Tandem Sonogashira coupling: An efficient tool for the synthesis of diarylalkynes

Article abstract of DOI:10.1021/ol047983f

(Chemical Equation Presented) The tandem Sonogashira coupling reaction of aryl halides provides an efficient method for the synthesis of diarylalkynes. Several aryl halides were coupled with 2-methyl-3-butyn-2-ol as acetylene source in the presence of PdCl₂(PPh₃)₂ and CuI. Following the deprotection of the acetylene moiety in the same pot using a strong base, the Sonogashira coupling of a second aryl halide led to the formation of the appropriate diarylakyne. The established protocoll was successfully extended to the preparation of compound libraries.

Full text of DOI:10.1021/ol047983f

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4917-4920
Tandem Sonogashira Coupling: An
Efficient Tool for the Synthesis of
Diarylalkynes
Zolta´n Nova´k, Pe´ter Nemes, and Andra´s Kotschy*
Department of General and Inorganic Chemistry, Eo¨tVo¨s Lora´nd UniVersity,
Pa´zma´ny Pe´ter s. 1/A, H-1117 Budapest, Hungary
kotschy@chem.elte.hu
Received October 1, 2004
ABSTRACT
The tandem Sonogashira coupling reaction of aryl halides provides an efficient method for the synthesis of diarylalkynes. Several aryl halides
were coupled with 2-methyl-3-butyn-2-ol as acetylene source in the presence of PdCl2(PPh3)2 and CuI. Following the deprotection of the
acetylene moiety in the same pot using a strong base, the Sonogashira coupling of a second aryl halide led to the formation of the appropriate
diarylakyne. The established protocoll was successfully extended to the preparation of compound libraries.
The palladium-catalyzed (Sonogashira) coupling of terminal
acetylenes with aryl and vinyl halides is an important and
widely used carbon-carbon bond-forming reaction in organic
synthesis.1 In addition to serving as synthetic intermediates
en route to complex systems including natural products,2 the
formed products often have interesting physical properties
that are utilized in materials science. The Sonogashira
coupling also offers a very powerful tool for the preparation
of oligomers and polymers.3 These conjugated systems have
received much attention recently as a result of their optical4
and electronic applications.5
A challenging objective in this chemistry is the construc-
tion of terminal arylacetylenes. If the use of acetylene is
considered tedious, coupling is usually carried out using a
protected acetylene that is simpler to handle, followed by
the release of the protecting group. Probably the most
frequently used monoprotected acetylene derivative in lab-
scale experiments is trimethylsilyl-acetylene.6 Removal of
the protecting group usually requires the presence of fluoride
ion or a base at ambient temperature, enabling the preparation
of terminal acetylene derivatives under mild conditions.
Another route is offered for the preparation of the same
compound classes by 2-methyl-3-butyn-2-ol as acetylene
source.7 Its low cost, however, is offset by the relative
harshness of the conditions required for the release of the
protecting group. The applied hard bases and high temper-
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (b) Sonogashira, K. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I. Eds; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 2.4, p
521 and references therein. (c) Bumagin, N. A.; Sukhomlinova, L. I.;
Luzikova, E. V.; Tolstaya, T. P.; Beletskaya, I. P. Tetrahedron Lett. 1996,
37, 897. (d) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729. (e) Erdelyi, M., Gogoll, A., J. Org. Chem. 2001,
66, 4165.
(2) (a) Nova´k, Z.; Timari, G.; Kotschy, A. Tetrahedron 2003, 59, 7509.
(b) Nova´k, Z.; Szabo´, A.; Re´pa´si, J.; Kotschy, A. J. Org. Chem. 2003, 68,
3327. (c) Hayashi, T.; Kawakami, T.; Kumazawa, H.; Kotschy, A. PCT
Int. Appl. 2003; Chem. Abstr. 2003, 140, 42196. (d) Nova´k, Z.; Kotschy,
A. Org. Lett. 2003, 5, 3495. (e) Beutler, U.; Mazacek, J.; Penn, G.; Schenkel,
B.; Wasmuth, D. Chimia 1996, 50, 154.
