Nickel-catalyzed direct alkynylation of azoles with alkynyl bromides

Article abstract of DOI:10.1021/ol901684h

The direct C - H alkynylation of azoles with alkynyl bromides proceeds efficiently In the presence of a nickel-based catalyst system. The reaction enables the introduction of various alkynyl groups bearing aryl, alkenyl, alkyl, and silyl substituents to t

Full text of DOI:10.1021/ol901684h

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4156-4159
Nickel-Catalyzed Direct Alkynylation of
Azoles with Alkynyl Bromides
Naoto Matsuyama, 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 July 23, 2009
ABSTRACT
The direct C-H alkynylation of azoles with alkynyl bromides proceeds efficiently in the presence of a nickel-based catalyst system. The
reaction enables the introduction of various alkynyl groups bearing aryl, alkenyl, alkyl, and silyl substituents to the azole cores. In some
cases, addition of a catalytic amount of CuI is observed to accelerate the direct coupling dramatically.
Metal-mediated reactions involving C-H bond cleavage have
received significant attention in modern organic chemistry
due to their possibilities for transformation of the ubiquitous
C-H bonds into diverse functions in one synthetic opera-
tion.1 In particular, catalytic C-C bond formation from
unreactive C-H bonds with organic halides or pseudohalides
may allow the facile increase of molecular complexity and
complement the conventional metal-catalyzed cross-coupling
strategies with organometallic compounds.2 To date, a variety
of catalyst systems have been explored for the direct sp2
C-H arylation and alkenylation. On the other hand, only a
few examples of the corresponding sp2 C-H alkynylation
with alkynyl halides have been reported.3-5 Yamaguchi
described the pioneering work, gallium-catalyzed direct
alkynylation of phenols and N-benzylanilines.3 Subsequently,
Gevorgyan4a and Gu4b developed palladium-based methods
for the alkynylation of highly electron-rich heteroarenes,
N-fused heterocycles and indoles, respectively. Very recently,
Tobisu and Chatani succeeded in the coordination-assisted
ortho-alkynylation of acetanilides under palladium catalysis.5
Although these processes can compensate for the conven-
tional Sonogashira coupling,6 the scope and generality are
still restricted. Thus, the development of new catalyst systems
for this type of transformation is strongly desired.
During our recent studies on the metal-catalyzed direct
arylation reaction of heteroarenes, we found the potential
catalytic activity of nickel complexes for the direct C2
arylation of azoles with aryl bromides.7 Here, we report the
nickel-catalyzed direct alkynylation of azoles with alkynyl
bromides. The nickel-based catalyst enables various alkynyl
bromides to serve as promising alkynyl sources to azoles.
Additionally, in some cases, addition of a catalytic amount
(1) Recent reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(c) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrichchim. Acta 2007, 40,
35. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (e)
Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (f)
Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (g) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(4) (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.
Moran also reported the palladium-catalyzed direct alkynylation of N-phenyl
sydnone with (bromoethynyl)benzene albeit with a low yield (34%). (c)
Rodriguez, A.; Fennessy, R. V.; Moran, W. J. Tetrahedron Lett. 2009, 50,
3942.
(5) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250.
(6) (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.
(2) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b) Tsuji,
J. Palladium Reagents and Catalysts, 2nd ed.; Wiley: Chichester, UK, 2004.
(c) Cross-Coupling Reactions; Miyaura, N., Ed. Topics in Current Chem-
istry; Springer: Berlin, Germany, 2002; No. 219.
(7) (a) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009,
11, 1737. See also: (b) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org.
Lett. 2009, 11, 1733. (c) Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org.
Lett. 2009, 11, 2679.
(3) (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/ol901684h CCC: $40.75
Published on Web 08/24/2009
 2009 American Chemical Society

