Copper porphyrin-catalyzed aerobic oxidative coupling of terminal alkynes with high TON

Article abstract of DOI:10.1016/j.tetlet.2016.02.075

Copper porphyrin-catalyzed Glaser-Hay-type couplings of terminal alkynes generating 1,3-diynes are described. This reaction features high TON (up to 950) and is complete in an hour, providing a facile, clean, and efficient protocol to access various 1,3-d

Full text of DOI:10.1016/j.tetlet.2016.02.075

Accepted Manuscript
Copper Porphyrin-Catalyzed Aerobic Oxidative Coupling of Terminal Alkynes
with High TON
Wen-Bing Sheng, Tie-Qiao Chen, Ming-Zhong Zhang, Mi Tian, Guo-Fang
Jiang, Can-Cheng Guo
PII:
S0040-4039(16)30183-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.075
TETL 47350
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 November 2015
16 February 2016
19 February 2016
Please cite this article as: Sheng, W-B., Chen, T-Q., Zhang, M-Z., Tian, M., Jiang, G-F., Guo, C-C., Copper
Porphyrin-Catalyzed Aerobic Oxidative Coupling of Terminal Alkynes with High TON, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.075
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Copper Porphyrin-Catalyzed Aerobic
Oxidative Coupling of Terminal Alkynes
with High TON
Wen-Bing Shenga,b, Tie-Qiao Chena, Ming-Zhong Zhanga , Mi Tiana , Guo-Fang Jianga and Can-Cheng Guoa, 

1
Tetrahedron Letters
Copper Porphyrin-Catalyzed Aerobic Oxidative Coupling of Terminal Alkynes
with High TON
Wen-Bing Shenga,b , Tie-Qiao Chena, Ming-Zhong Zhanga , Mi Tiana , Guo-Fang Jianga and Can-Cheng
Guoa, 
a College of Chemistry and Chemical Engineering, Hunan University, Changsha Hunan 410082, PR China
b School of Pharmacy, Hunan University of Chinese Medicine, Changsha Hunan 410208, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper porphyrin-catalyzed Glaser-Hay-type couplings of terminal alkynes generating 1,3-
diynes are described. This reaction features high TON (up to 950) and is complete in an hour,
providing a facile, clean and efficient protocol to access various 1,3-diynes including those with
functional groups under mild reaction conditions. This transformation would take place via a
radical process.
Available online
Keywords:
2015 Elsevier Ltd. All rights reserved.
Glaser-Hay coupling
Copper porphyrin
Terminal alkynes
1,3-Diynes
Aerobic oxidation
Introduction
copper porphyrin could also mediate the aerobic oxidative
coupling of terminal alkynes under mild reaction conditions,
1,3-Diynes have been widely applied in medicinal chemistry,
material chemistry and organic synthesis.1 They also occur in
many natural products.2 The copper mediated coupling of
terminal alkynes, namely Glaser-Hay coupling, is one of the most
straightforward methods for their synthesis. To date, many
efficient copper catalytic systems have been developed;3 however
they commonly suffered from high catalyst loading (> 2 mol%
copper catalyst) and low turnover numbers (< 50) due to the
catalyst deactivation.4 It would be appealing to develop an
efficient ligand, ligating to the copper and thus improving the
reaction efficiency.
generating the corresponding 1,3-diynes in high yields (eqn (1)).
In contrast to the reported copper catalytic system, the copper
porphyrin operates at much lower loading (0.1 mol%) and
catalyzes the Glaser−Hay coupling with high turnover numbers
(up to 950). Primary mechanistic studies show that this
transformation would proceed via a radical process.
