Influence of bases and ligands on the outcome of the Cu(I)-catalyzed oxidative homocoupling of terminal alkynes to 1,4-disubstituted 1,3-diynes using oxygen as an oxidant

Article abstract of DOI:10.1021/jo900246z

(Chemical Equation Presented) The efficient Cu(I)-catalyzed oxidative homocoupling of terminal alkynes in the presence of a base using an amine as a ligand and oxygen as an oxidant yields the symmetrical 1,3-diynes with yields of up to 99%. The outcome of the couplings critically depends on the proper choice of base and ligand as well as reaction conditions. Best results were observed with 2.0 mol%CuCl, 1.5 mol%TMEDA or DBEDA, and DBU or DABCO in acetonitrile.

Full text of DOI:10.1021/jo900246z

pubs.acs.org/joc
allows the reaction to be run under homogeneous condi-
Influence of Bases and Ligands on the Outcome of the
Cu(I)-Catalyzed Oxidative Homocoupling of
Terminal Alkynes to 1,4-Disubstituted 1,3-Diynes
Using Oxygen as an Oxidant
tions)6 and Hay’s procedure, which relies on the use of
catalytic amounts of Cu(I) salt as a catalyst, tertiary amines
such as pyridine or N,N,N’,N’-tetramethylethylenediamine
(TMEDA) as complexing agents, and O2 as an oxidant.7
Other methods for the synthesis of 1,4-disubstituted
1,3-diynes include the Cadiot-Chodkiewicz8 and the Sono-
gashira9 couplings. Recently, it has been shown that the
oxidative homocoupling of terminal alkynes can be accom-
plished by a combination of a Pd catalyst and a Cu(I) salt.10
Even if the Pd-catalyzed reactions are highly efficient and
proceed under mild reaction conditions, the Pd catalysts are
far more expensive than the cheap and easily available Cu(I)
salts. Another disadvantage of many of these protocols is
that oxidants other than O2 need to be used for the reoxida-
tion of Pd(0) to Pd(II).10a-10c,10f Finally, with some of the
Pd-catalyzed systems the formation of the desired homo-
coupling products is accompanied by the formation of side
products such as enynes. In addition, the Cu(II)-catalyzed
homocoupling reaction of terminal alkynes in supercritical
CO2 has been reported.11 This protocol requires special
equipment and high CO2 pressure at elevated temperatures.
Using CuAl-hydrotalcite as a catalyst, an additional step for
the preparation of the reagent is needed.12
Subbarayappa Adimurthy,† Chandi C. Malakar,‡ and
Uwe Beifuss*,‡
†Central Salt & Marine Chemicals Research Institute,
Gijubhai Badheka Marg, Bhavnagar 364 002, Gujrat, India,
and ‡Bioorganische Chemie, Institut fu€r Chemie, Universita€t
Hohenheim, Garbenstr. 30, D-70599 Stuttgart, Germany
ubeifuss@uni-hohenheim.de
Received February 10, 2009
The further development of the Cu(I) salt catalyzed
coupling using O2 as an oxidant appeared to be the most
attractive approach in order to meet the demand for high
yields and high selectivities, simple experimental proce-
dures under mild reaction conditions, avoidance of
expensive and/or harmful reagents, and use of O2 as an
environmentally benign oxidant. Quite unexpectedly we
found that only a few experiments have so far been
published on the influence of ligands, bases, and reaction
conditions on the outcome of this type of coupling.
Brandsma mentioned that the yields of the homocoup-
ling of terminal alkynes can be increased by adding
small amounts of 1,8-diazabicycloundec-7-ene (DBU).13
However, a detailed study of the influence of bases is
missing. The same holds true for the influence of ligands.
The efficient Cu(I)-catalyzed oxidative homocoupling of
terminal alkynes in the presence of a base using an amine
as a ligand and oxygen as an oxidant yields the symme-
trical 1,3-diynes with yields of up to 99%. The outcome of
the couplings critically depends on the proper choice of
base and ligand as well as reaction conditions. Best results
were observed with 2.0 mol % CuCl, 1.5 mol % TMEDA
or DBEDA, and DBU or DABCO in acetonitrile.