of CuI is observed to enhance the reaction dramatically. As
certain alkynyl-substituted azoles work as selective DNA
cleavage agents,8 and azole-containing π-conjugated mol-
ecules are found in many natural products, pharmaceuticals,
and functional materials,9 and this transformation appears
to be of considerable synthetic utility.
Table 2. Nickel-Catalyzed Direct Alkynylation of Benzoxazole
(1) with Various Alkynyl Bromides 2a
Table 1. Optimization for Nickel-Catalyzed Direct Alkynylation
of Benzoxazole (1) with (Bromoethynyl)benzene (2a)a
entry
ligand
temp
time (h)
3a, yield (%)b
1
2
3
4
5
6
7
8
9
phenc
dppbz
dppp
dppf
PPh3
PCy3
dppbz
dppp
dppf
rt
rt
rt
rt
rt
rt
reflux
reflux
reflux
reflux
reflux
72
72
72
72
72
72
1
6
6
1
1
14
29
29
36
trace
2
76
49
41
10d
11d,e
dppbz
dppbz
85 (84)
73
a A mixture of 1 (0.25 mmol), 2a (0.25 mmol), Ni(cod)2 (0.013 mmol),
ligand (0.013 mmol), and LiO-t-Bu (0.50 mmol) was stirred in toluene (2.5
mL). b GC yield. Yield of isolated compound is in parentheses. c phen )
1,10-phenanthroline. d 2a (0.30 mmol). e With Ni(acac)2 (0.013 mmol) and
Zn (0.025 mmol) instead of Ni(cod)2.
a A mixture of 1 (0.25 mmol), 2 (0.30 mmol), Ni(cod)2 (0.013 mmol),
dppbz (0.013 mmol), and LiO-t-Bu (0.50 mmol) was stirred in boiling
toluene (2.5 mL) for 1 h. b Yield of isolated compounds.
We initially investigated the effect of various ligands using
benzoxazole (1) and (bromoethynyl)benzene (2a) as model
substrates in the presence of 5 mol % of Ni(cod)2 and 2.0
equiv of LiO-t-Bu at room temperature (Table 1, entries
1-6). The reaction with our previous optimal ligand, 1,10-
phenanthroline (phen),7a in toluene afforded the alkynylated
product 3a albeit with only 14% yield (entry 1). The use of
P-based bidentate ligands resulted in higher yields of 3a
(entries 2-4), while common monodentate phosphines
showed no catalytic activity (entries 5 and 6). Elevating the
temperature effectively accelerated the coupling. Especially
with the Ni(cod)2/1,2-bis(diphenylphosphino)benzene (dp-
pbz) catalyst system in refluxing toluene, the direct alkyny-
lation was complete within 1 h to furnish 3a in 76% yield
(entry 7). An increase in the amount of 2a to 1.5 equiv further
improved the yield to 84% isolated yield (entry 10). Notably,
the combination of bench-stable Ni(acac)2 and Zn instead
of air-sensitive Ni(cod)2 was also available for use, providing
the desired product 3a in an acceptable yield (entry 11).
With the optimized conditions in hand, we carried out the
direct alkynylation of benzoxazole (1) with a variety of
alkynyl bromides 2 (Table 2). 4-Methyl-, 4-chloro-, 4-tri-
fluoromethyl-substituted (bromoethynyl)benzenes 2b-d re-
acted with 1 smoothly to give the corresponding alkynyla-
zoles 3b-d in good yields (entries 2-4). The sterically
demanding 1-naphthyl group did not interfere with the
reaction (entry 5). The conjugated enyne 2f was transformed
to the desired 3f in 73% yield with the olefin moiety left
intact (entry 6). The alkynyl bromide 2g bearing an aliphatic
substituent also participated in the direct coupling. It should
be noted that the use of such an aliphatic substrate is not
trivial in the catalytic direct alkynylation (entry 7).10 The
introduction of the silylethynyl group, which would be
readily further functionalized, to the benzoxazole core was
possible (entry 8).
The Ni(cod)2/dppbz system could be applied to the direct
alkynylation of 5-aryloxazoles (Table 3). Under reaction
conditions similar to those in Table 2, the alkynylation of
an array of oxazoles 4a-e with (bromoethynyl)benzene (2a)
proceeded efficiently to produce the azole core π systems
5aa-ea in good to high yields (entries 1-5). The bulky
(8) Kumar, D.; David, W. M.; Kerwin, S. M. Bioorg. Med. Chem. Lett.
2001, 11, 2971.
(9) (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (b) Corbet, J.-P.; Mignani, G. Chem. ReV.
2006, 106, 2651.
(10) Only one precedent, to the best of our knowledge: see ref 4a.
Org. Lett., Vol. 11, No. 18, 2009
4157