Results and discussion
We initiated our work by investigating the aerobic oxidative
homocoupling of phenylacetylene and the results obtained were
compiled in Table 1. In the presence of 0.1 mol% meso-
tetra(para-chlorophenyl)porphyrin copper(Ⅱ) (T(p-Cl)PPCu), 1
o
mmol phenylacetylenes were stirred in 1 mL methanol at 30 C
for 1 h under air atmosphere, the homocoupling product 2a was
generated in 78% yield (Table 1, entry 1). By elevating the
o
temperature to 50 C, the yield of 2a increased to 90% (Table 1,
Porphyrin is the key core unit of cytochromes P-450, which
acts as an efficient ligand and enables the metal to activate
molecular dioxygen efficiently.5 Thus, the corresponding
metallophorphyrins have been widely used for the
monooxygenation of inactive C−H bonds in hydrocarbons and
the epoxidation of alkenes.6 In particular, the oxidation of
cyclohexane to cyclohexanol/cyclohexanone catalyzed by
metalloporphyrins has been realized at large-scale industrial
process in our laboratory.7 During the extensive studies of
entry 2). When the reaction was performed under oxygen
atmosphere, the reaction efficiency was not improved (Table 1,
entry 3), whereas no product was detected under nitrogen
atmosphere (Table 1, entry 4). This reaction proceeded poorly in
other solvent such as DMSO, DMF and MeCN (Table 1, entries
6−8). It should be noted that copper porphyrin was essential for
this homocoupling reaction, in the absence of copper porphyrin
only a trace amount of product was yielded (Table 1, entry 5).
By using copper salts or the combination of copper salt and
porphyrin as catalyst instead, the reaction proceeded sluggishly
monooxygenation of C−H bonds, we accidently found that
———
 Corresponding author Tel. and Fax: +86-731-88821488; e-mail: ccguo@hnu.edu.cn

2
Tetrahedron
(Table 1, entries 9−12). These results also indicated that the
corresponding 1,3-diynes 2n, 2o and 2p were produced in 89%,
87% and 90% yields, respectively (Table 2, entries 14-16).
porphyrin ligand played an important role in the current Glaser-
Hay couplings and improved greatly the catalytic performance
of copper catalyst: lower catalyst loading (0.1 mol%) and higher
TON (up to 950).8 Other metalloporphyrin like Fe, Mn and Co
were ineffective for the coupling reaction under similar reaction
conditions (Table 1, entries 13−15).
Table 2 Copper porphyrin-catalyzed homocoupling of terminal
alkynesa
0.1 mol% T(p-Cl)PPCu/air
R1
R1
R1
CH3OH, 50 oC, 1 h
1
2
Table 1 Optimization of the reaction conditionsa
Entry
R1 group
Yieldb /%
90
Product 2
1
2
3
4
5
6
C6H5 (1a)
2a
2b
2c
2d
3-MeC6H4 (1b)
4-MeC6H4 (1c)
4-n-PrC6H4 (1d)
4-n-BuC6H4 (1e)
4-pentylC6H4 (1f)
92
93
92
93
92
2e
2f
7
4-MeOC6H4 (1g)
4-FC6H4 (1h)
2g
95
82
84
8
9
2h
4-ClC6H4 (1i)
4-BrC6H4 (1j)
4-NO2C6H4 (1k)
2i
10
2j
79
85
2k
2l
11
12c
2-pyridyl (1l)
< 1
3-thiophenyl (1m)
n-C5H11 (1n)
n-C6H13 (1o)
2m
2n
2o
2p
94
89
87
90
13
14
15
16
4-HOC4H8 (1p)
a
Conditions: terminal alkynes 1 (1 mmol), T(p-Cl)PPCu (0.1 mol%), MeOH
a Reaction conditions: 1a (1 mmol), catalyst (0.1 mol%), solvent (1.0 mL), O2
or air atmosphere, 1 h.
(1 mL), air, 50 oC, 1 h.
b Isolated yield.
c GC yield
b GC yield based on 1a.
This facile and efficient reaction is applicable to other
substrates. As shown in Table 2, both aliphatic and aromatic
terminal alkynes served well, affording the corresponding
coupling products 1,3-diynes in high yields. Thus, the aromatic
acetylenes bearing electron-donating groups like alkyl and
methoxy groups on benzene ring homocoupled readily, producing
the corresponding 1,3-diynes in high yields (Table 2, entries 1−7).