The dimerization of terminal alkynes through oxidative
homocoupling to give 1,3-diynes is an important C-C bond-
formation reaction.1 It has been employed for a number of
applications, including the construction of linear π-conju-
gated acetylenic oligomers and polymers,2 the synthesis of
natural products,3 and molecular recognition processes.4
The reaction dates back to 1869 when C. Glaser observed
the formation of a precipitate upon the reaction of a terminal
alkyne with a Cu(I) salt in the presence of aqueous ammonia;
after air oxidation the oxidative homocoupling product was
isolated.5 A number of improvements of the original method
have emerged, including the Eglington procedure (which
(7) Hay, A. S. J. Org. Chem. 1960, 25, 1275. Hay, A. S. J. Org. Chem.
1962, 27, 3320.
(8) Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H.
G., Ed.; Marcel Dekker: New York, 1969; p 597.
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (b) For a review, see: Sonogashira, K. Coupling reactions between
sp carbon centers. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1990; Vol. 3, p 521.
(10) (a) Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523.
(b) Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371. (c) Lei, A.;
Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 1969. (d) Fairlamb, I. J. S.;
€
Bauerlein, P. S.; Marrison, L. R.; Dickinson, J. M. Chem. Commun. 2003,
632. (e) Batsanov, A. S.; Collings, J. C.; Fairlamb, I. J. S.; Holland, J. P.;
Howard, J. A. K.; Lin, Z.; Marder, T. B.; Parsons, A. C.; Ward, R. M.; Zhu,
J. J. Org. Chem. 2005, 70, 703. (f) Li, J.-H.; Liang, Y.; Zhang, X.-D.
Tetrahedron 2005, 61, 1903. (g) Li, J. H.; Liang, Y.; Xie, Y.-X. J. Org. Chem.
2005, 70, 4393. (h) Shi, M.; Qian, H. X. Appl. Organomet. Chem. 2006, 20,
771. (i) Yang, F.; Cui, X.; Li, Y.; Zhang, J.; Ren, G.; Wu, Y. Tetrahedron
2007, 63, 1963.
(11) Li, J.; Jiang, H. Chem. Commun. 1999, 2369. Jiang, H.-F.; Tang, J.-Y.;
Wang, A.-Z.; Deng, G.-H.; Yang, S.-R. Synthesis 2006, 1155.
(12) Zhu, B. C.; Jiang, X. Z. Appl. Organomet. Chem. 2007, 21, 345.
(13) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier: Amsterdam,
1988; Chapter 10.
(1) For a review, see: Siemsen, P.; Livingston, R. C.; Diederich, F.
Angew. Chem., Int. Ed. 2000, 39, 2632.
(2) Tour, J. M. Chem. Rev. 1996, 96, 537. Martin, R. E.; Diederich, F.
Angew. Chem., Int. Ed. 1999, 38, 1350.
(3) For reviews, see: Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem.,
Int. Ed. 2006, 45, 1034. Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally
Occuring Acetylenes; Academic Press: New York, 1973.
(4) Lehn, J. M. Supramolecular Chemistry: Concepts and Perspectives;
VCH: Weinheim, 1995.
(5) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.
(6) Eglington, G.; Galbraith, R. J. Chem. Soc. 1959, 889.
5648 J. Org. Chem. 2009, 74, 5648–5651
Published on Web 06/11/2009
DOI: 10.1021/jo900246z
r
2009 American Chemical Society

Adimurthy et al.
JOCNote
This is why we decided to perform experiments toward
this end.
TABLE 1. Effect of Bases on Oxidative Dimerization of 1a Using a CuCl/
TMEDA Catalytic System and O2 as Oxidanta
Here we report on the effect of different bases and amines
on the yields of the CuCl-catalyzed homocouplings of term-
inal alkynes with O2 as an oxidant. The careful choice of
base, ligand, solvent, and reaction conditions enabled us to
develop convenient protocols that allow for the efficient
reaction of both aryl- and alkyl-substituted terminal alkynes
to give the corresponding 1,4-disubstituted 1,3-diynes with
high yields.
