New activators for the coupling reaction of terminal alkynes with organic halides

Article abstract of DOI:10.1246/bcsj.78.327

Cross-coupling reactions of terminal alkynes with organic halides catalyzed by palladium(0) or palladium(0)/Cu(I) take place in the presence of several activators, such as silver(I) oxide, tetrabutylammonium fluoride (TBAF), and tetrabutylammonium hydroxi

Full text of DOI:10.1246/bcsj.78.327

ꢀ 2005 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 78, 327–330 (2005)
327
New Activators for the Coupling Reaction of Terminal Alkynes
with Organic Halides
Mohamed S. Mohamed Ahmed, Akitoshi Sekiguchi, Tomohiro Shimada,
ꢀ
Jun Kawashima, and Atsunori Mori
Chemical Resources Laboratory, Tokyo Institute of Technology, R1-4, 4259 Nagatsuta, Yokohama 226-8503
Received August 19, 2004; E-mail: amori@res.titech.ac.jp
Cross-coupling reactions of terminal alkynes with organic halides catalyzed by palladium(0) or palladium(0)/Cu(I)
take place in the presence of several activators, such as silver(I) oxide, tetrabutylammonium fluoride (TBAF), and tet-
rabutylammonium hydroxide (TBAOH), to give the corresponding coupling products in good-to-excellent yields.
Carbon–carbon bond-forming reactions with terminal al-
kynes and organic electrophiles have attracted considerable at-
tention in organic synthesis, because compounds containing
the alkynyl moiety have appeared in a wide range of biologi-
cally important molecules and their synthetic intermediates.1
Sonogashira–(Hagihara) coupling, which is a palladium/cop-
per-catalyzed coupling reaction of terminal alkynes with or-
ganic halides, has been recognized as a highly practical meth-
od for introducing alkynyl moiety into organic molecules.2
However, the major drawback of the reaction is the use of
amine as a solvent or co-solvent, which sometimes causes dif-
ficulties in the removal of excess amine and the formed ammo-
nium salt. Decreasing the amount of amine, in general, lowers
the reactivity. Efforts to overcome such problems have been
devoted to the ligand design of a palladium catalyst, which
would enable the reaction using a reduced amount of amine.
Indeed, the use of bulky trialkylphosphines or heteroaromatic
carbenes as a ligand for the palladium catalyst achieved the
Sonogashira coupling with stoichiometric, or slightly excess,
amine under mild conditions.3,4
coupling of trimethylsilylalkynes with aryl halides was also
promoted by silver(I) oxide.8 However, the reaction of tri-
methylsilylethyne (1a) with iodobenzene (2a) did not replace
the trimethylsilyl group, but afforded 3aa, which is the C–H
substituted product, in 79% yield, as shown in Scheme 1.
The results show that silver(I) oxide has served as an acti-
vating agent for the coupling of terminal alkynes. Thus, we ex-
amined the reaction of several terminal alkynes with organic
halides. The results are summarized in Table 1. The reaction
of 1a also proceeded smoothly with aryl iodides 2b and 2c
bearing an electron-donating or electron-withdrawing substitu-
ent on the aromatic ring. In addition to 1a, terminal alkynes
with aryl and alkyl substituents coupled with aryl iodides.
