Copper salt-catalyzed homo-coupling reaction of potassium alkynyltrifluoroborates: a simple and efficient synthesis of symmetrical 1,3-diynes

Article abstract of DOI:10.1016/j.tetlet.2008.02.083

The copper-catalyzed dimerization of alkynyltrifluoroborates proceeds readily with good yields. The homo-coupling reaction can be effected in DMSO, in the open air, using Cu(OAc)₂ as catalyst in the absence of any other additives. A variety of functional groups are tolerated.

Full text of DOI:10.1016/j.tetlet.2008.02.083

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2366–2370
Copper salt-catalyzed homo-coupling reaction of potassium
alkynyltrifluoroborates: a simple and efficient synthesis
of symmetrical 1,3-diynes
a,
b
d
d
*
´
Marcio W. Paixao , Mineia Weber , Antonio L. Braga , Juliano B. de Azeredo ,
˜
d
a,b,c,
*
´
Anna M. Deobald , Helio A. Stefani
a Instituto de Quı´mica, Universidade de Sa˜o Paulo, SP, Brazil
b Departamento de Biofı´sica, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
c
ˆ
ˆ
Faculdade de Ciencias Farmaceuticas, Universidade de Sa˜o Paulo, Sa˜o Paulo—SP, Brazil
d Departamento de Quı´mica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
Received 18 December 2007; revised 29 January 2008; accepted 14 February 2008
Available online 19 February 2008
Abstract
The copper-catalyzed dimerization of alkynyltrifluoroborates proceeds readily with good yields. The homo-coupling reaction can be
effected in DMSO, in the open air, using Cu(OAc)2 as catalyst in the absence of any other additives. A variety of functional groups are
tolerated.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
dimerization of terminal alkynyl halides with terminal
alkynes under palladium-catalyzed conditions is another
route to diynes.11 The most common catalytic system is a
combination of Pd catalyst with an amine.12 However,
both are expensive and amines often have characteristic
foul smell and pungent flavors.
From the view of economic and environmental points,
development of cheaper metals as catalysts in place of Pd
is an attractive route, in spite of the difficult recovery as
well as recycling of the Pd catalyst.13 Although copper
has been applied as catalyst in many cross-coupling trans-
formations, little attention has been paid to the use of
copper as catalyst for homo-coupling reaction without
any other additives.14
Diverse organoboron components have been utilized
effectively for homo-coupling reactions. For example, lith-
ium alkylnyltriisopropoxyborates are generally efficient
partners, in this case, the procedure requires the use of a
catalytic amount of a homogenous palladium catalyst, cop-
per salt, and phosphine ligand.15 Boronic esters derived
from pinacol are also widely used in homo-coupling reac-
tions. There are several potential problems with these
Diyne compounds are of great importance as versatile
building blocks1 in organic synthesis. In this context, 1,3-
diynes have been prominently used as equivalents of
various functional groups in organic synthesis2 as well as
valuable intermediates for natural products3 and pharma-
ceuticals, particularly antifungal agents.4 Specially note-
worthy is that 1,3-diynes have been recently recognized as
a core functional group in organic molecular materials
such as molecular wires and molecular architecture on
the nanometer scale.5
This type of compound can be synthesized by the tradi-
tional Glaser oxidative dimerization of terminal acetylenes6
and can also be formed by Pd(0)–Cu(I) catalyzed self-cou-
pling of terminal alkynes in the presence of chloroacetone,7
ethyl bromoacetate,8 allyl bromide,9 and iodine.10 The
*
Corresponding authors. Tel.: +55 11 3091 3864; fax: +55 11 3815 4418
(H.A.S.).
E-mail addresses: marelloweber@gmail.com (M. W. Paixao), hstefani@
usp.br (H. A. Stefani).