(4) (a) Cheng, L. T.; Tam, W.; Marder, S. R.; Stiegman, A. E.; Rikken,
G.; Spangler, C. W. J. Phys. Chem. 1991, 95, 10643. (b) Moroni, M.; Le
Moigne, J.; Luzzati, S. Macromolecules 1994, 27, 562.
(5) (a) Bumm, L. A.; Arnold, J. J.; Cygan, M. T.; Dunbar, T. D.; Burgin,
T. P.; Jones, L., II; Allara, D. L.; Tour, J. M.; Weiss, P. S. Science 1996,
271, 1705. (b) Tour, J. M.; Jones, L.; Pearson, D. L.; Lamba, J. J. S.; Burgin,
T. P.; Whitesides, G. M.; Allara, D. L.; Parikh, A. N.; Atre, S. J. Am. Chem.
Soc. 1995, 117, 9529. (c) Schumm, J. S.; Pearson, D. L.; Tsur, J. M. Angew.
Chem., Int. Ed. 1994, 33, 1360.
(3) (a) Ziener, U.; Godt, A. J. Org. Chem. 1997, 62, 6137. (b) Francke,
V.; Mangel, T.; Muellen, K. Macromolecules 1998, 31, 2447. (c) Yu, C.
J.; Chong, Y.; Kayyem, J.-F.; Gozin, M. J. Org. Chem. 1999, 64, 2070. (d)
Huang, S.; Tour, J. M. Tetrahedron Lett. 1999, 40, 3347.
(6) (a) Lindstro¨m, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291.
(b) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Synlett
2002, 453.
10.1021/ol047983f CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/02/2004

ature in the presence of less tolerant functional groups lead
frequently to undesired side reactions.
Table 1. Testing of the Tandem Sonogashira Coupling of
Iodobenzene (1a) and 2-Methyl-3-butyn-2-ol (2) under Various
Conditions
In principle the release of the terminal acetylene might
be combined with another Sonogashira coupling and lead
formally to a tandem Sonogashira coupling on acetylene. An
elegant procedure developed by Chow follows this strategy,
realizing the simultaneous removal of acetone and the
Sonogashira coupling of the released terminal acetylene with
a second aryl halide under phase transfer conditions.8 Brisbois
and co-workers9 described an efficient method for the
preparation of symmetrical and nonsymmetrical diarylalkynes
from aryl halides and trimethylsilyl-acetylene, where both
the Sonogashira couplings and the removal of the silyl
protection by DBU are carried out in the same pot. The aim
of our research was to establish an efficient one-pot tandem
Sonogashira coupling protocol, where the more economic
2-methyl-3-butyn-2-ol could be used instead of trimethyl-
silylacetylene.10
entry
solvent
base
yield of 4aa(%)
1
2
3
4
5
6
7
8
9
n-butanol
n-butanol
isopropanol
DMSO
DMSO
DMSO
aq DMAc
aq DMAc
DIPA
KOH
K2CO3
KOH
78
0b
49
85
0
0
0d
0
100
100
KOH
K2CO3
DIPA
NaOH
K2CO3
KOH
10
toluene
NaHe
The first set of experiments was directed toward the
establishment of the optimal conditions for the removal of
the protecting acetone group and the subsequent Sonogashira
coupling. Iodobenzene (1a) was coupled as model compound
with 2-methyl-3-butyn-2-ol (2) in the presence of 5 mol %
bis(triphenylphosphino)palladium dichloride, 5 mol % cop-
per(I) iodide, and an added base in various solvents. In most
cases the first coupling leading to 3 was complete and the
deprotection-coupling sequence led to the appearance of
diphenylacetylene (4a) in the reaction mixture.
a The reactions were run for 24 h in a 110 °C oil bath or at the boiling
point of the solvent if below 110 °C. Yields were determined by the GC
analysis of the reaction mixture. b 4,4-Diphenyl-2-methyl-3-buten-2-ol was
formed in 74% yield.12 c A 20:1 mixture of DMA and distilled water.
d Already the first coupling fails. e 1.2 equiv of DIPA was added to facilitate
the first coupling.
hours. The use of toluene (entry 10) as a less polar, high
boiling solvent also led to tandem coupling. In this case only
sodium hydride was effective as base, and the reaction was
over in less than 1 h. The efficiency of the diisopropylamine/
KOH and the toluene/NaH systems prompted us to select
both for further testing.