The reaction of terminal alkynes with a hydroxy group (1d) al-
Table 1. Palladium-Catalyzed Cross-Coupling Reaction of
Terminal Alkynes with Aryl Halides in the Presence of
Ag2O
[Pd(PPh3)4]
X R2
R1
R2
R1
H
+
Ag2O
On the other hand, we envisaged that another solution to the
problem of the Sonogashira coupling is to design a new class
of activator of the reaction instead of (excess) amine. Herein,
we report that the coupling of terminal alkynes has been
achieved without amines using several additives, such as sil-
ver(I) oxide, tetrabutylammonium fluoride (TBAF), and tetra-
butylammonium hydroxide (TBAOH).5
1
2
3
THF, 60 °C
R1
X–R2
I–C6H5 (2a)
4-I–C6H4–OCH3 (2b)
4-I–C6H4–COCH3 (2c)
2a
Br–C6H5 (4a)
TfO–C6H5 (5a)
2a
Time/h 3, Yield/%
Me3Si (1a)
1a
1a
Ph (1b)
1b
1b
3
8
3
8
6
6
8
6
3aa, 79
3ab, 72
3ac, 99
3ba, 60
3ba,
3ba,
0
0
Results and Discussion
nC6H13 (1c)
HO(CH3)2C (1d) 2a
3ca, 90
3da, 73
While studying the cross coupling of silanols, we found that
silver(I) oxide serves as an activator for the reaction of organo-
silicon reagents.6,7 A palladium-catalyzed reaction of aryl- and
alkenylsilanols with several organic halides took place to form
a carbon–carbon bond smoothly. We learned that the cross-
The reaction was carried out with terminal alkyne (1) (1.1 mo-
lar amount), 2, 4, or 5, 0.05 mol. amt. of [Pd(PPh3)4] and
Ag2O (1.0 mol. amt.) in THF at 60 C.
ꢁ
[Pd(PPh3)4]
+
H
I
Me3Si
Me3Si
+
H
Ag2O
THF, 60 °C, 3 h
1a
2a
3aa: 79 %
1b: 0%
Scheme 1.
Published on the web February 11, 2005; DOI 10.1246/bcsj.78.327

328 Bull. Chem. Soc. Jpn., 78, No. 2 (2005)
New Activators for Alkyne Coupling
so took place without protection. The coupling promoted by
Ag2O proceeded specifically with aryl iodides. The results
are consistent with the related reaction of aryl- and alkenyl-
silanols using Ag2O, probably due to the interaction of silver
and iodine atoms. Indeed, the reaction with bromide 4a and tri-
flate 5a did not afford the coupling product at all. It was also
confirmed by X-ray diffraction analysis (XRD) that silver(I)
oxide is transformed into silver(I) iodide.6c Hence, another
by-product would be water. Worthy of note concerning the
Ag2O-promoted reaction of terminal alkynes is the ease of iso-
lation and purification for the coupling product. Since both
Ag2O and AgI were insoluble in organic solvents, removal
of the silver residue by filtration after the reaction, followed
by chromatography or recrystallization, easily produced ana-
lytically pure arylated alkynes.
reacted smoothly. Although TBAF is a well-known activator
for the coupling of aryl- and alkenylsilanes, as well as tri-
methylsilylated alkynes, the C–H bond of the terminal alkyne
was surprisingly activated by TBAF, and a coupling reaction
with organic halides took place. Other fluoride ions and inor-
ganic bases, such as KF (0%), CsF (0%), AgF (11%), and
K2CO3 (0%), were examined concerning the coupling reac-
tion; however, such additives showed little, or no, effect as
competent activators.
It should be pointed out that the addition of a catalytic
amount of CuI to the reaction system allowed it to undergo
the coupling reaction at room temperature, although the reac-
tion without CuI did not proceed at all under similar condi-
tions. The reaction with several alkynes and organic halides
took place similarly. It is also remarkable that isolation and pu-
rification procedures are quite simple to obtain the desired
product by simple silica-gel chromatography or recrystalliza-
tion after the usual workup.
In addition to TBAF, tetrabutylammonium hydroxide
(TBAOH) was also found to serve as an efficient activator
for the coupling reaction. Table 3 summarizes the results.
The reaction with TBAOH was generally faster than that with
TBAF. The reaction of phenylethyne (1b) with 4-iodoanisole
(2b) in the presence of a 0.01 molar amount of [PdCl2(PPh3)2],
a 0.02 molar amount of CuI, and a 2 molar amount of TBAOH
resulted in giving the coupling product 3bb in quantitative
yield after stirring for 5 h in THF at room temperature. 1-al-
kynes, such as 1-octyne, also underwent the reaction smoothly.
Several alkynes bearing a hydroxy substituent also reacted to
afford the coupling products. The reaction of 1d with 2b gave
the corresponding coupling product 3db in 95% as isolated
yield after stirring for 5 h at room temperature. The use of
1f and 1g also resulted in giving 3fb and 3gb in 83% and
89% isolated yields, respectively.