˜
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.083

M. W. Paixa˜o et al. / Tetrahedron Letters 49 (2008) 2366–2370
2367
Table 1
derivatives. Boronic esters or diethanolamine adducts are
often utilized as a means to purify these organoboron spe-
cies, but some of these esters are hydrolytically stable and/
or difficult to handle. Furthermore, the diols utilized to
create these derivatives (e.g., catechol, pinacol, or the dieth-
anolamine) add considerable expense to the overall process
and, additionally, must be separated from the desired prod-
uct. A lack of atom economy also exists for the boronic
esters in coupling processes, wherein again the diols com-
prising these reagents must be separated from the final
product and disposed. Finally, superstoichiometric
amounts of copper must often be used for efficient coupling
of alkylnylboronates.16
By contrast, potassium organotrifluoroborates have
been shown to overcome this particular limitation. These
salts are unique organoboron compounds, notable for their
stability to moisture and air.17 They are powders or crystal-
line solid that are easy to access and handle, and these
properties have made them attractive synthetic inter-
mediates.18
Copper-catalyzed homo-coupling of potassium phenylethynyltrifluoro-
borates using various solvents
CuXn, Solvent
BF3K
60 ºC, 6 h
Entry
CuXn (mol %)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
CuCl (10)
CuI (10)
CuCN (10)
CuOTf (10)
CuCl2 (10)
Cu(OAc)2 (5)
Cu(OAc)2 (2.5)
DMSO
THF
CH2Cl2
DMF
97
4
2
47
25
89
25
4
DME
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
8
10
11
12
a
34
65
10
Yields related to pure isolated products characterized by spectroscopic
data.
Herein, we describe our initial efforts to develop a con-
venient and practical access to symmetrical 1,3-diynes via
homo-coupling of potassium alkynyltrifluoroborates medi-
ated by a catalytic amount of copper salts in the absence of
any other additive (Scheme 1).
ings were also analyzed. It was observed that using 5 and
2.5 mol % of the catalyst, the desired 1,4-diphenylbuta-
1,3-diyne was obtained with 65% and 10% of yield, respec-
tively (entries 11 and 12).
First, we chose potassium phenylethynyltrifluoro-
borates, a very active substrate, to establish the viability
of the method. We examined the role of solvents, copper
sources, and loading of catalyst to elucidate the general
reaction conditions with the goal of high yields for a wide
survey of substrates. We hoped to achieve good reactivity
with this active substrate and then apply these conditions
to more difficult substrates.
A series of solvents were first examined for the homo-
coupling of phenylethynyltrifluoroborates in the presence
of Cu(OAc)2 (10 mol %) at 60 °C for 6 h under air atmo-
sphere (Table 1).
The mild reaction conditions, its speed and the excellent
yields obtained encouraged us to examine the scope and
generality of the present method. Various potassium
alkynyltrifluoroborates19 were then examined for the
homo-coupling reaction with the Cu(OAc)2/DMSO
system20 and the results are summarized in Table 2.
At first, aromatic alkynyltrifluoroborate bearing an elec-
tron-rich group reacted smoothly under these conditions to
afford the desired product in 84% yield (Table 2, entry 2).
Interestingly, naphthyl alkynyltrifluoroborate can also
undergo the self-coupling reaction with good yield (82%,
entry 3).
The desired 1,3-diyne was generated in low yields in
CH2Cl2, and THF (Table 1, entries 2 and 3), while moder-
ate to excellent yields were achieved in polar aprotic sol-
vents such as DMF, DME, and DMSO (entries 1 vs 4
and 5). It is noteworthy that the copper-catalyzed homo-
coupling reaction of potassium phenylethynyltrifluoro-
borates proceeded with a high efficiency in DMSO, which
was the best solvent for the reaction under palladium-
and base-free conditions (entry 1).
The next step was the determination of the best copper
catalyst, the copper(I) and (II) species were used in the cou-
pling reactions and the best result was achieved with
Cu(OAc)2 (compare entries 1 vs 6–10). The catalyst load-
We then examined the application of the present
Cu(OAc)2/DMSO system to the coupling reaction of vari-
ous aliphatic alkynyltrifluoroborates (entries 4–9). When
the alkynyltrifluoroborate derived from 1-hexyne was
employed as the substrate, the corresponding 1,3-diyne
was obtained in an excellent yield (86%). The substrate
derived from 1-octyne, underwent smooth homo-coupling
to give the product in 88% yield (entry 5). The reactivity
of the tert-butyl substituted alkynyltrifluoroborates was
also investigated; and the homo-coupling product was
obtained in 66% of yield (entry 6). Not surprisingly, four
more alkynyl substrates were also effectively homocoupled
under this catalytic system to furnish the desired products
in 87%, 88%, and 42%, respectively (entries 6–8).
