Ruthenium-catalyzed direct ortho-alkynylation of arenes with chelation assistance

Article abstract of DOI:10.1055/s-0032-1316556

The ruthenium-catalyzed direct alkynylation of arenes with the chelation assistance of nitrogen-containing heterocycles including pyridine, pyrimidine, pyrazole, and imidazole are described. The alkynylation is successful even in the presence of an acidic N-H bond. Broad compatibility with functional groups is observed under catalytic conditions. The obtained alkynylated products could serve as precursors for polycyclic heteroarenes. Copyright

Full text of DOI:10.1055/s-0032-1316556

CLUSTER
▌2763
cluster
Ruthenium-Catalyzed Direct ortho-Alkynylation of Arenes with Chelation
Assistance
Ruthenium-Catalyzed C–H Alkynylation
Yusuke Ano,a Mamoru Tobisu,*b Naoto Chatani*a
a
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax +81(6)68797396; E-mail: chatani@chem.eng.osaka-u.ac.jp
b
Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax +81(6)68797396; E-mail: tobisu@chem.eng.osaka-u.ac.jp
Received: 18.04.2012; Accepted after revision: 28.05.2012
nyl)pyridine (1) were unsuccessful (Table 1, entry 1).8c
Abstract: The ruthenium-catalyzed direct alkynylation of arenes
Next, we turned our attention to using ruthenium-based
with the chelation assistance of nitrogen-containing heterocycles in-
catalysts. One of the earliest examples of directed C–H
cluding pyridine, pyrimidine, pyrazole, and imidazole are de-
scribed. The alkynylation is successful even in the presence of an
bond functionalization was achieved using a ruthenium
acidic N–H bond. Broad compatibility with functional groups is ob- catalyst.11 More recently, Inoue, Oi, Ackermann, Dixneuf,
served under catalytic conditions. The obtained alkynylated prod-
ucts could serve as precursors for polycyclic heteroarenes.
and others successfully used ruthenium catalysts in C–H
bond functionalization reactions, such as arylations,12a–o
alkenylations,12a–c,p–s alkylations,12t–w and others.1h,12x–z
Key words: ruthenium, alkyne, heteroarene, C–H activation, che-
lation
However, ruthenium-catalyzed C–H bond activation has
never been applied to alkynylation reactions. Extensive
screening of catalyst precursors revealed that the desired
Transition-metal-catalyzed C–H bond activation–func- alkynylation was promoted by using [RuCl2(p-cymene)]2
tionalization reactions are recognized as a straightforward or RuCl2(cod) (Table 1, entries 2 and 3). Other ruthenium
method for the efficient and selective synthesis of the complexes, including RuCl2(PPh3)2, Cp*RuCl2, and
molecules used in the pharmaceutical, agrochemical, and Ru3(CO)12 were less effective as catalysts (Table 1, entries
material industries.1 Despite significant progress in this 4–6). The use of PivOH and Cs2CO3 to form CsOPiv in
field, there are far fewer methods for alkynylation via C– situ1h also afforded the alkynylated product 3 without re-
H bond activation2 than for arylation, alkenylation, and al- ducing the yield (Table 1, entry 7). We finally found that
kylation reactions. Since Gevorgyan’s pioneering work the use of 2 (1.5 equiv) and CsOPiv (1.5 equiv) at 100 °C
on the palladium-catalyzed alkynylation of N-fused het- afforded 3 in 74% yield (Table 1, entry 9).13
eroarenes,3b several catalytic alkynylation of heteroarenes
We next investigated the effect of the directing group un-
have been developed using palladium,3 nickel,4 copper,5
der the optimized conditions (Table 2). A pyrimidine ring
and gold6 catalysts.7 Our group reported the palladium-
also promoted alkynylation to give the corresponding
product 4 in good yield. A five-membered pyrazole di-
recting group, as in 5, was also applicable to this direct
alkynylation. 2-(2-Methylphenyl)-1H-benzimidazole un-
catalyzed alkynylation of arenes with the aid of chelation
assistance.8 Unactivated C(sp3)–H bonds can also be al-
kynylated by installing a suitable directing group.8b Sev-
eral catalytic methods that can effect alkynylation of
derwent alkynylation to form the corresponding product 6
electronically biased arenes have been developed.9 Re-
with the NH group remaining intact. The yield was signif-
cently, Waser’s group reported a para-selective alkynyl-
icantly decreased when oxazoline 7 and rigid ben-
zo[h]quinoline 8 were employed.
ation of aniline derivatives.10 In this paper, we report the
ruthenium-catalyzed C–H bond alkynylation of arenes us-
ing an N-heteroarene directing group.