It was also found that the coupling of terminal alkynes was
promoted by tetrabutylammonium fluoride (TBAF) in spite of
the fact that stoichiometry of the reaction suggests the forma-
tion of hydrogen fluoride. The reaction was found to proceed
with a smaller amount of palladium catalyst (0.005 molar
amount) (Eq. 1).
Cat [Pd(PPh3)4]
R1
H
R2
+
I
TBAF
THF
1
2
ð1Þ
R1
R2
HF
+
TBAI
+
3
When phenylethyne (1b) was treated with 2b in the pres-
ence of [Pd2(dba)3] (0.005 molar amount)–PPh3 (0.02 molar
ꢁ
amount) in THF at 60 C for 6 h, the corresponding coupling
product 3bb was obtained in 83% yield. As summarized in
Table 2, the reaction proceeded with various terminal alkynes
and aryl halides. In contrast to the case of Ag2O, bromides also
Table 2. Coupling of Terminal Alkynes in the Presence of TBAFaÞ
Catalyst
R2
R1
R2
R1
H
+
X
TBAF (2 mol. amt.)
THF
1
2
3
R1
X–R2
Catalyst (10ꢂ2 mol. amt.)
Temp
ꢁ
Time/h
3, Yield/%
Ph (1b)
1b
1b
nC6H13 (1c)
1c
HO(CH3)2C (1d)
HOCH2 (1e)
HO(CH2)2 (1f)
1b
1b
1b
1b
1b
1c
1c
1c
1c
4-I–C6H4–OCH3 (2b)
4-I–C6H4–CN (2d)
4-Br–C6H4–COCH3 (4c)
2b
4c
I–C6H5 (2a)
2a
2a
2a
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[Pd2(dba)3] (0.5), PPh3 (2.0)
[PdCl2(PPh3)2] (3.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (1.0), CuI (2.0)
[PdCl2(PPh3)2] (3.0), CuI (2.0)
60 C
ꢁ
6
5
3bb,
3bd,
3bc,
3cb,
3cc,
3da,
3ea,
3fa,
3ba,
3bb,
3bd,
3bc,
3be,
3ca,
3cb,
3cd,
3cc,
83
86
54
81
75
64
59
60 C
ꢁ
60 C
ꢁ
48
24
24
24
24
5
42
36
24
24
5
60 C
ꢁ
60 C
ꢁ
60 C
ꢁ
60 C
ꢁ
60 C
64
rt
rt
rt
rt
rt
rt
rt
rt
rt
93bÞ
99
2b
2d
99bÞ
84
2c
(E)-PhCH=CHBr (4e)
2a
2b
2d
4c
89
93
98
3
6
6
24
96bÞ
87
a) Unless noted the reaction was carried out using 0.5 mmol aryl halide 2 or 4 and 0.6 mmol terminal alkyne 1 in the pres-
ence of 2 mol. amt. of TBAF. b) 1.2 mol. amt. of TBAF was loaded.

M. S. Mohamed Ahmed et al.
Bull. Chem. Soc. Jpn., 78, No. 2 (2005)
329
Table 3. Coupling of Terminal Alkynes in the Presence of
TBAOH at Room TemperatureaÞ
jected to column chromatography on silica gel (hexane–ethyl ace-
tate 30:1) to give 3bd in 86% (87.4 mg).
The following coupling products were obtained in a manner
described above: 4-(Phenylethynyl)anisole (3bb),16 1-[4-(phenyl-
ethynyl)phenyl]-1-ethanone (3bc),17 1-[4-(1-octynyl)phenyl]-1-
ethanone (3cc),6c 3-phenyl-2-propyn-1-ol (3ea),2a 4-phenyl-3-bu-
tyn-1-ol (3fa).2c
4-(1-Octynyl)anisole (3cb).3e To a solution of [PdCl2(PPh3)2]
(3.5 mg, 0.005 mmol) and CuI (1.9 mg, 0.01 mmol) in 3 mL of
THF were added successively 2b (117 mg, 0.5 mmol), 1c (89
mL, 0.6 mmol), and TBAF (1 mL, as 1 M THF solution, 1.0 mmol)
under argon atmosphere. Stirring was continued at room temper-
ature for 6 h, and the resulting mixture was passed through a Cel-
ite pad. The filtrate was concentrated and subjected to column
chromatography on silica gel (hexane–ethyl acetate 50:1) to afford
3cb in 98% (106 mg).
