Nickel- and copper-catalyzed direct alkynylation of azoles and polyfluoroarenes with terminal alkynes under O2 or atmospheric conditions

Article abstract of DOI:10.1021/ol100699g

The direct C-H alkynylation of azoles with terminal alkynes proceeds efficiently under a nickel/O₂ catalytic system. On the other hand, a copper/air catalyst enables the coupling of polyfluoroarenes with terminal alkynes. These catalyses provide new accesses to arylacetylenes through the formal direct Sonogashira coupling.

Full text of DOI:10.1021/ol100699g

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2358-2361
Nickel- and Copper-Catalyzed Direct
Alkynylation of Azoles and
Polyfluoroarenes with Terminal Alkynes
under O2 or Atmospheric Conditions
Naoto Matsuyama, Masanori Kitahara, Koji Hirano, Tetsuya Satoh, and
Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
Received March 25, 2010
ABSTRACT
The direct C-H alkynylation of azoles with terminal alkynes proceeds efficiently under a nickel/O2 catalytic system. On the other hand, a
copper/air catalyst enables the coupling of polyfluoroarenes with terminal alkynes. These catalyses provide new accesses to arylacetylenes
through the formal direct Sonogashira coupling.
Arylacetylenes are among the most fundamental and impor-
tant π-conjugated systems in the various fields of organic
Scheme 1. Approaches to Arylacetylenes
chemistry. A powerful and reliable approach to these
molecules is the palladium/copper-catalyzed cross-coupling
of aryl halides with terminal alkynes, that is, Sonogashira
coupling (Scheme 1, eq 1).1 On the other hand, the metal-
catalyzed direct alkynylation of arene C-H bonds with
alkynyl halides or pseudohalides has recently been receiving
much attention as a complementary process to Sonogashira
coupling (Scheme 1, eq 2).2 Ultimately, the direct coupling
between arenes and terminal alkynes via C-H bond cleavage
of both substrates is an ideal goal since no preactivation step
is required (Scheme 1, eq 3). However, this type of cross-
coupling has been greatly challenging probably due to the
difficulties of catalyst control in the sequential activation of
two different C-H bonds.
Recently, we found that an appropriate copper species
enabled the direct sp2/sp C-H coupling of heteroarenes
involving 5-aryloxazoles and 1,3,4-oxadiazoles.3 Although
the reaction provided the most straightforward access to
arylacetylenes, use of a stoichiometric or substoichiometric
amount of copper was essential. Thus, the catalytic variants
(1) (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. (b) Negishi,
E.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (c) Tykwinski, R. R. Angew.
Chem., Int. Ed. 2003, 42, 1566. (d) Chinchilla, R.; Na´jera, C. Chem. ReV.
2007, 107, 874. (e) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007,
46, 834. (f) Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954.
10.1021/ol100699g  2010 American Chemical Society
Published on Web 04/23/2010