The alkynylation of 2-phenylpyridine (9) gave a mixture
of mono- and dialkynylated product 10 and 11 under the
As part of our continuing research on catalytic C–H al-
optimized conditions (Scheme 1). It was found that the
kynylation reactions, we intended expanding the scope of
second alkynylation occurred at an early stage of the reac-
tion. Although selective formation of 10 was not possible
with this substrate, the dialkynylated product 11 was ob-
the reaction with respect to directing groups. In view of a
plenty of precedents using pyridine-based directing
groups in ortho C–H bond activation1 as well as using the
tained exclusively by simply increasing the amount of 2.
π-conjugated structure of interest in materials science, we
In contrast, monoselective alkynylation was achieved us-
decided to identify a catalytic system applicable to 2-phe-
ing a bulkier 3-methypyridinyl directing group (Table 3,
nylpyridines. Our initial attempts to use palladium-cata-
entry 1). The steric repulsion between the methyl group in
lyzed conditions, which are effective for substrates
pyridine and the introduced alkynyl moiety suppresses the
bearing an amide-based director, to 2-(2-methylphe-
second alkynylation.14 Broad compatibility with various
functional groups, including ether, amine, amide, ester,
ketone, and fluorine groups (Table 3, entries 2–7), was ob-
served. The alkynylation of 18 took place at the ortho po-
SYNLETT 2012, 23, 2763–2767
Advanced online publication: 16.07.2012
DOI: 10.1055/s-0032-1316556; Art ID: ST-2012-Y0338-C
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2764
Y. Ano et al.
CLUSTER
Table 2 Effect of Directing Groupsa
Table 1 Optimization of Catalytic Alkynylation of 2-Arylpyridine
1a
2 (1.5 equiv)
[RuCl2(p-cymene)]2 (5 mol%)
Br
CsOPiv
L
L
catalyst (10 mol%)
CsOPiv
N
N
toluene, 100 °C, 15 h
+
toluene
TIPS
110 °C, 15 h
TIPS
TIPS
2 (1.2 equiv)
1
3
Entry
Product
Yield (%)
Entry
Catalyst
Yield (%)
N
N
1
Pd(OAc)2
<1
56
53
24
17
7
1
62b
2b
3
[RuCl2(p-cymene)]2
RuCl2(cod)
TIPS
4
5
4
RuCl2(PPh3)2
5
Cp*RuCl2
N
N
6c
Ru3(CO)12
2
3
64
7b,d
8b,e
9b,e,f
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
54
61
74
TIPS
N
a Reaction conditions: 2-(2-methylphenyl)pyridine (1, 0.30 mmol),
bromoalkyne 2 (0.36 mmol), catalyst (0.030 mmol), CsOPiv (0.30
mmol), toluene (1.0 mL), 110 °C, 15 h.
b Run using 5 mol% of catalyst.
N
H
74
TIPS
c Run using 3 mol% of catalyst.
d Run using PivOH (0.30 mmol) and Cs2CO3 (0.15 mmol) instead of
CsOPiv.
6
7
O
e Run at 100 °C.
f Run using 2 (0.45 mmol) and CsOPiv (0.45 mmol).
N
4
5
18c
sition of the pyridine ring, not ortho to the acetamide
group (Table 3, entry 4). This regioselectivity is in sharp
contrast to the case of palladium-catalyzed direct alkynyl-
ation, in which the ortho C–H bond of an acetamide group
was alkynylated selectively.8a Naphthalene (26) and thio-
phene (28) could serve as good substrates for this catalytic
alkynylation (Table 3, entries 8 and 9).
TIPS
N
19c
TIPS
When the alkynylation of 4,6-di(4-fluorophenyl)pyrimi-
dine (30) was carried out, dialkynylated product 31, in
which two alkynes are incorporated in the same arene
ring, was obtained in 50% yield, along with the trialkynyl-
ated product 32 in 11% yield (Scheme 2). The dialkynyl-
ated product 33 was not formed; this indicates that the
second C–H bond cleavage was faster than the dissocia-
tion of the catalyst from the sp2-nitrogen, as significant di-
alkynylation occurred in the reaction of 9 (Scheme 1).15
8
a Reaction conditions: substrate (0.30 mmol), bromoalkyne 2 (0.45
mmol), [RuCl2(p-cymene)]2 (0.015 mmol), CsOPiv (0.45 mmol), tol-
uene (1.0 mL), 100 °C, 15 h.
b Run at 120 °C.
c Run at 130 °C.
