Copper-catalyzed, aerobic oxidative cross-coupling of alkynes with arylboronic acids: Remarkable selectivity in 2,6-lutidine media

Article abstract of DOI:10.1039/c1ob05915g

Aerobic oxidative cross-coupling reactions between alkynes and boronic acids under mild conditions catalyzed by low loadings of a copper salt are reported. 2,6-Lutidine accelerated the reactions dramatically, and the desired coupling products were obtained in high yields with high selectivities.

Full text of DOI:10.1039/c1ob05915g

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 6208
www.rsc.org/obc
COMMUNICATION
Copper-catalyzed, aerobic oxidative cross-coupling of alkynes with
arylboronic acids: remarkable selectivity in 2,6-lutidine media†‡
Tomohiro Yasukawa, Hiroyuki Miyamura and Shu¯ Kobayashi*
Received 7th June 2011, Accepted 8th July 2011
DOI: 10.1039/c1ob05915g
Aerobic oxidative cross-coupling reactions between alkynes
and boronic acids under mild conditions catalyzed by low
loadings of a copper salt are reported. 2,6-Lutidine accel-
erated the reactions dramatically, and the desired coupling
products were obtained in high yields with high selectivities.
catalyst, nitrogen base, and molecular oxygen.12 Herein, we report
oxidative cross-coupling reactions of alkynes with boronic acids
catalyzed by relatively low loadings of copper catalysts (0.15–3.0
mol%) in the presence of 2,6-lutidine using molecular oxygen as
an oxidant. The remarkable effect of 2,6-lutidine on the selectivity
of the reactions is also described.
We began by investigating the cross-coupling reaction between
phenyl acetylene and phenylboronic acid as a model reaction in
methanol–pyridine media. To avoid undesired side reactions, we
used only 0.75 mol% of CuBr as a catalyst because it was suggested
that homocoupling reactions of alkynes proceeded via a dimerized
copper–alkyne complex caused by a high concentration of the
copper catalyst.12a,13 However, in the presence of 0.75 mol% of
CuBr, the reaction hardly proceeded (Table 1, entry 1). Amine
solvents were then screened, and it was found that the yield
was significantly improved to 57% in the presence of 2,6-lutidine
(Table 1, entry 2).14 It is noted that, although we also examined
other pyridine derivatives, only 2,6-lutidine media could promote
this reaction effectively (Table 1, entries 3–9). When N,N,N¢,N¢-
tetramethylethylenediamine (TMEDA) was used, high conversion
was observed; however, the major products were the homocoupled
product, biphenyl, and methyl 2-phenylacetate, and the desired
cross-coupled product was scarcely generated (Table 1, entry 10).
Moreover, while 3,5-dimethylpiperidine media also promoted the
cross-coupling reaction, 2,6-dimethylpiperidine did not gave good
results (Table 1, entries 11, 12).
Several copper salts were examined in the presence of 2,6-
lutidine (Table 2). It was shown that Cu(II) also catalyzed this
reaction; however, the yield was lower than that using Cu(I)
(Table 2, entries 1 vs. 2, 3 vs. 4, 8 vs. 9). Although Cu2O did
not dissolve completely, 3aa was obtained in 35% yield (entry 7).
From these results, CuBr and CuCN showed similar high activity,
and based on solubility, we chose CuBr as the best catalyst (entries
1–11)15 We also confirmed that the reaction did not proceed at all
in the absence of any Cu salts (entry 12).