The next experiments were directed at establishing the
scope and limitations of the tandem Sonogashira protocol.
In these reactions first an aryl halide (1a-e) was coupled
with 2-methyl-3-butyn-2-ol (2), and the intermediates then
were deprotected and coupled in situ to give the diaryl-
acetylenes 4a-n (Table 2.). We carried out the reactions
using two different sets of conditions. In DIPA (Method A)
the reactions were run at 70 °C in the presence of 5 mol %
of both PdCl2(PPh3)2 and CuI as catalyst,13 and after the
completion of the first step and addition of 8 equiv of KOH
another 5 mol % of catalyst had to be added to the system
to achieve high conversion in the second coupling.14
Although the deprotection is usually run in a heterogeneous
system in apolar solvents, such as toluene or benzene, it was
reported11 that the use of polar solvents, which usually have
a beneficial effect on the following Sonogashira coupling,
is also acceptable. n-Butanol as a high boiling solvent was
tested first, and using potassium hydroxide the reaction went
to near completion (Table 1, entry 1). Interestingly, change
of the base to potassium carbonate initiated a different
transformation and only the selective addition of benzene
onto 3 was observed (entry 2). By changing the solvent to
the lower boiling 2-propanol (entry 3) the second coupling
was less efficient in the presence of potassium hydroxide.
DMSO and KOH (entry 4) gave results similar to those with
entry 1, whereas the change of base to potassium carbonate
or diisopropylamine (entries 5 and 6) inhibited the second
coupling. The use of aqueous DMA (entries 7 and 8) not
only stopped the deprotection and the second coupling, but
using NaOH the first coupling did not take place either.
Change of the solvent to diisopropylamine (entry 9) increased
the efficiency of the tandem coupling dramatically, and using
KOH the reaction reached full conversion in a couple of
(12) A similar reaction was reported recently: Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Pace, P. Eur. J. Org. Chem. 2000, 4099.
(13) A number of tests were conducted to establish the optimal catalyst
system, but the use of more active palladium complexes did not have a
major influence on the outcome of the process, while the omitting of copper
stopped the process. The lowering of the catalyst loading did also lead to
decreased yields as a result of incomplete conversion.
(14) Method A. General Procedure. Aryl halide (10 mmol), 351 mg
of PdCl2(PPh3)2 (0.5 mmol, 5%), and 95 mg of CuI (0.5 mmol, 5%) were
placed into a flame-dried Schlenk flask. Next, 20 mL of diisopropylamine
was added to the flask, followed by 1260 µL of 2-methyl-3-butyn-2-ol (13
mmol, 1091 mg). The reaction mixture was stirred under argon for 1 h at
50 °C. Then 4.48 g of KOH (80 mmol), 351 mg of PdCl2(PPh3)2 (0.5 mmol,
5%), 95 mg of CuI (0.5 mmol, 5%), and 10 mmol of aryl halide were added,
and the rection mixture was heated for 5 h in a 110 °C oil bath. After
cooling to room temperature, the KOH was neutralized with 1 M HCl, and
then the mixture was extracted with DCM. The combined organic phases
were dried over MgSO4 and then evaporated. The crude product was purified
by column chromatography.
(7) (a) Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115. Ley, K. D.;
Li, Y.; Johnson, J. V.; Powell, D. H.; Shanze, K. S. Chem. Commun. 1999,
1749. (b) Melissaris, A.; Litt, M. H. J. Org. Chem. 1994, 59, 5818. (c) Ma,
L.; Hu, Q.; Pu, L. Tetrahedron: Asymmetry 1996, 7, 3103.
(8) Chow, H.; Wan, C.; Low, K.; Yeung, Y. J. Org. Chem. 2001, 66,
1910.
(9) Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gidzikwa, T. L.; Hull, K. L.;
Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199.
(10) There is an early report of such a transformation: Carpita, A.; Lessi,
A.; Rossi, R. Synthesis 1984, 571.