In summary, we have developed the first ruthenium-cata-
lyzed C–H bond alkynylation of arenes with the aid of
chelation assistance. In contrast to palladium-catalyzed
direct alkynylation, a wide range of heteroarene-based di-
recting groups are applicable. The method serves for the
expansion of a π-conjugate system by introducing an al-
kyne moiety into heterobiaryl frameworks. Thus obtained
alkynylated products can further be elaborated into a
range of molecules, including condensed aromatic com-
pounds.
Although this method requires a bulky triisopropylsilyl-
protected 2 as an alkynylating agent,16 this silyl group is
easily removed by treatment with TBAF, and the resultant
terminal alkyne can be used for further elaboration. For
example, the alkynylation of 2-(1-naphthyl)-1H-benz-
imidazole (34), followed by desilylative cyclization of 35
with TBAF gave the pentacyclic heteroarene 36 (Scheme
3).17
Synlett 2012, 23, 2763–2767
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Ruthenium-Catalyzed C–H Alkynylation
2765
Table 3 Ruthenium-catalyzed direct alkynylation of 2-phenylpyri-
dine 9 with bromoalkyne 2a
[RuCl2(p-cymene)]2 (5 mol%)
2 (1.5 equiv)
N
CsOPiv
toluene, 90 °C
2 (1.5 equiv)
[RuCl2(p-cymene)]2 (5 mol%)
N
N
9
CsOPiv
toluene, 100 °C, 15 h
TIPS
TIPS
Entry
Substrate
Product
Yield (%)
N
N
+
+
9
N
TIPS
TIPS
N
10
11
R
R
15 h
3 h
26%
13%
0%
22%
8%
0%
30%
0%
TIPS
1
12 R = H
13
65
66
48
74
68
57
62
15 h*
64%
* Run using 2 (3 equiv)
2
14 R = OMe
16 R = NMe2
18 R = NMeAc
20 R = CO2Me
22 R = COMe
24 R = F
15
17
19
21
23
25
Scheme 1Ruthenium-catalyzed direct alkynylation of 2-phenylpyri-
dine 9 with bromoalkyne 2
3b
4
F
F
5
2 (3 equiv)
[RuCl2(p-cymene)]2 (5 mol%)
CsOPiv (3 equiv)
6b
7
N
N
toluene, 100 °C, 15 h
30
TIPS
TIPS
N
F
F
F
F
N
8b
48
54
TIPS
+
26
N
N
N
N
27
TIPS
TIPS
TIPS
S
N
31 50%
32 11%
S
N
9c
F
F
TIPS
28
29
a Reaction conditions: as in Table 2 unless otherwise noted.
N
N
b Run at 90 °C.
c Run at 120 °C.
TIPS
TIPS
33 not formed
2 (1.5 equiv)
[RuCl2(p-cymene)]2 (5 mol%)
N
Scheme 2 Ruthenium-catalyzed direct alkynyaltion of 4,6-diaryl-
pyrimidine 30 with bromoalkyne 2
N
CsOPiv
H
toluene, 100 °C, 15 h
General Procedure
34
Ruthenium-Catalyzed Reaction of 1 with 2 (Table 1, Entry 9)
To an oven-dried 5 mL screw-capped vial, 2-(2-methylphenyl)pyr-
idine (1, 51 mg, 0.30 mmol), (bromoethynyl)triisopropylsilane (2,
120 mg, 0.45 mmol), [RuCl2(p-cymene)]2 (9.0 mg, 0.015 mmol),
CsOPiv (110 mg, 0.45 mmol), and toluene (1.0 mL) were added un-
der a gentle stream of nitrogen. The mixture was stirred for 15 h at
100 °C followed by cooling. The mixture was diluted with EtOAc
(10 mL) and washed with NaOH aq (1 M, 2 × 10 mL). The aqueous
layer was extracted with EtOAc (2 × 10 mL). The combined organ-
ic layers were washed with brine (20 mL), dried over MgSO4, fil-
N
N
N
TBAF
N
H
THF, r.t., 1 h
TIPS
36 55%
35 72%
Scheme 3 Synthetic application
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2763–2767

2766
Y. Ano et al.
CLUSTER
tered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (eluent: hexane–
EtOAc = 10:1) to afford the desired alkynylated product 3 (77 mg,
74%) as a colorless oil.