While C–C bond-forming reactions catalyzed by noble metals
(such as palladium) are among the most powerful tools for
organic synthesis,1 the development of reactions using abundant
metals as a replacement for noble metals has been intensively
studied recently,2 reflecting supply shortages of several important
elements.3 Copper is an abundant and inexpensive metal, and is
widely used in organic synthesis as a reagent or catalyst, thus
attracting much attention for this purpose.4
Internal alkynes are useful compounds as intermediates for
bioactive natural products1b,5 as well as materials such as poly-
mers and liquid crystals.5b,6 Palladium- and/or copper-catalyzed
Sonogashira-type cross-coupling reactions are well known as
a traditional method for construction of C(sp)–C(sp2) bonds
between terminal alkynes and aryl halides.5b,7 Palladium-catalyzed
oxidative Sonogashira-type cross-coupling reactions between
alkynes and arylboronic acids without using aryl halides have
also been developed.8 Although several groups have reported
copper-mediated C–O, C–N, or C–S bond-forming reactions
using boronic acids as aryl donors, there are few reports of
C(sp)–C(sp2) bond-formation reactions.9 In addition, most of the
reports required high temperature or a stoichiometric amount of
a silver salt.10 Recently, Fu’s group has developed Cu2O-catalyzed
reactions using molecular oxygen as a green oxidant under mild
conditions in pyridine-containing media.11 However, even in this
case, 10 mol% of Cu2O was required and the scope of the alkynes
was rather limited.
One of the significant difficulties of this reaction is how to
suppress undesired homocoupling reactions of alkynes or aryl
boronic acids, which readily occur in the presence of a copper
With CuBr, the ratio of methanol to 2,6-lutidine was examined
(Table 3). When the amount of 2,6-lutidine was decreased, 3aa was
obtained in lower yield. In addition, the yield of 3aa dropped in
the presence of an excess amount of 2,6-lutidine (Table 3, entries
1–7). The ratio of methanol to 2,6-lutidine was optimized as 1 : 2
(Table 3, entry 4). The yield of 3aa was improved to 83% at 45 ◦C
in the presence of 1.5 mol% of CuBr (Table 3, entry 8). Using
more than 1.5 mol% of copper salt and a higher concentration
did not accelerate the reaction.16 Reducing the equivalents of
Department of Chemistry, School of Science, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. E-mail: shu_kobayashi@
chem.s.u-tokyo.ac.jp
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05915g
‡ This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science (JSPS),
Global COE Program, The University of Tokyo, MEXT, Japan, and
NEDO. H. M. thanks the JSPS fellowship for Japanese Junior Scientist.
6208 | Org. Biomol. Chem., 2011, 9, 6208–6210
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 Effect of nitrogen-containing solventsa
Table 2 Effect of copper saltsa
Yield (%)b
Conv.
Entry Cu
1a (%)b 3aa 4a
5ac
6a 7ac 8ac
1
2
3
4
5
6
7
8
CuBr
CuBr2
Cu(OAc)
Cu(OAc)2·H2O
CuI
Cu(PPh3)2NO3
Cu2O
64
55
31
22
59
42
42
57
46
26
13
50
33
35
42
21
41
59
0
4
2
2
2
2
2
1
2
1
1
1
0
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
9
7
5
4
8
5
5
7
4
7
10
0
9
7
5
2
8
6
6
6
3
9
9
0
Yield (%)b
Entry Solvent
1
Conv. 1a (%)b 3aa
4a 5ac
6a 7ac 8ac
10
64
11
25
16
7
1
1
4
0
2
1
0
1
1
1
1
1
2
1
0
1
0
0
0
0
0
0
0
28
0
0
1
9
2
4
2
0
2
0
1
2
1
8
2
2
57
7
1
9
CuOTf·1/2PhMe 52
9
Cu(OTf)2
CuSbF6
CuCN
—
27
50
67
<1
trace trace
10d
11
12
3
3
0
2
3
0
3
trace
2
4
16
1
1
6
a Reaction conditions: 30 ◦C, alkyne (0.25 mmol), boronic acid (0.5 mmol),
methanol (0.5 ml), 2,6-lutidine (0.5 ml). b Determined by GC analysis.
c Yield was determined based on amount of 2a used. d Cu salt was prepared
from CuI and AgSbF6.
