Highly efficient copper-catalyzed synthesis of internal alkynes via aerobic oxidative arylation of terminal alkynes

Article abstract of DOI:10.1002/adsc.200900723

We have developed a novel and highly efficient, copper-catalyzed synthesis of internal alkynes via oxidative couplings of aromatic boronic acids with terminal alkynes at room temperature. The protocol uses inexpensive copper(I) oxide [Cu₂O] as the catalyst, oxygen in the air as the stoichiometric oxidant; no ligand and sealed reaction vessels are required, and remarkable functional group tolerability is observed with coupling occurring.

Full text of DOI:10.1002/adsc.200900723

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DOI: 10.1002/adsc.200900723
Highly Efficient Copper-Catalyzed Synthesis of Internal Alkynes
via Aerobic Oxidative Arylation of Terminal Alkynes
Honghua Rao,a Hua Fu,a,* Yuyang Jiang,a,b and Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University,
b
Shenzhen 518057, Peopleꢀs Republic of China
Received: October 18, 2009; Revised: November 25, 2009; Published online: February 9, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900723.
Abstract: We have developed a novel and highly effi- dant; no ligand and sealed reaction vessels are re-
cient, copper-catalyzed synthesis of internal alkynes quired, and remarkable functional group tolerability
via oxidative couplings of aromatic boronic acids is observed with coupling occurring.
with terminal alkynes at room temperature. The pro-
À
tocol uses inexpensive copper(I) oxide [Cu2O] as the Keywords: C H activation; copper; internal alkynes;
catalyst, oxygen in the air as the stoichiometric oxi- oxidative coupling; synthetic methods
Introduction
oped an efficient, copper-catalyzed approach to pri-
mary aromatic amines by couplings of aromatic bor-
The development of methods for forming C C bonds onic acids with aqueous ammonia[13] via the Chan–
plays a central role in synthesis design,[1] and the Lam amination strategy.[14] Herein, we report a novel
metal-catalyzed cross-coupling reactions are the most and highly efficient, copper-catalyzed synthesis of in-
powerful.[2] Internal alkyne intermediates are widely ternal alkynes via aerobic oxidative arylation of ter-
used in the synthesis of many antimycotics,[3] antibiot- minal alkynes at room temperature.
ics,[4] liquid crystals, polymers, and optical or electron-
À
ic materials.[5] The traditional palladium/copper co-
catalyzed Sonogashira-type coupling[6] is a popular Results and Discussion
2
[7]
À
strategy for the construction of CACTHNUTRGNE(NUG sp ) C(sp) bonds,
and the protocol shows high efficiency and tolerance Initially, 2-formylphenylboronic acid and phenylacety-
of functional groups under mild conditions (even at lene were chosen as the model substrates to optimize
room temperature). A palladium-free, copper-cata- the reaction conditions [Eq. (A) in Table 1]. As
lyzed Sonogashira reaction was also reported under shown in Table 1, the effect of additives was tested by
CuBr/rac-BINOL catalysis at 1308C.[8] Oxidative cou- using Cu2O as the catalyst, methanol as the solvent,
pling reactions, particularly methods that enable the and the target product was not observed in the ab-
À
direct functionalization of C H bonds, have been the sence of additive (entry 1) or in the presence of Et3N
focus of significant recent interest.[9] Unfortunately, (entry 2). When pyridine was used as the additive, the
some methods often require stoichiometric special ox- desired target product (3a) was obtained in 40% yield
idants and this reduces their appeal relative to classi- while a 40% yield of the by-product – 2-methoxyben-
cal cross-coupling reactions. Obviously, it is economi- zaldehyde from the coupling of 2-formylphenylboron-
cal and environmentally benign to employ molecular ic acid with methanol – was observed (entry 3). How-
oxygen in air as the stoichiometric oxidant.[10] Recent- ever, the coupling reaction did not work when pyri-
ly, copper- or palladium-catalyzed Sonogashira-type dine was used as the solvent instead of methanol
couplings of terminal alkynes with arylboronic acids/ (entry 4). Inspiringly, a high-yield of product was ob-
esters,[11] or aryltrimethoxysilanes[12] have been inves- tained by using CHCl3 as the solvent and pyridine as
tigated in the presence of 1–3 equivalents of Ag(I) the additive (entry 5). The target product was also ob-
salts as the additives. Very recently, we have devel- tained in the presence of 0.5 equivalents of pyridine
458
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Adv. Synth. Catal. 2010, 352, 458 – 462