T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2010, 75, 1764. (d) Berciano, B. P.; Lebrequier, S.;
Besselièvre, F.; Piguel, S. Org. Lett. 2010, 12, 4038.
(6) (a) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem. Int.
Ed. 2009, 48, 9346. (b) Brand, J. P.; Waser, J. Angew. Chem.
Int. Ed. 2010, 49, 7304. (c) Brand, J. P.; Gonzalez, D. F.;
Nicolai, S.; Waser, J. Chem. Commun. 2011, 47, 102.
(7) Catalytic alkynylation using metals other than shown above:
Gallium: (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. For
heterogeneous catalysis, see: (c) Trofimov, B. A.;
2-{2-Methyl-6-[(triisopropylsilyl)ethynyl]phenyl}pyridine (3)
1H NMR (399.78 MHz, CDCl3): δ = 0.90–0.94 (m, 21 H), 2.11 (s, 3
H), 7.22–7.26 (m, 3 H), 7.37–7.44 (m, 2 H), 7.72 (ddd, J = 7.8, 7.7,
1.9 Hz, 2 H), 8.67–8.69 (m, 1 H). 13C NMR (100.53 MHz, CDCl3):
δ = 111.05, 18.48, 20.10, 93.70, 105.78, 121.85, 122.80, 124.97,
127.68, 130.27, 130.34, 135.95, 136.35, 142.92, 149.21, 158.84. IR
(neat): 3062 (m), 2943 (s), 2864 (s), 2148 (s), 1589 (s), 1462 (s),
1423 (s), 1383 (m), 1252 (m), 1020 (s), 993 (s), 883 (s), 789 (s), 748
(s). MS: m/z (%): = 349 (1) [M+], 308 (13), 307 (48), 306 (100), 264
(15), 220 (21), 125 (29), 117 (20). HRMS: m/z calcd for C23H31NSi:
349.2226; found: 349.2227.
Stepanova, Z. V.; Sobenina, L. N.; Mikhaleva, A. I.;
Ushakov, I. A. Tetrahedron Lett. 2004, 45, 6513.
(d) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z. V.;
Vakul’skaya, T. I.; Kazheva, O. N.; Aleksandrov, G. G.;
Dyachenko, O. A.; Mikhaleva, A. I. Tetrahedron 2008, 64,
5541.
Acknowledgment
(8) (a) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11,
3250. (b) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem.
Soc. 2011, 133, 12984. (c) Ano, Y.; Tobisu, M.; Chatani, N.
Org. Lett. 2011, 14, 354.
(9) (a) de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132,
1512. (b) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M.
J. Am. Chem. Soc. 2010, 132, 2522; see also ref. 4b.
(10) Brand, J. P.; Waser, J. Org. Lett. 2012, 14, 744.
(11) (a) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108,
2728. (b) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.;
Kamatani, A.; Sonoda, M.; Chatani, N. Nature (London)
1993, 366, 529.
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Molecular Activation Directed to-
ward Straightforward Synthesis’ from MEXT, Japan and by the
JSPS Japanese-German Graduate Externship. M.T. acknowledges
the HISHO Program of Osaka University. Y.A. expresses his spe-
cial thanks to JSPS for a Research Fellowship for Young Scientists
and to the Global COE Program of Osaka University. We also thank
the Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for assistance with the MS, HRMS, and elemental ana-
lyses.
(12) Selected examples of ruthenium-catalyzed C–H
functionalization: For arylation, see: (a) Oi, S.; Fukita, S.;
Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett.
2001, 3, 2579. (b) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y.
Org. Lett. 2002, 4, 1783. (c) Oi, S.; Aizawa, E.; Ogino, Y.;
Inoue, Y. J. Org. Chem. 2005, 70, 3113. (d) Ackermann, L.
Org. Lett. 2005, 7, 3123. (e) Oi, S.; Funayama, R.; Hattori,
T.; Inoue, Y. Tetrahedron 2008, 64, 6051. (f) Ackermann,
L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115.
(g) Oezdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.;
Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc.
2008, 130, 1156. (h) Oi, S.; Sato, H.; Sugawara, S.; Inoue,
Y. Org. Lett. 2008, 10, 1823. (i) Arockiam, P. B.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
maotrin
r
t
References and Notes
(1) Selected reviews on catalytic C–H bond-functionalization
reactions: (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem. Int. Ed. 2009, 48, 5094. (c) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (d) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Rev. 2010, 111, 1293. (g) Hirano, K.; Miura, M. Synlett
2011, 294. (h) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(2) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010,
49, 2096.