R1
X–R2
Time/h 3, Yield/%
Ph (1b)
1b
1b
nC6H13 (1c)
1c
HO(CH3)2C (1d)
HO(CH2)2 (1f)
HO(CH3)CH (1g)
4-I–C6H4–OCH3 (2b)
4-Br–C6H4–OCH3 (4b)
4-Br–C6H4–COCH3 (4c)
5
24
7
1
6
3bb, 99
3bb, 30bÞ
3bc, 94cÞ
3cb, 90
3cb, 98dÞ
3db, 95
3fb, 83
2b
2b
2b
2b
2b
5
3
3
3gb, 89
a) Unless noted the reaction was carried out using 0.01 mol. amt.
of [PdCl2(PPh3)2], 0.02 mol. amt. of CuI and 2 mol. amt. of
TBAOH at room temperature in THF. b) [PdCl2{P(o-tol)3}2]
(0.03 mol. amt.) was loaded. c) [PdCl2(PPh3)2] (0.03 mol.
amt.) was loaded. d) 1.2 mol. amt. of TBAOH was employed.
The following coupling products were obtained in the manner
described above: 1,4-Diphenyl-1-buten-3-yne (3be),18 4-(1-octy-
nyl)benzonitrile (3cd).19
In summary, since we have several new activators for the
coupling of terminal alkynes, described herein as Ag2O, tetra-
butylammonium fluoride (TBAF), and tetrabutylammonium
hydroxide (TBAOH) in hand, the method would be a powerful
tool for the synthesis of a variety of organic molecules bearing
alkynyl moieties, leading to biologically active compounds
and functional organic materials.
4-(Phenylethynyl)anisole (3bb).16 To a solution of PdCl2-
(PPh3)2 (3.5 mg, 0.005 mmol) and CuI (1.9 mg, 0.01 mmol) in
3 mL of THF were added successively 2b (117 mg, 0.5 mmol),
1b (66 mL, 0.6 mmol), and TBAOH (0.655 mL, 1.0 mmol) under
an argon atmosphere. Stirring was continued at room temperature
for 5 h, and the resulting mixture was passed through a Celite pad.
The filtrate was concentrated and subjected to column chromatog-
raphy on silica gel (hexane–ethyl acetate 30:1) to afford 3bb in
99% (103 mg).
Experimental
All reactions were performed under an atmosphere of argon
using standard Schlenk tubes. Commercially purchased terminal
alkynes and aryl halides were used as received without further
treatment. Tetrabutylammonium fluoride (TBAF) was purchased
as a 1 M (¼ 1 mol dmꢂ3) solution in THF, and tetrabutylammoni-
um hydroxide (TBAOH) was purchased as a 40% (w/w) aqueous
solution.
The following coupling products were obtained in the manner
described above: 4-(4-Methoxyphenyl)-2-methyl-3-butyn-2-ol
(3db),20 4-(4-methoxyphenyl)-3-butyn-1-ol (3fb),21 4-(4-methoxy-
phenyl)-3-butyn-2-ol (3gb).22
References
Trimethylsilylethynylbenzene (3aa).9
To a Schlenk tube
1
a) D. E. Frantz, R. Fassler, and E. M. Carreira, J. Am.
¨
were added [Pd(PPh3)4] (11.6 mg, 0.01 mmol), Ag2O (46.3 mg,
0.2 mmol), and THF (2 mL). Then, 2a (0.2 mmol), and 1a
(0.24 mmol) were successively added to the mixture. The result-
ing mixture was heated at 60 ꢁC and stirring was continued for
3 h. After cooling to an ambient temperature, the mixture was di-
luted with diethyl ether and then passed through a Celite pad to
remove the silver residue, which was washed with diethyl ether.