entry
base (mol %)
K2CO3 (300)
Cs2CO3 (120)
DIPA (210)
TEA (100)
DIPEA (100)
DIPEA (12.5)
NMP (12.5)
NMP (100)
DBU (6.25)
DBU (12.5)
DBU (25)
DBU (33)
DBU (100)
DBN (12.5)
DBN (100)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
24
6
12
6
37
46
20
53
74
90
80
79
84
79
87
89
91
99
66
88
77
97
36
60
73
Our initial studies focused on the development of an
optimum set of reaction conditions for the homocoupling
reaction of phenylacetylene (1a) using CuCl as a catalyst and
TMEDA as a ligand. Some preliminary studies revealed that
best results were obtained when the couplings were run with
2 mol % CuCl, 1.5 mol % TMEDA, and CH3CN as the
solvent at rt. Using this CuCl/TMEDA system, the effect of
bases was studied. The results with different bases in differ-
ent concentrations are summarized in Table 1. First, a
control experiment without any additional base was per-
formed. Under these conditions 2a was obtained with a yield
of merely 37% (Table 1, entry 1). After some disappointing
experiments with inorganic bases such as K2CO3, and
Cs2CO3 (Table 1, entries 2, 3) and diisopropylamine (DIPA)
(Table 1, entry 4), the reaction was carried out with triethyl-
amine (TEA) (Table 1, entry 5), diisopropylethylamine
(DIPEA) (Table 1, entries 6, 7), N-methylpyrrolidine
(NMP) (Table 1, entries 8, 9), 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (Table 1, entries 10-14), 1,5-diazabicyclo
[4.3.0]non-5-ene (DBN) (Table 1, entries 15, 16), 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) (Table 1, entries 17, 18), and
1,5-naphthyridine (Table 1, entries 19-21).
12
24
24
18
24
36
24
20
18
18
24
24
16
24
24
24
24
DABCO (12.5)
DABCO (100)
1,5-naphthyridine (12.5)
1,5-naphthyridine (50)
1,5-naphthyridine (100)
aReaction conditions: 1a (2.0 mmol), CuCl (2.0 mol %), O2, base,
TMEDA (1.5 mol %), CH3CN (10 mL), r.t. bYields are not optimized.
TABLE 2. Ligand Screening for the Oxidative Dimerization of 1aa
The results clearly show that the CuCl/TMEDA system
can successfully be used in combination with many bases.
The best results, however, were obtained with sterically
hindered amine bases such as DBU and DABCO. Using
these bases 2a was isolated in yields of 99% and 97%,
respectively (Table 1, entries 14, 18). To study the influence
of the base concentration, the reaction with DBU was chosen
as an example. The results indicate that the reaction can be
performed in the presence of as little as 6.25 mol % and still
yields 79% of 2a (Table 1, entry 10). A gradual increase in the
amount of DBU from 6.25 to 33 mol % leads to an increase
in yields from 79% to 91% (Table 1, entries 10-13). From
our experience the best compromise between base concen-
tration and yield could be achieved with 12.5 mol % of DBU;
this is why additional couplings with some of the other bases
were performed at a concentration of 12.5 mol %. The results
clearly indicate that DBU is superior to the other bases.
Therefore most of the following experiments were carried
out with DBU.
In all experiments described so far O2 was bubbled
through the reaction mixture. It was also possible to perform
the reactions in static O2 atmosphere. If the coupling of 1a
with 2 mol % CuCl, 1.5 mol % TMEDA, 100 mol % DBU,
and 2 mL of CH3CN was performed using a balloon filled
with O2 at rt for 18 h, the yield of 2a amounted to 98%. It is
worth mentioning that the amount of CH3CN could be
reduced from 10 to 2 mL under these conditions. A compar-
able yield of 2a (97%) was observed when the balloon
was filled with air (2 mol % CuCl, 1.5 mol % TMEDA,
100 mol % DBU, 2 mL of CH3CN, rt, 24 h) instead of O2.
entry
ligand
TMEDA
1,5-cis-diazadecalin
DCU
DBEDA
DBU (mol %) time (h) yield (%)b
1
2
3
4
5
6
100
12.5
24
24
24
24
15
24
55
87
74
65
91
72
12.5
12.5
12.5
12.5
Salen
aReaction conditions: 1a (2.0 mmol), CuCl (2.0 mol %), O2, base,
ligand (1.5 mol %), CH3CN (10 mL), r.t. bYields are not optimized.
The yield of 2a dropped to 87% when only 1 mL of CH3CN
was used (2 mol % CuCl, 1.5 mol % TMEDA, 100 mol %
DBU, O2 balloon, rt, 20 h).