Scheme 1
Table 3. Nickel-Catalyzed Direct Alkynylation of Various
5-Aryloxazoles 4 with Alkynyl Bromides 2a
nyl)benzothiazole (7) was isolated in 70% yield. Moreover,
the Ni/Cu cooperative catalyst system allowed the use of
N-phenylbenzimidazole (8) and 3,4-diphenyl-4H-1,2,4-tria-
zole (10) (Scheme 1, eq 2) as well, as it improved the reaction
efficiency in the coupling of 4a with 2h (Scheme 1, eq 3 vs.
entry 7 in Table 3).
Scheme 2
a A mixture of 4 (0.25 mmol), 2 (0.30 mmol), Ni(cod)2 (0.013 mmol),
dppbz (0.013 mmol), and LiO-t-Bu (0.50 mmol) was stirred in boiling
toluene (1.0 mL) for 3 h. b Yield of isolated compounds. c At 150 °C in
o-xylene.
naphthalene motif and electron-donating methoxyphenyl
substitution in the alkynyl bromide were tolerant toward the
reaction (entries 6 and 8). On the contrary, the coupling with
silylethynyl bromide 2h led to compound 5ah in a lower
yield (entry 7).
Next, we attempted the direct alkynylation of benzothia-
zole (6) with 2a (Scheme 1, eq 1). On exposure of 6 and 2a
to the standard reaction conditions, however, no expected
coupled product was detected. After some additional opti-
mization studies, the addition of 5 mol % of CuI was found
to enhance the reaction dramatically,11 and 2-(phenylethy-
We are tempted to assume the mechanism of the reaction
as follows (Scheme 2). Initial oxidative addition of alkynyl
bromide 2 to a zerovalent Ni species 12 affords the
corresponding (alkynyl)nickel intermediate 13. Subsequent
transmetalation with heteroaryllithium compound 14 gener-
ated in situ from heteroarene and LiO-t-Bu12 followed by
(11) A similar effect of CuI was observed in the palladium-catalyzed
direct arylation of azoles: Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura,
M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
(12) Deprotonation of heteroarenes with LiO-t-Bu: (a) Do, H.-Q.; Khan,
M. R. K.; Daugulis, O J. Am. Chem. Soc. 2008, 130, 15185. (b) Do, H.-Q.;
Daugulis, O. Org. Lett. 2009, 11, 421.
4158
Org. Lett., Vol. 11, No. 18, 2009

productive reductive elimination furnishes the alkynylated
product along with the starting nickel complex to complete
the catalytic cycle. Although the exact role of CuI as seen
in Scheme 1 is not clear at this stage, the formation of
heteroarylcopper 15 would be most plausible.13 Such species
may undergo transmetalation with 13 more readily than the
corresponding organolithium.14
In summary, we have described an effective nickel-based
strategy for the direct alkynylation of azoles with alkynyl
bromides. The catalytic system is quite effective for the
relatively electron-deficient heteroarenes so as to complement
the precedent gallium- and palladium-mediated processes.3-5
Ongoing work seeks to develop the related C-H cleavage
processes by nickel catalysts.
(13) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett.
2008, 10, 3081. (c) Besselie`vre, F.; Piguel, S.; Mahuteau-Betzer, F.;
Grierson, D. S. Org. Lett. 2008, 10, 4029. (d) Yoshizumi, T.; Tsurugi, H.;
Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598. (e) Yotphan, S.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11, 1511. (f) Yoshizumi,
T.; Satoh, T.; Hirano, K.; Matsuo, D.; Orita, A.; Otera, J.; Miura, M.
Tetrahedron Lett. 2009, 50, 3273. (g) Zhao, D.; Wang, W.; Yang, F.; Lan,
J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (h)
Kawano, T.; Yoshizumi, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 3072.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
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.
(14) Nevertheless, our preliminary investigation indicated that 19% GC
yield of 7 was detected only in the presence of a catalytic amount of CuI
although the formation of diyne side product predominantly occurred
(Scheme 1, eq 1). Further efforts for the clarification of the role of CuI are
ongoing.
OL901684H
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