The halogen group like F, Cl and Br survived under the present
reaction conditions and the 1,3-diynes with halogen groups on
benzene ring were prepared from the homocoupling of the
expected terminal alkynes in good yields, facilitating further
functionalization via transition metal-catalyzed cross couplings
(Table 2, entries 8-10). The substrate with electron-withdrawing
group exemplified by 1-ethynyl-4-nitrobenzene served well and
the coupling product 1,4-bis(4-nitrophenyl)buta-1,3-diyne 2k was
given in 85% yield under similar reaction conditions(Table 2,
entry 13). The heteroatom-containing 3-ethynylthiophene were
converted to the 1,3-diyne 2m in 94% yield (Table 2, entry 13).
However, when 2-pyridylacetylene was employed as substrate,
only a trace amount of product was detected (Table 2, entry 12).
The result perhaps was ascribed to the catalyst deactivation by
coordination of pyridine group with copper porphyrin. The guess
was supported by the experiment: by addition of an equivalent of
pyridine, the homocoupling of phenylacetylene did not work and
no coupling product 2a was generated under the standard reaction
conditions, indicating that pyridine indeed poisoned the copper
porphyrin. Other substrates bearing amine groups like prop-2-yn-
1-amine and 4-ethynylaniline also did not work under the reaction
conditions. Aliphatic terminal alkynes 1n, 1o and 1p were proved
to be good substrates in the present catalytic system and the
The synthetic value of the transformation was further
displayed by the synthesis of 1,3-diyne bearing bioactive
fragment. Thus, by employing the copper porphyrin-catalyzed
aerobic oxidative coupling, the bioactive ethisterone
homocoupled readily to produce the corresponding 1,3-diynes 2q
in 82% yield (Scheme 1).
O
OH
OH
0.1 mol%T(p-Cl)PPCu/air
CH3OH, 50 oC, 2 h
HO
O
yield: 82%
2q
ethisterone
O
1q
Scheme
1 Copper porphyrin-catalyzed aerobic oxidative
homocoupling of bioactive ethisterone.
Usually, the asymmetric 1,3-diynes were synthesized by
cross coupling of one terminal alkynes with over stoichiometric
another alkyne (> 5 equiv).9 To our delight, by employing the
present copper porphyrin-catalyzed transformation, the
asymmetric 1,3-diynes were also synthesized in moderate yields
and good selectivity from cross coupling between two terminal
alkynes with a 1.2:1 ratio.10 As shown Table 3, in the presence of
0.1 mol% copper porphyrin, hept-1-yne coupled readily with 1-
ethynyl-4-methoxybenzene to produce the cross coupling product
1-methoxy-4-(nona-1,3-diynyl)benzene in 40% yield with 65%
selectivity. Phenylacetylene reacted with other aromatic terminal
alkynes, generating the cross coupling in moderate yields with
good selectivity. The cross coupling between 1-ethynyl-4-
methoxybenzene and 1-chloro-4-ethynylbenzene also took place,

3
2.
3.
Shun A. L. K. S.; Tykwinski, R. R. Angew. Chem. Int. Ed. 2006,
45, 1034−1057
giving the cross coupling 1,3-diyne 1-chloro-4-(4-(4-
methoxyphenyl)buta-1,3-diynyl)benzene in 45% yield with 93%
selectivity. This reaction provided a facile method to access the
asymmetric 1,3-diynes.
(a) Hay, A. S. J. Org. Chem. 1962, 27, 3320–3321. (b) Valenti, E.;
Pericas, M. A.; Serratosa, F. J. Am. Chem. Soc.1990, 112, 7405–
7406. (c) Li, J.; Jiang, H. Chem. Commun. 1999, 2369–2370. (d)
Heuft M. A.; Collins S. K.; Yap G. P. A.; Fallis A. G. Org.
Lett. 2001, 3 (18), 2883–2886. (e) Liao, Y.; Fathi, R.; Yang, Z.