The combined filtrate was concentrated under reduced pressure
to leave a crude oil, which was subjected to column chromatogra-
phy on silica gel (hexane–ethyl acetate 100:1) to give 3aa in 79%
(28 mg).
Chem. Soc., 121, 11245 (1999). b) D. Tzalis and P. Knochel,
Angew. Chem., Int. Ed., 38, 1463 (1999).
2
a) K. Sonogashira, Y. Tohda, and N. Hagihara, Tetra-
hedron Lett., 16, 4467 (1975). b) A. L. Casalnuovo and J. C.
Calabrese, J. Am. Chem. Soc., 112, 4324 (1990). c) M. Alami,
F. Ferri, and G. Linstrumelle, Tetrahedron Lett., 34, 6403
(1993). d) C. Amatore, E. Blart, J. P. Genet, A. Jutand, S.
Lemaire-Audoire, and M. Savignac, J. Org. Chem., 60, 6829
(1995). e) J.-F. Nguefack, V. Bolitt, and D. Sinou, Tetrahedron
Lett., 37, 5527 (1996). f) N. A. Bumagin, L. I. Sukhomlinova,
E. V. Luzikova, T. P. Tolstaya, and I. P. Beletskaya, Tetrahedron
Lett., 37, 897 (1996). g) K. Sonogashira, ‘‘Metal-Catalyzed
Cross-Coupling Reaction,’’ ed by F. Diederich and P. J. Stang,
Wiley-VCH, Weinheim (1998), Chap. 5, pp. 203–229. h) K.
Sonogashira, J. Organomet. Chem., 653, 46 (2002). i) E. Negishi
and L. Anastasia, Chem. Rev., 103, 1979 (2003).
The following coupling products were obtained in the manner
described above: 4-(Trimethylsilylethynyl)anisole (3ab),10 1-[4-
(trimethylsilylethynyl)phenyl]-1-ethanone (3ac),11 diphenyl-
ethyne (3ba),12 1-phenyl-1-octyne (3ca),13 2-methyl-4-phenyl-3-
butyn-2-ol (3da).14
4-(Phenylethynyl)benzonitrile (3bd).15 To a Schlenk tube
3
a) W. A. Herrmann, C.-P. Reisinger, and M. Spiegler,
were added [Pd2(dba)3] CHCl3 (2.6 mg, 0.0025 mmol), PPh3
J. Organomet. Chem., 557, 93 (1998). b) K. Nakamura, H. Okubo,
and M. Yamaguchi, Synlett, 1999, 549. c) G. W. Kabalka, L.
Wang, V. Namboodiri, and R. M. Pagni, Tetrahedron Lett., 41,
ꢃ
(2.6 mg, 0.01 mmol), and 1b (66 mL, 0.6 mmol). The mixture
was dissolved in 2 mL of THF under an argon atmosphere. To
the solution were successively added 2d (114.5 mg, 0.5 mmol)
and TBAF (1.0 mL, 1.0 mmol; 1 M THF solution, water content
5 wt %: available from Aldrich). The resulting mixture was then
heated at 60 ꢁC for 5 h. After the reaction was completed, the mix-
ture was cooled to room temperature and the solvent was removed
under reduced pressure to leave a crude sample, which was sub-
5151 (2000). d) V. P. W. Bohm and W. A. Herrmann, Eur. J.
¨
Org. Chem., 2000, 3679. e) T. Hundertmark, A. F. Littke, S. L.
Buchwald, and G. C. Fu, Org. Lett., 2, 1729 (2000). f) D. A.
`
Alonso, C. Najera, and M. C. Pacheco, Tetrahedron Lett., 43,
9365 (2002). g) R. J. Heidenreich, K. Kohler, J. G. E. Krauter,
¨
and J. Pietsch, Synlett, 2002, 1118. h) T. Fukuyama, M. Shinmen,

330 Bull. Chem. Soc. Jpn., 78, No. 2 (2005)
New Activators for Alkyne Coupling
S. Nishitani, M. Sato, and I. Ryu, Org. Lett., 4, 1691 (2002). i) Y.
Uozumi and Y. Kobayashi, Heterocycles, 59, 71 (2003). j) A. S.