(11) MacBride, J. A. H.; Wade, K. Synth. Commun. 1996, 26, 2309.
4918
Org. Lett., Vol. 6, No. 26, 2004

benzene (1a) the coupling with 4-iodoanisole (1b) gave 4b
in 29% (entry 2) yield, whereas running the process in reverse
order (entry 6) gave 64% yield. In the same reactions Method
B turned out to be less sensitive and gave 57% and 68%
yields, respectively. The increased sensitivity of Method A
is even more pronounced in entry 7, where its poor yield of
4f (17%) is facing a 66% yield by Method B.
Table 2. Synthesis of Diarylacetylenes in the Tandem
Sonogashira Coupling of Various Aryl Halides (1a-e) and
2-Methyl-3-butyn-2-ol (2)
In the coupling of less electron-rich substrates (1d,e) on
the other hand, Method A has a clear advantage over Method
B, and in the preparation of the symmetrical systems 4l,n
(entries 18 and 20), it gave superior yields.
entry
ArX
Ar′X product yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
iodobenzene (1a)
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1b
1c
1d
1a
1b
1c
1d
1d
1e
4a
4b
4c
4d
4e
4b
4f
4g
4h
4i
4c
4g
4j
4k
4d
4h
4k
4l
84,a,c 56b
29,a 57b
69b
1a
1a
1a
1a
Using Method B on electron-deficient substrates, we face
a situation similar to that of Method A for electron-rich
compounds. The coupling of 1a or 1b with 1d (entries 4
and 9), for example, gave only mediocre yields (47% and
41%), whereas reversing the order and carrying out the first
coupling on the less electron-rich aryl halide 1d (entries 15
and 16) resulted in a significant improvement, yielding 71%
and 75%. In general, the two protocols seem to complement
one another, as one is usually effective where the other fails
to achieve good yields.
The scope of the presented tandem Sonogashira reaction
does not have to be limited to the preparation of diaryl-
ethynes. Because the products of the Sonogashira coupling
frequently have interesting physical (e.g., fluorescence)
properties, we decided to test the effectivity of the protocol
in the preparation of compound libraries. Such compositions,
which would arise from the addition of a mixture of aryl
halides in the second coupling step, might be separated using
simple thin-layer chromatography, and some of their more
important photophysical characteristics might be determined
“from the plate”.
38,a 47b
56a
4-iodoanisole (1b)
64,a 68b
17,a 66b
79b
1b
1b
1b
1b
68,a 41b
65a
3-iodotoluene (1c)
84b
1c
1c
1c
66b
78b
40b
2-bromochlorobenzene (1d)
71b
1d
1d
1d
75b
59b
67,a 32b
62a
3-bromo-pyridine(1e)
4m
4n
1e
84a
a Method A, isolated yield of 4. b Method B, isolated yield of 4. c The
reaction worked equally well on the mole scale.
Running the reactions in toluene (Method B) we used only
2.8 mol % of both PdCl2(PPh3)2 and CuI as catalyst and 1.2
equiv DIPA as base to facilitate the first coupling, which
was complete in 1 h (except for 1d, which required 48 h) at
80 °C. Heating for 5 h at 110 °C after the addition of 2
equiv of NaH and the other aryl halide led in most cases to
complete conversion (N.B. no extra catalyst was needed).15
The products were isolated using column chromatography.
On the basis of the data presented in Table 2, we can
establish that both tandem coupling protocols are quite
efficient, and practically all products could be prepared in
good yield. There are some significant differences in the
behavior of the two methods, however, that should be
mentioned.
In our first test 3-bromopyridine (1e) was coupled with 2
following literature procedures,2b and the pyridylbutynol (3e)
was isloated. The deprotection of 3e and the sequential
Sonogashira coupling were carried out using the KOH/DIPA
system, and a 1:1:1 mixture (0.33 equiv each) of iodobenzene
(1a), 4-iodoanisole (1b), and 3-iodotoluene (1c) was used
as coupling partner (Figure 1.). The progress of the reaction
was monitored by GC, GC-MS, and TLC (Figure 2).