Org. Lett. 2003, 5, 909–912. (f) Abe, H.; Kurokawa H.; Chida, Y.;
Inouye, M. J. Org. Chem. 2011, 76 (1), 309–311. (f) Yin, K.; Li,
C.; Li, J.; Jia, X. Green Chem. 2011, 13, 591–593. (g) Tripp, V.
T.; Lampkowski, J. S.; Tyler R.; Young, D. D. ACS Comb.
Sci. 2014, 16, 164–167. (h) Lei, A.; Srivastava, M.; Zhang, X. J.
Org. Chem., 2002, 67, 1969-1971.
Table 3 Oxidative cross-coupling of various alkynes catalyzed
by T(p-Cl)PPCua
4.
(a) Diederich, F.; Rubin, Y.; Knobler, C. B.; Whetten, R. L.;
Schriver, K. E.; Houk, K. N.; Li, Y. Science 1989,
245,1088−1090. b) Kanis, D. R.; Ratner, M. A.; Marks, T. J.
Chem. Rev. 1994, 94, 195−242. (c) Xu, Z.; Kaha, M.; Walker, K.
L.; Wilkins, C. L.; Moore, J. S. J. Am. Chem. Soc. 1994, 116,
4537−4550. (d) To the best of our knowledge, there is only one
example reporting that the TON can be up to 468 in
a
heterogeneous catalytic system. However, this reaction was
performed at an elevated temperature (100 oC) in a toxic solvent
PhCN with a long reaction time (18 hours). See: Kamata K.;
Yamaguchi S.; Kotani M.; Yamaguchi K.; Mizuno N.; Angew.
Chem. Int. Ed. 2008, 47, 2407−2410.
The Porphyrin Handbook; Kadish K. M., Smith, K. M., Guilar, R.,
Eds.; Academic Press: San Diego, 1999; Vol. 4, pp 119−144.
(a) Jiang, Q.; Xiao,Y.; Tan, Z.; Li, Q. H.; Guo, C. C. J. Mol.
Catal. A: Chem. 2008, 285, 162−168. (b) Huang, G.; Guo,C. C.;
a
Reaction conditions: a 0.6 mmol and b 0.5 mmol respectively, T(p-
Cl)PPCu (10-6 mol) in 1 mL of MeOH under 1 atm of air at 50 oC for 1 h.
b Isolated yields. The yield and selectivity were calculated on the basis of
5.
6.
coupling partner b.
c GC yield
Tang, S. S. J. Mol. Catal. A: Chem.
(c)
Sheng, W. B.; Jiang, Q.; Luo, W. P.; Guo, C. C. J. Org. Chem.
2013, 78, 5691−5693. (d) Xia, Q. H.; Ge, H. Q.; Ye, C.P.; Liu, Z.
M.; Su, K. X. Chem. Rev. 2005, 105, 1603–1662.
Organometallic mechanism involving Cu(I) and Cu(II)
complexes has been proposed and most accepted, however this
copper porphyrin-catalyzed Glaser-Hay coupling seems different.
In the presence of 2.0 equiv TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy), the homocoupling of phenylacetylene 1a
proceeded sluggishly under the standard reaction conditions,
indicating that this reaction would be a radial process. In the
ultraviolet absorption spectrums of the reaction mixture, an
absorption peak appeared at 463.5 nm (the Q band was also a
little blue sifted, for UV-Vis spectrum, see SI), this peak would
be assigned to a Cu(III) species,11 implying that Cu(III) porphyrin
would be an efficient intermediate in the aerobic oxidative
couplings. Considering that copper salts showed rather low
catalytic efficiency for the homocoupling of phenylacetylene
(Table 1, entries 11 and 12), it was deduced the porphyrin ligand
modified the electronic properties of copper and stabilized the
related copper species involved in the reaction process, and thus
improved the catalytic performance of the catalyst.
7.
(a) Guo, C. C.; Liu, X. Q.; Liu, Q.; Liu, Y.; Chu, M. F.; Liu, M. Y.