Karpov, F. Rominger, and T. J. Muller, J. Org. Chem., 68, 1503
(2003). k) A. L. Braga, D. S. Ludtke, F. Vargas, R. K. Donato,
C. C. Silveira, H. A. Stefani, and G. Zeni, Tetrahedron Lett.,
8 Y. Koseki, K. Omino, S. Anzai, and T. Nagasaka, Tetra-
hedron Lett., 41, 2377 (2000).
9
331.
M. Isobe, M. Kitamura, and T. Goto, Chem. Lett., 1980,
10 J. A. Soderquist, A. M. Rane, K. Matos, and J. Ramos,
Tetrahedron Lett., 36, 6847 (1995).
44, 1779 (2003). l) A. Kollhofer, T. Pullmann, and H. Plenio,
¨
Angew. Chem., Int. Ed., 42, 1056 (2003). m) R. R. Tykwinski,
Angew. Chem., Int. Ed., 42, 1566 (2003). n) A. Elangovan,
Y.-H. Wang, and T.-I. Ho, Org. Lett., 5, 1841 (2003). o) W. P.
Gallagher and R. E. Maleczka, Jr., J. Org. Chem., 68, 6775
(2003).
11 S. Takahashi, Y. Kuroyama, K. Sonogashira, and N.
Hagihara, Synthesis, 1980, 627.
12 G. H. Coleman, W. H. Holst, and R. D. Maxwell, J. Am.
Chem. Soc., 58, 2310 (1936).
13 J. K. Crandall, P. Battioni, J. T. Wehlacz, and R. Bindra,
J. Am. Chem. Soc., 97, 7171 (1975).
4
a) M. Nishiyama, T. Yamamoto, and Y. Koie, Tetrahedron
Lett., 39, 617 (1998). b) T. Yamamoto, M. Nishiyama, and Y.
Koie, Tetrahedron Lett., 39, 2367 (1998).
14 J. Klein and S. Zitrin, J. Org. Chem., 35, 666 (1970).
15 L. Cassar, J. Organomet. Chem., 93, 253 (1975).
16 R. D. Stephens and C. E. Castro, J. Org. Chem., 28, 3313
(1963).
17 E. Shirakawa, H. Hoshida, and H. Takaya, Tetrahedron
Lett., 38, 3759 (1997).
5
Preliminary communications: a) A. Mori, J. Kawashima, T.
Shimada, M. Suguro, and Y. Nishihara, Org. Lett., 2, 2935 (2000).
b) A. Mori, T. Shimada, M. Suguro, T. Kondo, and A. Sekiguchi,
Synlett, 2001, 649.
6
a) K. Hirabayashi, J. Kawashima, Y. Nishihara, A. Mori,
18 S. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, and
K. Kondo, J. Org. Chem., 44, 2408 (1979).
19 A.-S. Castanet, F. Colobert, and T. Schlama, Org. Lett., 2,
3559 (2000).
20 H. Mayr and I. K. Halberstadt-Kausch, Chem. Ber., 115,
3479 (1982).
and T. Hiyama, Org. Lett., 1, 299 (1999). b) K. Hirabayashi, T.
Kondo, F. Toriyama, Y. Nishihara, and A. Mori, Bull. Chem.
Soc. Jpn., 73, 985 (2000). c) K. Hirabayashi, A. Mori, J.
Kawashima, M. Suguro, Y. Nishihara, and T. Hiyama, J. Org.
Chem., 65, 5342 (2000).
7
Tetrahedron Lett., 39, 7893 (1998). b) C. Mateo, C. Fernandez-
´
16, 1997 (1997). c) S. E. Denmark and D. Wehrli, Org. Lett., 2,
565 (2000).
a) K. Hirabayashi, Y. Nishihara, A. Mori, and T. Hiyama,
´
Rivas, A. M. Echavarren, and D. J. Cardenas, Organometallics,
21 R. J. Blade and J. E. Robinson, Tetrahedron Lett., 27, 3209
(1986).
22 B. Tao, J. C. Ruble, D. A. Hoic, and G. C. Fu, J. Am.
Chem. Soc., 121, 10452 (1999).