Finally, we next employed a series of alkynyltrifluoro-
borates bearing an oxy-functionality (entries 10–12). The
reaction of methyl ether of propargyl alkynyltrifluoro-
borates provide the corresponding 1,3-diyne in 58% iso-
lated yield (entry 10). Sterically hindered methyl ether
alkynyltrifluoroborates were also effectively applicable to
Cat- Cu
R
BF3K
R
R
Palladium and
Base Free
R= Alkyl, Aryl
Scheme 1. Preparation of symmetrical 1,3-diynes.

2368
M. W. Paixa˜o et al. / Tetrahedron Letters 49 (2008) 2366–2370
Table 2
Preparation of symmetrical 1,3-diynes from potassium alkynyltrifluoroborates using Cu(OAc)2/DMSO system
Cu(OAc)2 (10 mol %)
R
BF3K
R
R
DMSO, 60 ºC, 6 h
Entry
1
Substrate
Product
Yielda (%)
97
BF3K
2
3
84
82
BF3K
OMe
BF3K
MeO
MeO
4
5
6
n-C4H9
n-C4H9
n-C4H9
86
88
66
BF3K
BF3K
n-C6H13
n-C6H13
n-C6H13
BF3K
7
8
87
88
BF3K
BF3K
BF3K
9
42
58
O
O
10
BF3K
O
BF3K
11
60
28
O
O
O
BF3K
12
O
O
O
a
Yields related to pure isolated products characterized by spectroscopic data.
the homo-coupling to give the corresponding 1,3-diynes
(entries 11 and 12).
suitable for the homo-coupling of potassium alkynyltri-
fluoroborate salts. The reaction proved to be tolerant
to a variety of functional groups. It can be carried
out in DMSO in the air, with 10% of catalyst loading
in relatively short reaction times. The high yields, in
addition to the environmental characteristics of the
boron byproducts, allow simple workup techniques to
be applied to obtain products with greater than 97%
purity. These features, combined with the shelf stability
of the alkynyltrifluoroborate salts, make this technique
environmentally sound, economical, and very attractive
for use in industrial processes and combinatorial
chemistry.
As outlined in Scheme 2, we have formulated a pro-
posed mechanism for the copper-catalyzed homo-coupling
of alkynyltrifluoroborates. First, the alkynyltrifluorobo-
rates reacted with copper(II) acetate 1 to form alkynylcop-
per(II) 2 in the presence of DMSO as a solvent. Reductive
elimination of the dialkynylcopper(II) intermediate 3 could
undergo to form the desired diyne and Cu(0). Finally,
Cu(0) was oxidated by O2 and DMSO to generate the
active Cu(II) species 1 leading to a new catalytic cycle.21
In summary, copper-catalyzed conditions in the
absence of palladium and base have been found to be

M. W. Paixa˜o et al. / Tetrahedron Letters 49 (2008) 2366–2370
2369
Zh. 1966, 19, 938; Chem. Abstr. 1966, 67, 43373z; (c) Valenti, E.;
Pericas, M. A.; Serratosa, F. J. Am. Chem. Soc. 1990, 112, 7405; (d)
Maruyama, K.; Tsukube, H.; Araki, T. J. Polym. Sci., Polym. Chem.
Ed. 1980, 18, 749; (e) Liao, Y.; Fathi, R.; Yang, Z. Org. Lett. 2003, 5,
909.
Cu(OAc)2
L = DMSO
R
R
II
R
BF3K
L2Cu(OAc)2
7. Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523.
8. Lei, A.; Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 196.
9. Vlasa, M.; Ciocan-Tarta, I.; Margineanu, F.; Oprean, I. Tetrahedron
1996, 52, 1337.
Oxidation
1
R
BF K
3
OAc
+
10. Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371.
11. (a) Kurita, T.; Abe, M.; Maegawa, T.; Monguchi, Y.; Sajiki, H.
Synlett 2007, 2521; (b) Shi, M.; Quian, H.-X. Appl. Organometal.