The effect of the ligand could clearly be demonstrated
when the coupling of 1a was run with 1 equiv of DBU in the
absence of a ligand; under these conditions the yield of 2a
dropped to 55% (Table 2, entry 1). To identify the most eff-
ective ligand, the dimerization of 1a was run in the presence
of 12.5 mol % DBU and 1.5 mol % of different ligands,
including TMEDA, 1,5-cis-diazadecalin, N,N’-dicyclohexyl-
urea (DCU), N,N’-dibenzylethylenediamine (DBEDA), and
N,N’-bis(salicylidene)ethylenediamine (Salen); the results
are summarized in Table 2. It turned out that
DBEDA (91% yield of 2a) was the best choice (Table 2,
entry 5), followed by TMEDA (87% yield of 2a) (Table 2,
entry 2). Lower yields of 2a were obtained with
J. Org. Chem. Vol. 74, No. 15, 2009 5649

Adimurthy et al.
JOCNote
TABLE 3. Oxidative Homocoupling of Terminal Alkynesa
entry
1
base (mol %) temp (°C) time (h)
2
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
b
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (12.5)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (12.5)
DBU (12.5)
DBU (12.5)
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
5
24
36
24
36
24
36
36
36
24
36
28
36
6
36
12
36
24
36
36
24
6
b
99
97
99
87
97
83
90
61
72
34
93
69
97
89
94
87
92
66
54
75
55
37
58c
70d
70e
c
d
e
f
c
d
e
f
FIGURE 1. Terminal alkynes 1b-m used for the oxidative homo-
coupling.
g
h
i
g
h
i
1,5-cis-diazadecalin, DCU, and Salen (Table 2, entries 3, 4, 6).
Despite the higher yields obtained with DBEDA, the cheaper
TMEDA was chosen for the following experiments.
To demonstrate the efficiency and to explore the scope of
the CuCl/DBU/TMEDA catalytic system for the synthesis
of symmetrical 1,3-diynes, a number of terminal alkynes
(Figure 1) were homocoupled using 2 mol % CuCl, 1.5 mol %
TMEDA, 1 equiv of DBU, and O2 as an oxidant. In
addition, the transformations were also studied with
12.5 mol % DBU. The results are given in Table 3.
j
j
k
l
k
l
0
24
24
24
5
36
24
30
36
m
m
Under the conditions mentioned the reactions proceeded
smoothly and delivered the diynes with yields ranging from
55% to 99% when 1 equiv of DBU was used. In 8 out of 10
cases the yields exceeded 90%. When only 12.5 mol % of
DBU was employed, the yields ranged between 34% and
97%. It is obvious that alkenyl, hydroxyl, fluoride, and ether
groups are not affected under the reaction conditions. The
transformations proceeded without any side product forma-
tion, except with 9-ethynyl-9-fluorenol (1m) (Table 3, entries
23-25), where considerable amounts of fluorene-9-one were
isolated. This may be due to cleavage of the sp3-sp C-C
bond in the starting material followed by oxidation to give
fluorenone. The amount of fluorene-9-one could be reduced
from 33% to 11% when the reaction temperature was
decreased from rt to 0 °C.
0
a Reaction conditions: 1b-m (2.0 mmol), CuCl (2.0 mol %), O2, base,
TMEDA (1.5 mol %), CH3CN (10 mL). b Yields are not optimized.
c 33% fluorenone was obtained. d 14% fluorenone was obtained. e 11%
fluorenone was obtained.
TABLE 4. Base and Ligand Screening for the Homocoupling of n-Octyne
(1l)a
entry
base (mol %)
ligand (mol %)
time (h)
yield (%)b
The advantages of our protocol include the use of com-
mercially available and cheap CuCl (2 mol %), bases (1
equiv), and amines (1.5 mol %), the exclusive use of O2 as an
oxidant, a simple experimental setup, mild reaction condi-
tions, a simple workup, high yields, and no contamination of
the product with enynes. In our protocol there is no need for
the extra preparation of special Cu catalysts such as CuAl-
hydrotalcites;12 for an additional Pd catalyst such as Pd
(PPh3)4,10a PdCl2(PPh3)2,10b-10e PdCl2,10f Pd(OAc)2,10g an
N-heterocyclic carbene-Pd(II) complex10h or cyclopalla-
dated ferrocenylimine;10i for additional stoichiometric oxi-
dants such as ClCH2COCH3,10a I2,10b BrCH2CO2Et10c or
1
2
3
4
5
6
7
8
9
DBU (100)
DBU (12.5)
DBU (100)
DBU (12.5)
DBU (12.5)
DABCO (12.5)
DABCO (100)
DABCO (12.5)
DABCO (100)
TMEDA (1.5)
TMEDA (1.5)
DBEDA (1.5)
DBEDA (1.5)
DBEDA (5.0)
TMEDA (1.5)
TMEDA (1.5)
DBEDA (1.5)
DBEDA (1.5)
6
36
18
18
16
16
18
18
18
55
37
44
20
58
46
71
51
61
aReaction conditions: 1l (5.0 mmol), CuCl (2.0 mol %), O2, base,
ligand, CH3CN (15 mL). bYields are not optimized.