Using Method A the process is sensitive to the order in
which electron-rich reagents are added. Starting from iodo-
Figure 1. Arylethynyl-pyridine library synthesis using the tandem
Sonogashira protocol.
(15) Method B. General Procedure. Aryl halide (5 mmol), 100 mg of
PdCl2(PPh3)2 (0.14 mmol, 2.8%), and 28 mg of CuI (0.14 mmol, 2.8%)
were placed into a flame-dried Schlenk flask. Next, 12 mL of toluene and
1200 µL of diisopropylamine were added to the flask, followed by 630 µL
of 2-methyl-3-butyn-2-ol (6.5 mmol, 546 mg). The reaction mixture was
stirred at 80 °C under argon until the first coupling was complete. Then
the temperature of the oil bath was increased to 110 °C, and 400 mg of
NaH (55% dispersion, 9.16 mmol) was addedd slowly to the mixture. After
5 min of stirring, 5 mmol of the appropriate aryl halide was added to the
reaction mixture, and the stirring was continued. After 25 min another 100-
mg portion of NaH (1.83 mmol) was added carefully, and the solution was
stirred further at 110 °C until the reaction was complete (ca. 1 h). After
cooling to room temperature, the suspension was filtered, and the separated
amine-hydrochloride was washed with toluene. Evaporation of the combined
toluene solutions gave a crude product, which was purified by column
chromatography.
The deprotection-coupling sequence worked well for all
three aryl iodides, iodoanisole (1b) reacting somewhat more
slowly than the others, and the library synthesis was complete
in 2 h.
In the next experiment we carried out the whole library
synthesis in one pot. Following the conversion of 1e to 3e
under the conditions outlined for Method A, the mixture of
the aryl iodides (1a-c), KOH, and 5 mol % catalyst were
Org. Lett., Vol. 6, No. 26, 2004
4919

In summary, an efficient method is reported for the one-
pot synthesis of different diarylalkynes starting from easily
available aryl halides and 2-methyl-3-butyn-2-ol. By variation
of the conditions a complementary set of conditions was
established, which allows for the efficient coupling of both
electron-rich and electron-deficient substrates. The protocol
was also successfully extended to the preparation of diaryl-
ethyne libraries.
Acknowledgment. The authors thank Dr. K. Torkos for
providing the necessary analytical background. The financial
support of the Hungarian Scientific Research Fund (OTKA
F047125/2004 and D048657) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 2. Product formation in the two-step (a) and tandem (b)
3-arylethynyl-pyridine library synthesis (GC).
added to the reaction, and the second coupling was complete
in less than 0.5 h.16 The fact that in the one-pot reaction we
observe faster product formation and also the absence of an
induction period might be attributed to the fact that some of
the catalyst used in the first coupling is still in its active
form. Unfortunately, neglect of the addition of the second
catalyst portion leads to incomplete conversion in the second
coupling. These results prove that the tandem Sonogashira-
coupling protocol is effective in the synthesis of product
mixtures, and its application for the preparation and screening
of new fluorescent materials is in progress in our laboratories.
OL047983F
(16) One-Pot Library Synthesis. PdCl2(PPh3)2 (180 mg, 0.25 mmol,
5%) and 47 mg of CuI (0.25 mmol, 5%) were placed into a flame-dried
Schlenk flask, followed by 12 mL of diisopropylamine. Then 790 mg (5
mmol) of 3-bromopyridine and 532 µL of 2-methyl-3-butyn-2-ol (5.5 mmol,
462 mg) were added to the solution. The reaction mixture was stirred at 70
°C under argon until the first coupling was complete (1 h). Then 180 mg
of PdCl2(PPh3)2 (0.25 mmol, 5%), 47 mg of CuI (0.25 mmol, 5%), 186 µL
of iodobenzene (1.66 mmol, 339 mg), 213 µL of 3-iodotoluene (1.66 mmol,
362 mg), and 388 mg of 4-iodoanosole (1.66 mmol) were added to the
mixture, followed by 2.24 g KOH. The Schlenk flask was purged with argon,
sealed, and heated in an oil bath at 110 °C until completion of the second
coupling.
4920
Org. Lett., Vol. 6, No. 26, 2004