Chem. 2006, 20, 771; (c) Yan, J.; Wu, J.; Jin, H. J. Organometal.
Chem. 2007, 692, 3636.
II
II
Cu L2
R
CuL2(OAc)
2
3
R
12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467.
13. For papers on the other coupling reactions catalyzed by a catalytic
amount of copper see: (a) Okuro, K.; Furuune, M.; Enna, M.; Miura,
M.; Nomura, M. J. Org. Chem. 1993, 58, 4716; (b) Gujadhur, R. K.;
Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315; (c)
Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem. 2004, 6,
215; (d) Ma, D.; Liu, F. Chem. Commun. 2004, 1934; (e) Wang, Y. F.;
Deng, W.; Liu, L.; Guo, Q. X. Chin. Chem. Lett. 2005, 16, 1197;
Chem. Abstr. 2005, 144, 22662; (f) Saejueng, P.; Bates, C. G.;
Venkataraman, D. Synthesis 2005, 1706; (g) Xie, Y.-X.; Deng, C.-L.;
Pi, S.-F.; Li, J.-H.; Yin, D.-L. Chin. J. Chem. 2006, 24, 1290; (h)
Kang, S.-K.; Kim, J.-S.; Choi, S.-C. J. Org. Chem. 1997, 62, 4208; (i)
Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 1109; (j) Mohapatra, S.;
Bandyopadhyay, A.; Barma, D. K.; Capdevila, J. H.; Falck, J. R.
Org. Lett. 2003, 5, 4759; (k) Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.;
Ho, P.-S. J. Org. Chem. 1996, 61, 9082; (l) Li, J.-H.; Tang, B.- X.;
Tao, L.-M.; Liang, Y.; Zhang, M.-B. J. Org. Chem. 2006, 71, 7488.
14. (a) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang,
M.-B.; Hu, X.-C. J. Org. Chem. 2007, 72, 2053; (b) Li, J.-H.; Li, J.-L.;
Xie, Y.-X. Synthesis 2007, 7, 984; (c) Zhu, B. C.; Jiang, X. Z. Appl.
Organometal. Chem. 2007, 21, 345.
15. Oh, C. H.; Reddy, V. R. Tetrahedron Lett. 2004, 45, 5221.
16. Nishihara, Y.; Okamoto, M.; Inoue, Y.; Miyazaki, M.; Miyasaka,
M.; Takagi, M. Tetrahedron Lett. 2005, 46, 8661.
17. For the synthesis of organotrifluoroborates, see: (a) Vedejs, E.;
Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org.
Chem. 1995, 60, 3020; (b) Vedejs, E.; Fields, S. C.; Hayashi, R.;
Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc.
1999, 121, 2460; (c) Molander, G. A.; Katona, B. W.; Machrouhi, F.
J. Org. Chem. 2002, 67, 8416.
R
BF3K
BF K
3
OAc
+
Scheme 2. Possible mechanism for the copper-catalyzed homo-coupling
reaction.
Acknowledgments
The authors gratefully acknowledge CNPq, CAPES
(fellowship to M.W.), and FAPESP (Grant 07/59404-2
and fellowship to M.W.P.) for a financial support.
References and notes
1. (a) Hunstman, V. D. In The Chemistry of the Carbon–Carbon Triple
Bond; Patai, S., Ed.; Wiley-Interscience: London, 1978; p 553; (b)
Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632.
2. For general reviews on coupling reactions between an sp carbon
center, see: (a) Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 3, pp 551–
561; (b) Hay, A. S. J. Org. Chem. 1962, 27, 3320; (c) Rossi, R.;
Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523; (d) Jones, G.
E.; Kendrick, D. A.; Holmes, A. B. Org. Synth. 1987, 65, 52; (e)
Valenti, E.; Pericas, M. A.; Serratosa, F. J. Am. Chem. Soc. 1990, 112,
7405; (f) Liu, G.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371; (g)
Kitamura, T.; Lee, C. H.; Taniguchi, Y.; Fujiwara, Y. J. Am. Chem.
Soc. 1997, 119, 619; (h) Siemsen, P.; Livingston, R. C.; Diederich, F.