Me3NO 2H2O;10f for a large excess of bases;10b,10d-10g or for
combinations (Table 4). It turned out that the yield of 2l
could be raised to 71% when the coupling was performed
with a combination of DABCO (100 mol %) and TMEDA
(1.5 mol %) (Table 4, entry 7).
In conclusion, we have developed a mild and efficient
synthetic protocol for the catalytic oxidative homocoupling
of terminal alkynes by optimizing reagents and reaction
conditions. For most alkynes the CuCl/DBU/TMEDA cata-
lytic system proved to be successful; for less acidic alkynes
3
additional phosphines such as PPh3.10d,10e
The results of the coupling of the alkyl-substituted alkyne
1l were unsatisfactory since 2l was obtained in yields of no
more than 55% or 37% (Table 3, entries 21, 22). The low
reactivity of 1l is probably due to its weak acidity; this
phenomenon is well-known for homocouplings of alkyl-
substituted alkynes.13 To increase the yield of 2l the homo-
coupling of 1l was carried out with several base/ligand
5650 J. Org. Chem. Vol. 74, No. 15, 2009

Adimurthy et al.
JOCNote
the CuCl/DABCO/TMEDA catalytic system was found to
be the most suitable combination. Our protocols differ from
others in that the reactions can be easily performed,
all reagents are commercially available, cheap O2 can be
used as an oxidant, and in most cases a single product can
be isolated in very high yields without any side product
formation.
chromatography over silica gel (ethyl acetate/hexane=1: 9) to
afford 2j (263 mg, 92% yield) as a white solid.
1,4-Bis(2,4,5-trimethylphenyl)buta-1,3-diyne (2j). Mp 232-
233 °C. IR (ATR): ν 2918 cm-1, 2140, 1485, 1452, 1377, 1256,
1022, 1000, 879. 1H NMR (CDCl3): δ (ppm) 7.30 (brs, 2H), 7.01
(brs, 2H), 2.45 (s, 6H), 2.27 (s, 6H), 2.23 (s, 6H). 13C NMR
(CDCl3): δ (ppm) 139.2, 138.3, 134.1, 134.0, 131.2, 119.2, 81.4,
77.0, 20.4, 20.0, 19.3. MS (EI, 70 eV): m/z (%) 286 (100) [M+],
271 (23), 256 (43), 239 (14), 143 (15), 128 (14). HRMS (EI, M+)
calcd for C22H22: 286.1722, found 286.1757.
Experimental Section
General Procedure for Homocoupling of Alkynes 2 (2j as
Example). DBU (304 mg, 2.0 mmol), TMEDA (3.5 mg, 0.03
mmol, 1.5 mol %), and CuCl (4 mg, 0.04 mmol, 2.0 mol %) were
added at 24 °C under stirring to 10 mL of acetonitrile while
oxygen was bubbled through the solution. After 10 min 286 mg
(2.0 mmol) of 2,4,5-trimethyl phenylacetylene (1j) was added.
The reaction mixture was stirred at 24 °C while oxygen was
bubbled through the solution for 24 h. The progress of the
reaction was monitored by TLC. After completion of the
reaction, the solvent was removed under reduced pressure
and the crude product obtained was purified by column
Acknowledgment. S.A. is grateful to the Department
of Science & Technology, Govt. of India, New Delhi, for
the award of a BOYSCAST fellowship (SR/BY/C-05/06) for
the year 2006-07. We thank Ms. S. Mika and Dr. J. Conrad
for NMR spectra and Dipl.-Chem. F. Mert-Balci and
Dr. H. Leutbecher for mass spectra.
Supporting Information Available: Detailed spectroscopic
data for diynes 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 15, 2009 5651