still remain elusive.4 Herein, we report the nickel- and
copper-catalyzed direct alkynylations of azoles and poly-
fluoroarenes; while the nickel catalyst is effective for the
reaction with azoles, the copper one shows unique activity
for polyfluoroarenes. Since the acetylenes conjugated with
these aromatics are often found in medicinal5 and material6
chemistry areas, this transformation appears to be of interest
in organic synthesis.
Table 1. Nickel-Catalyzed Direct Alkynylation of Benzoxazole
(1a) with Terminal Alkynes 2a
During our recent studies on the nickel-catalyzed direct
alkynylation of azoles with alkynyl bromides,2g we hypoth-
esized that the replacement of alkynyl bromides with terminal
alkynes could be possible and the use of O2 rendered the
reaction catalytic on nickel. Indeed, treatment of benzoxazole
(1a) with (2-methylphenyl)acetylene (2a) in the presence of
5 mol % of NiBr2·diglyme, 5 mol % of 4,4′-di(tert-butyl)-
2,2′-bipyridine (dtbpy), and LiO-t-Bu in toluene at 100 °C
under O2 (1 atm, balloon) gave the direct cross-coupling
product 3aa in 62% yield (Table 1, entry 1).7 Under similar
reaction conditions, arylacetylenes with various substitution
patterns participated in the direct coupling (entries 2-8). The
naphthylalkynyl moiety could also be introduced to the
benzoxazole core (entry 9). The alkyne 2j reacted with 1a
to afford the corresponding heteroarylacetylene 3aj in an
acceptable yield, leaving the terminal olefin moiety un-
touched (entry 10). The alkylacetylene 2k was also available
for use by simple temperature control (entry 11). The slow
addition of 1a was beneficial for the reaction with silylacety-
lene 2l (entry 12).
The above reaction conditions, with some variations as
noted, could be applied to the alkynylation of other azoles
(Table 2). The benzoxazoles bearing methyl, phenyl, and
chloro substituents at the 5-position coupled with pheny-
lacetylene (2d) as well as silylacetylene 2l to create the
(2) Ga: (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. Pd: (c) Seregin, I. V.; Ryabova, V.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (d) Gu, Y.; Wang, X.-
m. Tetrahedron Lett. 2009, 50, 763. (e) Rodriguez, A.; Fennessy, R. V.;
Moran, W. J. Tetrahedron Lett. 2009, 50, 3942. (f) Tobisu, M.; Ano, Y.;
Chatani, N. Org. Lett. 2009, 11, 3250. Ni: (g) Matsuyama, N.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156. Cu: (h) Besselie´vre, F.;
Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553. (i) Kawano, T.;
Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75,
1764. Au: (j) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int.
Ed. 2009, 48, 9346. See also: (k) Dudnik, A. S.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2010, 49, 2096.
(3) (a) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M.
Chem.sEur. J. 2010, 16, 1772. A gold-mediated process is also known:
(b) Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem. Soc., Dalton Trans.
2001, 2330.
a A mixture of 1a (0.50 mmol), 2 (1.0 mmol), NiBr2·diglyme (0.025
mmol), dtbpy (0.025 mmol), and LiO-t-Bu (1.5 mmol) was stirred in toluene
(2.5 mL) at 100 °C for 1 h under O2 atmosphere (1 atm). b Yield of isolated
compounds. c With 1.5 mmol of 2 and 2.0 mmol of LiO-t-Bu. d In 1.5 mL
of toluene. e At 80 °C. f A solution of 1a in 1.0 mL of toluene was slowly
added to a mixture of 2l, NiBr2·diglyme, dtbpy, and LiO-t-Bu in toluene
(1.5 mL) over 30 min at 80 °C, and the resulting mixture was stirred for
the additional 1.5 h at the same temperature.
(4) During the preparation of this manuscript, two successful examples
of the catalytic direct coupling of arenes with terminal alkynes have been
reported. Au: (a) de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132,
1512. Cu: (b) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem.
Soc. 2010, 132, 2522.
(5) Kumar, D.; David, W. M.; Kerwin, S. M. Bioorg. Med. Chem. Lett.
2001, 11, 2971.
(6) (a) Callstrom, M. R.; Neenan, T. X.; McCreery, R. L.; Alsmeyer,
D. C. J. Am. Chem. Soc. 1990, 112, 4954. (b) Dai, C.; Nguyen, P.; Marder,
T. B.; Scott, A. J.; Clegg, W.; Viney, C. Chem. Commun. 1999, 2493. (c)
Meyer, E. A.; Castelano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003,
42, 1210.
heteroarylalkyne conjugations in moderate to good yields
(3bd-dd and 3bl-dl). Notably, various 5-aryloxazoles
having not only electron-rich 1e-g but also electron-deficient
aryl groups 1h-j underwent the direct alkynylation with 2l
albeit with the higher catalyst loading (3el-jl). The sterically
demanding naphthalene motif did not interfere with the
(7) Other N-based ligands such as 1,10-phenanthroline and 2,2′-
bipyridine resulted in the lower yield by ca. 10% and had no influence on
product selectivity. The combination of toluene and LiO-t-Bu was necessary
for the reaction. The use of polar solvents and other bases such as Na- or
KO-t-Bu was detrimental due to the rapid decomposition of the starting
materials.
Org. Lett., Vol. 12, No. 10, 2010
2359