Angew. Chem., Int. Ed. 2000, 39, 2632.
3. (a) Holmes, A. B.; Jennings-White, C. L. D.; Kendrick, D. A. J.
Chem. Soc., Chem. Commun. 1983, 415; (b) Nicolaou, K. C.; Zipkin,
R. E.; Dolle, R. E.; Harris, B. D. J. Am. Chem. Soc. 1984, 106, 3548;
(c) Crombie, L.; Hobbs, A. J. W.; Horsham, M. A. Tetrahedron Lett.
1987, 28, 4875; (d) Holmes, A. B.; Tabor, A. B.; Baker, R. J. Chem.
Soc., Perkin Trans. 1 1991, 3307; (e) Hoye, T. R.; Chanson, P. R.
Tetrahedron Lett. 1993, 34, 5043; (f) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2006, 45, 1034.
18. For reviews of organotrifluoroborate salts, see: (a) Molander, G. A.;
Figueroa, R. Aldrichim. Acta 2005, 38, 49; (b) Darses, S.; Genet, J.-P.
Eur. J. Org. Chem. 2003, 4313; (c) Molander, G. A.; Ellis, N. Acc.
Chem. Res. 2007, 40, 275; (d) Stefani, H. A.; Cella, R.; Vieira, A. S.
Tetrahedron 2007, 63, 3623.
ˆ
19. General procedure for the preparation of potassium alkynyltrifluoro-
borate salts. A solution of alkyne (10 mmol, 1 equiv) in 20 mL of dry
THF was cooled to À78 °C under argon. n-BuLi (6.25 mL, 1.6 M in
hexane, 10 mmol, 1 equiv) was added dropwise, and the solution was
stirred for 1 h at this temperature. Trimethylborate (1.56 g, 15 mmol,
1.5 equiv) was then added dropwise at À78 °C. The solution was
stirred at this temperature for 1.5 h after which it was allowed to
warm to À20 °C for 1.5 h. A saturated aqueous solution of KHF2
(4.7 g, 60 mmol, 6.0 equiv) was added to the vigorously stirred
solution. The resulting mixture was allowed to stir for 1 h at À20 °C
after which it was allowed to warm to room temperature for 1 h. The
solvent was removed under reduced pressure, and the resulting white
solid was dried under high vacuum for 2 h to remove all water. The
solid was then washed with acetone and with hot acetone. The
resulting organic solution was filtered, and the solvent was removed to
afford a white solid. This solid was then dissolved in hot acetone and
precipitated with diethyl ether, after which the solution was cooled to
À20 °C to complete precipitation of the solid.
4. (a) Stuuts, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 320; (b) Shun, A.
¨
L. K. S.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006, 45, 1034.
5. (a) Fouquey, C.; Lehn, J.-M.; Malthete, J. J. Chem. Soc., Chem.
Commun. 1987, 1424; (b) Diederich, F.; Rubin, Y.; Knobler, C.
B.; Whetten, R. L.; Schriver, K. E.; Houk, K. N.; Li, Y.
Science 1989, 245, 1088; (c) Kanis, D. R.; Ratner, M. A.;
Marks, T. J. Chem. Rev. 1994, 94, 195; (d) Xu, Z.; Kaha, M.;
Walker, K. L.; Wilkins, C. L.; Moore, J. S. J. Am. Chem. Soc.
1994, 116, 4537.
6. (a) Has, A. S. J. Org. Chem. 1962, 27, 3320; (b) Mkryan, M. G.;
Papazyan, N. A.; Voskayan, E. S.; Khachaturyan, I. V. Arm. Khim.

2370
M. W. Paixa˜o et al. / Tetrahedron Letters 49 (2008) 2366–2370
20. General procedure for the alkynyltrifluoroborates dimerization. To a
mixture of alkynyltrifluoroborates (0.5 mmol) and Cu(OAc)2
(10 mol %), DMSO (3 mL) was added. The mixture was stirred at
60 °C for 6 h. After this time, the mixture was filtered and the solvents
evaporated. The crude product was purified by silica gel column
chromatography, eluting with hexane to give the corresponding pure
1,3-diyne.
21. (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
2337; (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400.