(3) (a) Kalinin, V. K.; Pashchenko, D. N.; She, F. M. Mendeleev
Commun. 1992, 2, 60. (b) Seregin, I. V.; Ryabova, V.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (c) Gu,
Y.; Wang, X.-m. Tetrahedron Lett. 2009, 50, 763.
(d) Rodriguez, A.; Fennessy, R. V.; Moran, W. J.
Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Angew. Chem.
Int. Ed. 2010, 49, 6629. (j) Miura, H.; Wada, K.; Hosokawa,
S.; Inoue, M. Chem.–Eur. J. 2010, 16, 4186. (k) Yu, B.; Yan,
X.; Wang, S.; Tang, N.; Xi, C. Organometallics 2010, 29,
3222. (l) Seki, M.; Nagahama, M. J. Org. Chem. 2011, 76,
10198. (m) Lakshman, M. K.; Deb, A. C.; Chamala, R. R.;
Pradhan, P.; Pratap, R. Angew. Chem. Int. Ed. 2011, 50,
11400. (n) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.;
Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161.
(o) Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012,
14, 1154. For alkenylation, see: (p) Matsuura, Y.; Tamura,
M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am.
Chem. Soc. 2007, 129, 9858. (q) Ackermann, L.; Lygin, A.
V.; Hofmann, N. Angew. Chem. Int. Ed. 2011, 50, 6379.
(r) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012,
3, 177. (s) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin,
A. V. Org. Lett. 2012, 14, 728. For alkylation, see:
(t) Kozhushkov, S. I.; Yufit, D. S.; Ackermann, L. Org. Lett.
2008, 10, 3409. (u) Ackermann, L.; Novak, P. Org. Lett.
2009, 11, 4966. (v) Ackermann, L.; Novak, P.; Vicente, R.;
Hofmann, N. Angew. Chem. Int. Ed. 2009, 48, 6045.
(w) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett.
2011, 13, 1875. For other reactions, see: (x) Oi, S.; Tanaka,
Y.; Inoue, Y. Organometallics 2006, 25, 4773. (y) Kochi, T.;
Tetrahedron Lett. 2009, 50, 3942. (e) Kim, S. H.; Chang, S.
Org. Lett. 2010, 12, 1868. (f) Yang, L.; Zhao, L.; Li, C.-J.
Chem. Commun. 2010, 46, 4184. (g) Kim, S. H.; Yoon, J.;
Chang, S. Org. Lett. 2011, 13, 1474. (h) Mousseau, J. J.;
Bull, J. A.; Ladd, C. L.; Fortier, A.; Sustac Roman, D.;
Charette, A. B. J. Org. Chem. 2011, 76, 8243.
(i) Ackermann, L.; Kornhaass, C.; Zhu, Y. Org. Lett. 2012,
14, 1824.
(4) (a) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2009, 11, 4156. (b) Matsuyama, N.; Kitahara, M.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358.
(5) (a) Besselièvre, F.; Piguel, S. Angew. Chem. Int. Ed. 2009,
48, 9553. (b) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh,
T.; Miura, M. Chem.–Eur. J. 2010, 16, 1772. (c) Kawano,
Synlett 2012, 23, 2763–2767
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Urano, S.; Seki, H.; Mizushima, E.; Sato, M.; Kakiuchi, F.
Ruthenium-Catalyzed C–H Alkynylation
2767
(15) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull. Chem.
Soc. Jpn. 1997, 70, 3117.
(16) The alkynylation using phenylethynyl bromide, 1-bromo-1-
hexyne, methyl 3-bromopropionate, and (triisopropylsilyl)-
acetylene instead of 2 was unsuccessful.
J. Am. Chem. Soc. 2009, 131, 2792. (z) Saidi, O.; Marafie, J.;
Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok-Köhn,
G.; Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011,
133, 19298.
(13) See Supporting Information for the details of the
optimization studies on reaction conditions.
(14) (a) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem.
1997, 62, 2604. (b) Tobisu, M.; Ano, Y.; Chatani, N. Chem.–
Asian J. 2008, 3, 1585.
(17) Selected examples of the synthesis of benzimidazo[2,1-
a]isoquinolines via the cyclization of 2-(2-alkynylaryl)-1H-
benzimidazoles: (a) Dyker, G.; Stirner, W.; Henkel, G. Eur.
J. Org. Chem. 2000, 1433. (b) Okamoto, N.; Sakurai, K.;
Ishikura, M.; Takeda, K.; Yanada, R. Tetrahedron Lett.
2009, 50, 4167.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2763–2767

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.