Highly Efficient Copper-Catalyzed Synthesis of Internal Alkynes
Table 1. Copper-catalyzed oxidative coupling of 2-formylphenylboronic acid with phenylacetylene [Eq. (A)] or phenylboron-
ic acid with 1-ethynyl-1-cyclohexanol [Eq. (B)]: optimization of conditions.[a]
Entry
Catalyst
Solvent
Additive(s) [mL]
Yield [%][b]
1[f]
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
MeOH
MeOH
MeOH
–
–
trace
trace
40[c]
0d
72
59
30
60
18
50
40
35
40
30
70
55
55
30
2[f]
Et3N (0.4)
Pyridine (0.4)
Pyridine (2)
Pyridine (0.2)
Pyridine (0.5 equiv.)
DMAP (1.0 equiv.)
Pyridine (0.4)
Pyridine (0.4)
Pyridine (0.2)
Pyridine (0.2)
Pyridine (0.2)
Pyridine (0.2)
Pyridine (0.2)
Pyridine (0.2)+MeOH (0.2)
Pyridine (0.2)+MeOH (0.1)
Pyridine (0.2)+MeOH (0.4)
Pyridine (0.2)+EtOH (0.2)
Pyridine (0.2)+i-PrOH (0.2)
Pyridine (0.2)+MeOH (0.2)
3[f]
4[f]
5[f]
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
6[f]
7[f]
8[f]
9[f]
10[f]
11[f]
12[f]
13[f]
14[g]
15[g]
16[g]
17[g]
18[g]
19[g]
20[g]
Cu
N
CuSO4
CuI
Cu
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
20
Trace[e]
[a]
Reaction conditions: room temperature (~258C), catalyst (0.05 mmol), arylboronic acid (0.5 mmol), alkyne (1 mmol), sol-
vent (2 mL).
[b]
[c]
[d]
[e]
[f]
Isolated yield.
2-Methoxybenzaldehyde was obtained in 40% yield.
Pyridine (2 mL) as the solvent.
Under nitrogen atmosphere.
Eq. (A).
[g]
Eq. (B).
(entry 6) or one equivalent of DMAP (entry 7), and creased as the amount of methanol was changed (en-
the yield gradually increased as reaction time was tries 16 and 17). The coupling reaction provided lower
elongated, the result showed that pyridine or DMAP yields when ethanol (entry 18) or isopropyl alcohol
acted as catalyst together with Cu2O. Some other sol- (entry 19) replaced methanol in entry 15 as the addi-
vents were investigated, and CHCl3 was the best sol- tive. Only trace amounts of product appeared if air
vent (compare entries 5, 8 and 9). Several copper cat- was excluded by introducing a nitrogen atmosphere
alysts were tested, and Cu2O was proved to be most to the reaction system (entry 20), and this result
effective (compare entries 5, 10–13). Unexpectedly, showed that oxygen participated in the coupling reac-
the desired target product was observed in only 30% tion, so the reaction underwent an oxygen-involving
yield (entry 14) when phenylboronic acid and 1-ethyn- oxidation process like the Chan–Lam amination.[14]
yl-1-cyclohexanol [Eq. (B) in Table 1] were used as
After the optimization process above, copper-cata-
the model substrates under the optimized condition lyzed oxidative couplings of aromatic boronic acids
above, so we had to continue our optimization pro- with terminal alkynes were carried under the follow-
cess. Coupling of phenylboronic acid with 1-ethynyl-1- ing conditions: 10 mol% Cu2O (relative to the aro-
cyclohexanol provided the target product (3k) in 70% matic boronic acid) as the catalyst, CHCl3 as the sol-
yield when pyridine and methanol (volume ratio 1:1) vent, pyridine (conditions A) or pyridine and metha-
were used as the additives (entry 15). The yield de- nol (volume ratio 1:1) (conditions B) as the addi-
Adv. Synth. Catal. 2010, 352, 458 – 462
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asc.wiley-vch.de
459

