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
©