obtained
The negligible primary kinetic isotope effect (KIE) observed
in the alkynylation of d-labeled 5-methylbenzoxazole (eq 2)21
may support that the transmetalation step does not proceed via
the C-H bond activation pathway.22 However, since the KIE
value is in the range of those for the arylation of heterocycles
via an electrophilic pathway,4a an alternative route involving
an electrophilic addition of deprotonated heterocycles to the
Pd-acetylide complex A can also be considered. In addition,
although a palladacyclic species was suggested by Chatani
as a plausible intermediate in the coupling reaction of
1-bromoalkynes with aromatic C-H bonds in anilides,6 this
can be ruled out herein since 1,3-diynes were detected as
side products albeit in trace amounts in all cases examined.
In summary, we have developed a highly efficient and
versatile Pd-catalyzed direct alkynylation reaction of het-
erocycles with 1-bromoalkynes to afford 2-alkynylhetero-
cycles. The substrate scope of the reaction turned out to be
very broad to include not only azoles but also partially
saturated azolines for the first time, thus offering an important
advance in the direct functionalization of heterocycles.
Scheme 1
.
Plausible Mechanism of the Pd-Catalyzed Direct
Alkynylation of Heterocycles
kinetic data and precedent reports on the relevant arylation
reactions.3d,18
Acknowledgment. This research was supported by the
Korea Research Foundation (KRF-2008-C00024, Star Fac-
ulty Program) and MIRC (SRC). We acknowledge the Korea
Basic Science Institute (KBSI) for the mass analysis.
An oxidative addition of 1-bromoalkyne (2) to a zerovalent
Pd species is envisioned to take place as an initial step
leading to a Pd-acetylide intermediate (A). In fact, it was
observed that Pd(PPh3)4 also catalyzed the alkynylation with
a comparable yield under otherwise identical conditions.19
It is then presumed that the employed base (LiO-t-Bu)
abstracts a proton at the C-2 position of heterocycles
employed, and a transmetalation process of thus-formed
lithiated heterocyclic species with the Pd-acetylide complex
A would occur to generate a heterocyclic alkynylpalladium
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100488V
(20) (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.
(16) Leonard, W. R.; Romine, J. L.; Meyers, A. I. J. Org. Chem. 1991,
56, 1961.
(17) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96,
835. (b) Meyers, A. I. J. Org. Chem. 2005, 70, 6137.
(18) Sa´nchez, R. S.; Zhuravlev, F. A. J. Am. Chem. Soc. 2007, 129,
(21) For the preparation of d-labeled 5-methylbenzoxazole, see: Crowe,
E.; Hossner, F.; Hughes, M. J. Tetrahedron 1995, 51, 8889.
(22) For examples of higher KIE values in the case of C-H bond
activation, see: (a) Jones, W. D. Acc. Chem. Res. 2003, 36, 140. (b) Lafrance,
M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
8754.
5824
.
(19) A reaction of 5-methylbenzoxazole with 1-bromophenylacetylene
using Pd(PPh3)4 instead of Pd(OAc)2 under the optimized conditions afforded
79% yield of the corresponding product.
Org. Lett., Vol. 12, No. 8, 2010
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