5
1
3
6
0
0
0
Table 3 Effect of solvent ratiosa
7
11
7
6
trace
0
2
8
trace
6
trace
24
10
6
Entry MeOH (ml) 2,6-Lutidine (ml) Conv. 1a (%)b
Yield (%)b
9
16
77
21
68
3
1
2
3
4
5
6
0.8
0.66
0.5
0.33
0.25
0.2
0.05
0.33
0.33
0.2
45
54
64
70
65
69
6
38
49
57
62
59
61
0
10
11
12
20
11
49
58
0.33
0.5
0.66
0.75
0.8
0.95
0.66
0.66
trace
5
7
9
8c
9c,d
97
94
83
85
a Reaction conditions: 30 ◦C, alkyne (0.25 mmol), boronic acid (0.5 mmol),
methanol (0.5 ml), amine solvent (0.5 ml). b Determined by GC analysis.
c Yield was determined based on amount of 2a used.
a Reaction conditions: 30 ◦C, alkyne (0.25 mmol), boronic acid (0.5 mmol).
b Determined by GC analysis. c Reaction temperature was 45 ◦C and 1.5
mol% of CuBr was used. d 1.9 equiv of boronic acid was used.
phenylboronic acid was also examined and 3aa was obtained in
85% yield when 1.9 equivalents of phenylboronic acid were used
(Table 3, entry 9).17
lutidine were effective in achieving better selectivity. In other cases,
decomposition of the substrate was observed (Table 4, entries 8–
12).19 In addition, the amount of boronic acid could be decreased
and the reaction temperature lowered while keeping high reactivity.
Because the ease of formation of copper–acetylide species differs,
the basicity of solvents may become the key to controlling the
reaction. Ortho-, meta-, and para-substituted phenylacetylenes
gave good yields of 3ca, 3da, or 3ea (Table 4, entries 13–15). For
phenylacetylene with a methoxy group, which has a lower acidity
than the nonsubstituted phenylacetylene, more 2,6-lutidine was
required to afford good yields of 3fa or 3ga (Table 4, entries
16, 17). Phenylacetylene with electron-withdrawing groups or
biphenylacetylene gave good or moderate yields of 3ha, 3ia, or 3ja
(Table 4, entries 18–20). In the same way as for 2-naphthylboronic
acid, diluted conditions improved the yield (Table 4, entries 18,
20).18 4-Pyridylacetylene is one of the most difficult substrates
because of the possibility that the nitrogen on the pyridine ring will
The substrate scope is summarized in Table 4 and Chart 1.
Ortho- or meta-substituted phenylboronic acids gave good to
high yields of 3ab or 3ac (Table 4, entries 2, 3). In the cases of
phenylboronic acids with electron-withdrawing groups, the use
of fewer equivalents of substrates improved the yields of 3ad or
3ae, presumably because the homocoupling reaction of boronic
acids was suppressed (Table 4, entries 4, 5).18 On the other hand,
the reactions with phenylboronic acids bearing electron-donating
groups proceeded slowly. The yield of 3af was improved when
the amount of the catalyst was increased (Table 4, entry 6).
When 2-naphthylboronic acid was used, more diluted conditions
(0.125 M and 0.75 mol% of CuBr) afforded a good yield of 3ag
(Table 4, entry 7). When an alkyne with an ester group was used,
interestingly, diluted conditions and a significant decrease of 2,6-
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6208–6210 | 6209
©

View Article Online
Table 4 Substrate scopea
demonstrated. It is noted that lower amounts of the catalyst and
lower concentration can improve the yields significantly for some
substrates. Further investigations including mechanistic insights
and more environmentally benign catalytic systems are currently
underway in our laboratory.