and productive reductive elimination provides the cross-
coupling product 3 along with the zerovalent nickel complex
8. The oxidation of 8 with molecular oxygen regenerates 4,
possibly via a Ni(O2) species,10-12 to complete the catalytic
cycle. If the reaction of 5 with the second alkyne 2 preferably
occurred, the undesired diyne would be obtained via forma-
tion of bis(alkynyl)nickel 9. Indeed, a detectable amount of
the homocoupling product was often confirmed by GC
analysis. The findings and the beneficial effect of the alkyne
slow addition technique observed in some cases (Table 2,
3el-3ll) are consistent with the proposed mechanism.
Next, we attempted the direct alkynylation of polyfluo-
roarenes since the pKa value of their sp2 C-H bonds is as
high as those of azoles so that the effective activation by
nickel catalysts was anticipated.8 However, pentafluoroben-
zene (10a) showed no activity under the above reaction
conditions. Any changes of reaction parameters gave no
positive effect. On the basis of our previous observation,3a
we then turned our attention to the copper catalyst.4b To our
delight, a combination of Cu(OTf)2/phen·OH2 (phen )1,10-
phenanthroline) in DMSO was found to catalyze without any
other additives the direct coupling of 10a with 2d even at
room temperature under atmospheric conditions to produce
11ad (Table 3).13 By using the copper-based catalyst system,
the reaction of an array of terminal alkynes 2 with poly-
Table 2. Nickel-Catalyzed Direct Alkynylation of Various
Azoles 1 with Terminal Alkynes 2d or 2l
a Yield of isolated compounds. b Conditions A: see Table 1. Conditions
B: a solution of 1 (0.50 mmol) in toluene (1.0 mL) was slowly added to a
mixture of 2 (1.0 mmol), NiBr2·diglyme (0.025 mmol), dtbpy (0.025 mmol),
and LiO-t-Bu (1.5 mmol) in toluene (2.5 mL) over 1 h under O2 atmosphere
(1 atm), and the resulting mixture was stirred for the indicated time.
Conditions C: a solution of 2 (1.5 mmol) in toluene (1.0 mL) was slowly
added to a mixture of 1 (0.50 mmol), NiBr2·diglyme (0.075 mmol), dtbpy
(0.075 mmol), and LiO-t-Bu (2.0 mmol) in toluene (2.5 mL) over 30 min
under O2 atmosphere (1 atm), and the resulting mixture was stirred for the
indicated time. Conditions D: a solution of 2 (1.5 mmol) in toluene (1.0
mL) was slowly added to a mixture of 1 (0.50 mmol), NiBr2·diglyme (0.075
mmol), dtbpy (0.075 mmol), and LiO-t-Bu (2.0 mmol) in toluene (2.5 mL)
over 1 h under O2 atmosphere (1 atm), and the resulting mixture was stirred
for the indicated time.
Table 3. Copper-Catalyzed Direct Alkynylation of
Polyfluoroarenes 10 with Terminal Alkynes 2a
reaction (3kl). Moreover, the coupling of benzothiazole (1l)
with 2l was also possible (3ll).
We are tempted to assume the reaction mechanism as
follows (Scheme 2). A nickel(II) complex 4 generated in
Scheme 2
a A mixture of 10 (1.5 mmol), 2 (0.50 mmol), Cu(OTf)2 (0.10 mmol),
phen·OH2 (0.20 mmol), and LiO-t-Bu (0.50 mmol) was stirred in DMSO
(1.5 mL) at room temperature under air. Key: 10a, X ) F; 10b, X ) CF3;
2d, Ar ) Ph; 2b, Ar ) 4-MeC6H4; 2e, Ar ) 4-MeOC6H4; 2m, Ar )
4-Me2NC6H4; 2n, Ar ) 4-FC6H4; 2o, Ar ) 4-MeO2CC6H4. b Yield of
isolated compounds. Yield on 5.0 mmol scale is in parentheses.
situ initially reacts with terminal alkyne 2 with the aid of
LiO-t-Bu to generate (alkynyl)nickel intermediate 5. Sub-
sequently, heteroaryllithium 6 formed through the deproto-
nation of the relatively acidic sp2 C-H bond of azole 18 by
the action of LiO-t-Bu9 undergoes transmetalation with 5,
2360
Org. Lett., Vol. 12, No. 10, 2010