Honghua Rao et al.
FULL PAPERS
tive(s) under an atmosphere of air at room tempera- alysis conditions (conditions A and B in Table 2) and
ture (~258C). As shown in Table 2, all the substrates reaction rates mainly depended on the structural spe-
examined provided good to excellent yields at room cialty of the terminal alkynes. For alkynes containing
temperature. The electronic effect of substituent hydroxy (entries 11–13) or imino groups (entry 14), a
groups on the aromatic boronic acids did not show small amount of methanol as extra additive was re-
any evident difference of reactivity. The choice of cat- quired. The coupling reactions could tolerate various
Table 2. Copper-catalyzed oxidative couplings of aromatic boronic acids with terminal alkynes.[a]
Entry
1
Substrate 1
Conditions/Time [h]
Product 3
Yield [%][b]
1a
A/24
3a
79
2
3
1b
1c
A/28
A/24
3b
3c
77
82
4
5
1d
1e
A/24
A/24
3d
3e
69
73
6
7
1f
1g
A/29
A/28
3f
3g
82
71
8
9
1h
1i
A/29
A/26
3h
3i
70
67
10
1j
A/26
3j
71
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Adv. Synth. Catal. 2010, 352, 458 – 462

Highly Efficient Copper-Catalyzed Synthesis of Internal Alkynes
Table 2. (Continued)
Entry
Substrate 1
Conditions/Time [h]
Product 3
Yield [%][b]
76
11
1k
B/36
3k
12
13
1d
B/36
3l
75
1l
B/33
B/36
3m
3n
76
83
14
1k
[a]
Reaction conditions: arylboronic acid (0.5 mmol), alkyne (1.0 mmol), Cu2O (0.05 mmol), CHCl3 (2 mL), room tempera-
ture (~258C). Conditions A: pyridine (0.2 mL) as the additive; conditions B: pyridine (0.2 mL) and methanol (0.2 mL) as
the additives.
Isolated yield.
[b]
functional groups including aldehyde (entries 1–3), flask (Note: extra methanol (0.2 mL) was added to the solu-
tion for entries 11–14 in Table 2). The flask was not sealed so
that air was allowed to enter the flask, and the mixture was
stirred for a time shown in Table 2 under an atmosphere of
air at room temperature (~258C). After completion of the
reaction (the reaction progress was monitored by TLC), the
mixture was filtered, and the solvent of the filtrate was re-
moved with the aid of a rotary evaporator. The residue was
purified by column chromatography on silica gel to provide
the desired product.
ether (entries 3, 4 and 10), nitro (entry 5), carbon-hal-
ogen bonds (entries 6 and 7) in the aromatic boronic
acids, as well as ester (entries 2, 6–10), hydroxy (en-
tries 11–13) and amino groups (entry 14) in the termi-
nal alkynes.
Conclusions
We have developed a novel and highly efficient
method for copper-catalyzed synthesis of internal al-
kynes by oxidative couplings of aromatic boronic
acids with terminal alkynes at room temperature, and
the target products were obtained in good to excellent
yields by using inexpensive Cu2O as the catalyst, O2
in the air as the stoichiometric oxidant and, moreover,
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 20672065, 20972083), the
Ministry of Science and Technology of China (Grant Nos.
no ligand and sealed reaction vessels were required. 2007AA02Z160, 2006DFA43030) and the Key Subject Foun-
dation
(XK100030514).
from
Beijing
Department
of
Education
The method is of high tolerance towards various func-
tional groups in the substrates, and the syntheses of
these compounds will attract much attention in indus-