CuBr
(mol%) (M)
Conc.b
Yield
(%)c
Entry
1
2 (equiv)
x : y
Product
Notes and references
1
2
3
4
1a 2a (1.9)
1a 2b (1.9)
1a 2c (1.9)
1a 2d (1.2)
1a 2e (1.3)
1a 2f (1.9)
1a 2g (1.9)
1b 2a (1.5)
1b 2d (1.1)
1b 2e (1.5)
1b 2b (1.5)
1b 2c (1.5)
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
39 : 1 1.5
79 : 1 0.75
79 : 1 0.75
39 : 1 1.5
79 : 1 0.75
1 : 2
1 : 2
1 : 2
1 : 4
1 : 4
1 : 2
1 : 2
1 : 2
1 : 4
1 : 2
1 : 2
1 : 2
1.5
1.5
1.5
1.5
1.5
3
0.25
0.25
0.25
0.25
0.25
0.25
0.125
0.0625
0.03125 3bd
0.0625
0.0625
0.03125 3bc
0.25
0.25
0.25
0.125
0.125
0.125
0.25
0.125
0.125
0.25
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ba
85d
85
70
62
75
63
86
82d
71
77
44
66
81
80
83
75
76
74
51
71
44
56
80
66
1 (a) Handbook of Palladium-Catalyzed Organic Reactions, J. C. Fiaud,
J.-L. Malleron, J. Y. Legros, ed., Academic Press, London, 1997; (b) K.
C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005,
44, 4442; (c) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094.
2 (a) C. Bolm, J. Legros, J. L. Paih and L. Zani, Chem. Rev., 2004, 104,
6217; (b) G. Cahiez and A. Moyeux, Chem. Rev., 2010, 110, 1435; (c) R.
Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417.
3 E. Nakamura and K. Sato, Nature Mater., 2011, 10, 158.
4 Comprehensive Organometallic Chemistry II, E. W. Abel, F. G. A. Stone,
G. Wilkinson, ed., Pergamon Press, Oxford, 1995, Vol. 3.
5 (a) J. W. Grissom, G. U. Gunawardena, D. Klingberg and D. Huang,
Tetrahedron, 1996, 52, 6453; (b) R. Chinchilla and C. Na´jera, Chem.
Rev., 2007, 107, 874; (c) C. Lamberth, Bioorg. Med. Chem., 2009, 17,
4047.
6 (a) J. M. Tour, Chem. Rev., 1996, 96, 537; (b) R. E. Martin and F.
Diederich, Angew. Chem., Int. Ed., 1999, 38, 1350; (c) U. H. F. Bunz,
Chem. Rev., 2000, 100, 1605.
7 (a) K. Sonogashira in Comprehensive Organic Synthesis, B. M. Trost,
I. Fleming, ed., Pergamon Press, New York, 1991, vol. 3, pp. 521–549;
(b) K. Sonogashira in Metal-Catalyzed Cross-Coupling Reactions, F.
Diederich, P. J. Stang, ed., Wiley-VCH, Weinheim, Germany, 1998, pp.
203–229.
5
6
7e
0.75
8f
9f
10f
11f
12f
13
14
15
16
17
18
19
20e
21g
22
23
24h
3be
3bb
1c
2a (1.9)
1.5
1.5
1.5
0.75
0.75
0.75
1.5
0.75
0.15
1.5
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
1d 2a (1.9)
1e
1f
2a (1.9)
2a (1.9)
1g 2a (1.9)
1h 2a (1.9)
1i
1j
2a (1.9)
2a (1.9)
1k 2a (3.0)
1l 2a (1.9)
1m 2a (1.9)
1n 2a (1.9)
1.5
1.5
0.25
0.25
3ma
3na
8 (a) G. Zou, J. Zhu and J. Tang, Tetrahedron Lett., 2003, 44, 8709; (b) F.
Yang and Y. Wu, Eur. J. Org. Chem., 2007, 3476; (c) M.-B. Zhou, W.-
T. Wei, Y.-X. Xie, Y. Lei and J.-H. Li, J. Org. Chem., 2010, 75, 5635;
(d) K. Mitsudo, T. Shiraga, J. Mizukawa, S. Suga and H. Tanaka, Chem.