J. Porphyr. Phthalocya. 2009, 13, 1250−1254. (b) Liu, Q.; Guo,
C.C. Sci. China Chem. 2012, 55, 2036−2053. (c) In our laboratory,
the metalloporphyrins like Fe, Mn, Co and Cu can be simply
prepared at a large scale (up to 1000 ton/year). These complexes
can be commercially available at a low price now (ca. 10 yuan/g).
See: Liu, Q.; Guo, C.C. Sci. China Chem. 2012, 55, 2036−2053.
We also tried the reaction with 0.01 mol% copper porphyrin
catalyst, however prolonging reaction time (> 24 h) was required
under similar reaction conditions.
To the best of our knowledge, there is two examples about the
cross coupling with almost equivalent terminal alkynes. See: (a)
Tripp, V. T.; Lampkowski,J. S.; Tyler,R.; Young, D. D. ACS
Comb. Sci. 2014, 16, 164−167. (b) Ma, Z.; Wang, X.; Wei, S.;
Yang, H.; Zhang,F.; Wang,P.; Xie, M.; Ma, J. Catal. Commun.
2013, 39, 24–29.
8.
9.
10. This reaction is a dynamic process. Terminal alkynes a are more
reactive to undergo homocoupling, thus 1.2 equiv a was loaded in
the reaction. By lengthening the reaction time, the selectivity will
decrease as a is consumed.
Conclusions
11. (a) Guo, C.-C.; Song, J.-X.; Chen, X.-B.; Jiang, G.-F. J. Mol.
Catal. A: Chem. 2000, 157, 31–40. (b) (a) Guo, C.-C.; Huang, G.;
Li, Z.-P.; Song, J.-X.; J. Mol. Catal. A: Chem. 2001, 170, 43–49.
(c) (c) Beaumont, S. K.; Kyriakou, G.; Lambert, R. M. J. Am.
Chem. Soc. 2010, 132, 12246–12248. (d) Zhang, G.; Yi, H.;
Zhang, G.; Deng, Y.; Bai, R.; Zhang, H.; Miller, J. T.; Kropf, A.
J.; Bunel, E. E.; Lei, A. J. Am. Chem. Soc. 2014, 136, 924−926.
12. General procedure: a 10-mL glass test-tube was equipped with
magnetic stirring bar and charged with 1 mmol alkynes, 10-6 mol
metalloporphyrins, 1 mL methanol, heated at 50 ℃ under 1 atm
of air for 1 hour, then cooled to room temperature. After the
usually workup the crude collected and purified by column
chromatography on silica gel using hexane as eluent. All the
compounds, after purification, were weighted and characterized by
In summary, copper porphyrin acted as an efficient catalyst
and enabled the aerobic oxidative Glaser-Hay-type couplings of
terminal alkynes to take place at much lower loading (0.1 mol%)
than that of the reported catalytic system. A variety of 1,3-diynes
including those bearing functional groups were produced under
mild reaction conditions with high TON (up to 950). Further
studies on the mechanism are underway in our laboratory.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21372068), the Education Department of
Hunan Province (13C676) and Natural Science Foundation of
Hunan Province (2015JJ6082).
13
MS, 1H NMR, C NMR, and then compared them with the
spectral data of authentic samples.
Supplementary Material
References and notes
Supplementary data associated with this article can be found,
in the online version.
1.
(a) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979−2017.
(b) Shi, W.; Lei, A. Tetrahedron Lett. 2014, 55, 2763−2772. (c)
Sindhu, K. S.; Anilkumar, G. RSC Adv. 2014, 4, 27867–27887.

4
Tetrahedron
Highlights
• UV-Vis spectra is carried out to
detect the efficient intermediate
intermediate Cu(III)-porphyrin.
• Copper-porphyrin is effective
catalyst for the cross-coupling of
terminal alkynes with excellent
selectivity.
• This reaction features high TON
(up to 950) in homo-coupling of
terminal alkynes with functional
groups.