trial and academic research because of their biological
and pharmaceutical properties. Further mechanistic
investigations are now in progress.
References
[1] E. J. Corey, X. M. Cheng, The Logic of Chemical Syn-
thesis, John Wiley & Sons, New York, 1989, pp. 1–91.
[2] A. de Meijere, F. Diederich, (Eds.), Metal Catalyzed
Cross-Coupling Reactions, 2nd edn., Wiley-VCH, Chi-
chester, 2004, Vols. 1 and 2.
Experimental Section
[3] U. Beutler, J. Mazacek, G. Penn, B. Schenkel, D. Was-
General Procedure for Synthesis of Internal Alkynes
3a–n
muth, Chimia 1996, 50, 154.
[4] J. W. Grissom, G. U. Gunawardena, D. Klingenberg, D.
Huang, Tetrahedron 1996, 52, 6453.
[5] a) L. Anastasia, E. Negishi, Org. Lett. 2001, 3, 3111;
b) C. Yang, S. P. Nolan, Organometallics 2002, 21, 1020;
c) H. Plenio, J. Hermann, A. Sehring, Chem. Eur. J.
A round-bottom flask was charged with a magnetic stirrer
and CHCl3 (2 mL), and the substituted aromatic boronic
acid (0.5 mmol), the terminal alkyne (1 mmol), Cu2O
(0.05 mmol, 8 mg) and pyridine (0.2 mL) were added to the
Adv. Synth. Catal. 2010, 352, 458 – 462
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Honghua Rao et al.
FULL PAPERS
2000, 6, 1820; d) M. Alami, B. Crousse, F. Ferri, J. Or-
ganomet. Chem. 2001, 624, 114; e) R. A. Batey, M.
Shen, A. J. Lough, Org. Lett. 2002, 4, 1411.
[10] a) T. Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc.
2008, 130, 833; b) X. Wang, W. Qin, N. Kakusawa, S.
Yasuike, J. Kurita, Tetrahedron Lett. 2009, 50, 6293.
[11] a) C. Pan, F. Luo, W. Wang, Z. Ye, J. Cheng, Tetrahe-
dron Lett. 2009, 50, 5044; b) G. Zou, J. Zhu, J. Tang,
Tetrahedron Lett. 2003, 44, 8709; c) F. Yang, Y. Wu,
Eur. J. Org. Chem. 2007, 3476.
[6] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron
Lett. 1975, 16, 4467.
[7] a) R. Chinchilla, C. Najera, Chem. Rev. 2007, 107, 874;
b) H. Doucet, J.-C. Hierso, Angew. Chem. 2007, 119,
850; Angew. Chem. Int. Ed. 2007, 46, 834.
[8] J. Mao, J. Guo, S.-J. Ji, J. Mol. Catal. A: Chem. 2008,
284, 85.
[9] For recent reviews, see: a) C. Jia, T. Kitamura, Y. Fuji-
wara, Acc. Chem. Res. 2001, 34, 633; b) V. Ritleng, C.
Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731; c) K.
Godula, D. Sames, Science 2006, 312, 67; d) A. R. Dick,
M. S. Sanford, Tetrahedron 2006, 62, 2439; e) X. Chen,
K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem.
2009, 121, 5196; Angew. Chem. Int. Ed. 2009, 48, 5094;
f) C. I. Herrerias, X. Yao, Z. Li, C.-J. Li, Chem. Rev.
2007, 107, 2546; g) C.-J. Li, Acc. Chem. Res. 2009, 42,
335; h) J. Li, S. D. Yang, Z. J. Shi, Synlett 2008, 949.
[12] Z. Ye, M. Liu, B. Lin, H. Wu, J. Ding, J. Cheng, Tetra-
hedron Lett. 2009, 50, 530.
[13] H. Rao, H. Fu, Y. Jiang, Y. Zhao, Angew. Chem. 2009,
121, 1134; Angew. Chem. Int. Ed. 2009, 48, 1114.
[14] Selected references, see: a) P. Y. S. Lam, C. G. Clark, S.
Saubern, J. Adams, M. P. Winters, D. M. T. Chan, A.
Combs, Tetrahedron Lett. 1998, 39, 2941; b) A. P.
Combs, S. Saubern, M. Rafalski, P. Y. S. Lam, Tetrahe-
dron Lett. 1999, 40, 1623; c) P. Y. S. Lam, C. G. Clark,
S. Saubern, J. Adams, K. M. Averill, D. M. T. Chan, A.
Combs, Synlett 2000, 674.
462
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Adv. Synth. Catal. 2010, 352, 458 – 462