Commun., 2010, 46, 9256; (e) X. Nie, S. Liu, Y. Zong, P. Sun and J. Bao,
J. Organomet. Chem., 2011, 696, 1570.
a All reactions were conducted on a 0.125 mmol scale of alkynes. b Conc.
means concentration. c Isolated yield. d Determined by GC analysis.
e Reaction time was 30 h. f Reaction temperature was 30 ◦C. g Reaction
temperature was 60 ◦C and reaction time was 36 h. h A mixture of
diastereomers.
9 (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400;
(b) T. Morishita, H. Yoshida and J. Oshita, Chem. Commun., 2010, 46,
640; (c) H. Rao and H. Fu, Synlett, 2011, 6, 745.
10 (a) J. Mao, J. Guo and S.-J. Ji, J. Mol. Catal. A: Chem., 2008, 284, 85;
(b) M. Wu, J. Mao, J. Guo and S. Ji, Eur. J. Org. Chem., 2008, 4050;
(c) C. Pan, F. Luo, W. Wang, Z. Ye and J. Chene, Tetrahedron Lett.,
2009, 50, 5044.
11 H. Rao, H. Fu, Y. Jiang and Y. Zhao, Adv. Synth. Catal., 2010, 352,
458.
12 (a) P. Siemsen, R. C. Livingston and F. Diederich, Angew. Chem.,
Int. Ed., 2000, 39, 2632; (b) N. Kirai and Y. Yamamoto, Eur. J. Org.
Chem., 2009, 1864; (c) H. A. Stefani, A. S. Guarezemini and R. Cella,
Tetrahedron, 2010, 66, 7871; (d) K. Yin, C. Li, J. Li and X. Jia, Green
Chem., 2011, 13, 591; (e) G. Cheng and M. Luo, Eur. J. Org. Chem.,
2011, 2519.
13 (a) F. Bohlmann, H. Scho¨nowsky, E. Inhoffen and G. Grau, Chem.
Ber., 1964, 97, 794; (b) N. Mizuno, K. Kamata, Y. Nakagawa, T. Oishi
and K. Yamaguchi, Catal. Today, 2010, 157, 359.
14 It was reported that an amine additive can change the selectivity of
copper catalysis: J. Xu, D.-F. Luo, B. Xiao, Z.-J. Liu, T.-J. Gong, Y. Fu
and L. Liu, Chem. Commun., 2011, 47, 4300.
15 No contamination of palladium in CuBr was observed by ICP analysis
(<2.7 ppm as a detection limit, see ESI† 2–7).
Chart 1 List of starting materials.
16 The effects of the amount of copper salt are shown in ESI† Table S-1.
17 The results of the reaction using varying amounts of the phenylboronic
acids in various conditions are shown in ESI† Table S-3.
18 Using the optimized conditions for the formation of 3aa, lower yields
of these products and undissolved yellow solid were obtained (see
ESI† Table S-6). This yellow solid was formed in the presence of
phenylacetylene and 2,6-lutidine (see ESI† Scheme S-2). It might be
an organocopper species formed from the copper catalyst and alkynes:
(a) S. S. Y. Chui, M. F. Y. Ng and C.-M. Che, Chem.–Eur. J., 2005,
11, 1739; (b) B. R. Buckley, S. E. Dann and H. Heaney, Chem.–Eur. J.,
2010, 16, 6278.
coordinate to copper in an unfavorable manner. As expected, 0.15
mol% of CuBr improved the reactivity and 3ka was obtained with
thehighest turnover number (293)at60 ◦C after 36 h (Table 4, entry
21).18 Aliphatic alkynes were also examined and gave moderate or
good yields of 3la, 3ma, or 3na (Table 4, entries 22–24).
In conclusion, we have developed cross-coupling reactions be-
tween alkynes and boronic acids using a small amount of a copper
salt in methanol and 2,6-lutidine media. This reaction proceeded
smoothly with high selectivity, and undesired homocoupling
reactions were suppressed. Wide substrate generality has been
19 The ratios of solvent and concentrations were screened (see ESI† Tables
S-4, S-5).
6210 | Org. Biomol. Chem., 2011, 9, 6208–6210
This journal is
The Royal Society of Chemistry 2011
©