fluoroarenes 10 was implemented (Table 3). The substitutions
of electron-donating groups on the benzene ring at the alkyne
terminus increased the yield of the products (11ab, 11ae,
and 11am). On the contrary, the electron-deficient nature of
fluoro and methoxycarbonyl groups dropped the reaction
efficiency, and the detectable amounts of diyne side products
were observed (11an and 11ao). Among other polyfluoro-
arenes tested, 1,2,4,5-tetrafluoro-3-(trifluoromethyl)benzene
(10b) was available for use, and the corresponding (poly-
fluoroaryl)acetylenes 11be and 11bm were obtained, albeit
with moderate yields.14 Moreover, a 10-fold larger scale
synthesis of 11ae was possible, indicating the good reliability
of the process.
In summary, we have described effective nickel- and
copper-based catalyst systems for the direct alkynylation of
azoles and polyfluoroarenes with terminal alkynes using
molecular oxygen as the sole oxidant, which is quite
beneficial from an atom-economical point of view. These
strategies are regarded as direct Sonogashira coupling and
represent a new, concise avenue to arylacetylenes. Ongoing
work seeks to develop the related C-H cleavage processes
under the oxidative nickel- or copper-oxygen catalysis.
(8) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007,
63, 1568.
(9) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185.
(10) The isolation of η2-Ni(O2) complex has been reported. Yao, S.;
Bill, E.; Milsmann, C.; Wieghardt, K.; Driess, M. Angew. Chem., Int. Ed.
2008, 47, 7110. (b) In our system, a zerovalent Ni precursor, Ni(cod)2,
worked as the catalyst under the conditions in Table 1, which also supports
the existence of the η2-Ni(O2) complex as the active species.
(11) An analogous reaction of the Pd(O2) complex with arylboronic
acids: Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J. Am.
Chem. Soc. 2006, 128, 6829.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
(12) Generation of the Ni(O2) species from the zerovalent Ni and O2:
(a) Wilke, G.; Schott, H.; Heimbach, P. Angew. Chem., Int. Ed. Engl. 1967,
6, 92. (b) Otsuka, S.; Nakamura, A.; Tatsuno, Y. J. Am. Chem. Soc. 1969,
91, 6994. A similar intermediate was proposed in other nickel-catalyzed
reaction: (c) Yin, W.; He, C.; Chen, M.; Zhang, H.; Lei, A. Org. Lett. 2009,
11, 709. Also see: (d) Truong, T.; Alvarado, J.; Tran, L. D.; Daugulis, O.
Org. Lett. 2010, 12, 1200. However, the mechanism involving nucleophilic
attack of the nickel acetylide intermediate on azole is not completely
discarded: (e) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009,
131, 12070.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) The use of dried 1,10-phenanthroline resulted in poor reproducibility.
With LiOH instead of LiO-t-Bu, which is conceivably generated in situ from
LiO-t-Bu and H2O, the reaction proceeded to give 11ad in a somewhat lower
yield (ca. 40%). We do not have an explanation for the reason at this stage.
The choice of solvent was also crucial. Less polar solvent such as toluene
completely failed to lead to the formation of 11ad.
OL100699G
(14) The reaction with tri- and difluoroarenes or alkylalkynes was
unsuccessful probably due to their insufficient acidities of C-H bonds.
Org. Lett., Vol. 12, No. 10, 2010
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