A highly effective Pd/Cu-catalyzed coupling reaction of terminal alkynes with organic halides promoted by tetrabutylammonium fluoride or hydroxide

Article abstract of DOI:10.1055/s-2001-13390

Coupling reaction of terminal alkynes catalyzed by Pd/Cu with several organic electrophiles is shown to proceed by use of tetrabutylammonium fluoride (TBAF) or tetrabutylammonium hydroxide (TBAOH) as an activator. Treatment of 1-octyne and 4-methoxy-iodob

Full text of DOI:10.1055/s-2001-13390

LETTER
649
A Highly Effective Pd/Cu-Catalyzed Coupling Reaction of Terminal Alkynes
with Organic Halides Promoted by Tetrabutylammonium Fluoride or
Hydroxide
Atsunori Mori,* Tomohiro Shimada, Tatsuhiro Kondo, Akitoshi Sekiguchi
Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8503, Japan
Fax +81-459245224; E-mail: amori@res.titech.ac.jp
Received 1 March 2001
cat Pd/Cu
Abstract: Coupling reaction of terminal alkynes catalyzed by Pd/
Cu with several organic electrophiles is shown to proceed by use of
tetrabutylammonium fluoride (TBAF) or tetrabutylammonium hy-
droxide (TBAOH) as an activator. Treatment of 1-octyne and
4-methoxy-iodobenzene in the presence of 2.0 equiv of TBAOH,
1 mol% of PdCl2(PPh3)3, and 2 mol% of CuI affords 1-phenyl-1-oc-
tyne in 98% yield after stirring at room temperature for 1 h. The new
coupling reaction is also applied to polymer synthesis via polycon-
densation of a diyne and a diiodoarene.
+
Aryl
X
R
H
R
Aryl
excess R'3N
Equation 1
cat Pd
+
Aryl
X
R
Y
R
Aryl
activator
Key words: Sonogashira-Hagihara coupling, Pd/Cu catalyst, termi-
nal alkynes, tetrabutylammonium fluoride, tetrabutylammonium
hydroxide, polycondensation
Equation 2 Y: H, SiMe3; activator: nBu4NF, nBu4NOH, Ag2O
Sonogashira-(Hagihara) coupling, the reaction of a termi-
nal alkyne with various organic halides catalyzed by Pd/
Cu systems, is a powerful tool for the introduction of an
alkynyl moiety into a variety of organic molecules and has
been widely utilized in synthetic organic chemistry (eq
1).1 A major procedural disadvantage of the Sonogashira
coupling, however, is the requirement for large amounts
of amine as solvent or co-solvent. The removal of the usu-
ally high boiling amine from the reaction mixture can be
a serious procedural difficulty. If the amount of amine re-
quired could be decreased or eliminated altogether, the
utility of the Sonogashira coupling would be significantly
enhanced. Buchwald and Fu recently described one possi-
ble solution to this problem, by the tuning of phosphine
ligand of the palladium catalyst. It was found that t-Bu3P,
a bulky and electron donating ligand could affect the So-
nogashira coupling using only an equimolar amount of
amine.2
The reaction of 1-octyne (1) with iodobenzene (2a) was
carried out using 1 mol% of PdCl2(PPh3)2, 2 mol% of CuI,
and 2.0 equivalents of TBAF in THF. The reaction was
complete after stirring at room temperature for 3 h. The
reaction was clearly accelerated by the addition of a cata-
lytic amount of CuI, since in its absence, there was no re-
action at room temperature, although 59% yield of the
desired product was obtained after 6 h at 60 °C.3a
The Table summarizes the reactions of several terminal
alkynes and organic halides. The use of 2.0 molar equiva-
lents of TBAF seems to be optimum to affect the reaction
within a short reaction period although reaction was ob-
served with smaller amounts (1.2 equiv) of TBAF. The re-
actions with aryl iodides bearing an electron-withdrawing
or -donating substituent, such as 4-methoxy-1-iodoben-
zene (2b) and 4-cyano-1-iodobenzene (2c), were found
similarly useful affording the corresponding coupled
products in 98% and 92% yields, respectively, after stir-
ring for 6 h. Several aryl or alkenyl bromides were also re-
active organic electrophiles. Tetrabutylammonium
hydroxide (TBAOH) was found to be equally effective as
an activator. It should be pointed out that the TBAOH em-
ployed was a 40% aqueous solution suggesting that the
coupling reaction can be performed in the presence of a
significant amount of water. The reactions could also be
performed with alkynes bearing a hydroxy group, such as
3-butyn-1-ol (4), 3-butyn-2-ol (5), and 2-methyl-3-butyn-
2-ol (6) to afford the corresponding coupling products in
good yields. In addition, the coupling reaction with an
alkyne bearing a primary amino group 7 proceeded al-
though the reaction was found to be slower.
An alternative solution was described in our recent study
on the palladium-catalyzed coupling of a terminal alkyne
that proceeds by the action of a promoter such as Ag2O,
tetrabutylammonium fluoride (TBAF) or tetrabutylam-
monium hydroxide (TBAOH) (eq 2).3 Under these condi-
tions, the reaction takes place without the addition of any
amine. During further study it was revealed that the addi-
tion of a catalytic amount of CuI to our reaction system
improved the reaction rate dramatically. Accordingly, a
reaction equivalent to the Sonogashira coupling is avail-
able using neither a stoichiometric nor excess amount of
amine at room temperature when the reaction is carried
out with TBAF or TBAOH as an activator.
Synlett 2001 No. 5, 649–651 ISSN 0936-5214 © Thieme Stuttgart · New York

650
A. Mori et al.
LETTER
Table Cross Coupling of a Terminal Alkyne with an Organic Halide Catalyzed by Pd/Cu in the Presence of TBAF or
TBAOHa
activator
(equiv)
temp, °C
alkyne
halide
%yield
time, h
nC6H13
H
rt
rt
I
93
98
(2a)
(2b)
TBAF (2.0)
TBAF (2.0)
3
6
1
I
OMe
CN
TBAOH (1.2)
TBAOH (2.0)
98
>99b
rt
rt
6
1
TBAF (1.2)
92
(2c)
I
rt
6
rt
rt
24
42
>99b,c
93
Br
COMe
TBAF (2.0)
TBAF (1.2)
Ph
H
2a
2b
TBAF (2.0)
TBAOH (2.0)
rt
rt
36
5
99
>99
(3)
Br
OMe
TBAOH (2.0)
37b,d
rt
24
2c
rt
rt
24
24
TBAF (1.2)
TBAF (2.0)
>99
84
(2d)
I
COMe
COMe
TBAOH (2.0)
TBAF (2.0)
rt
rt
7
5
>99b,c
89
Br
Ph
Br
MeO
I
(2f)
60
rt
5
3
TBAOH (1.2)
TBAOH (2.0)
95
83
2b
2b
HOCH2CH2
H
H
(4)
Me
HO
TBAOH (2.0)
rt
3
89
95
90
(5)
(6)
(7)
Me
Et
Me
HO
H
2b
2b
TBAOH (2.0)
TBAOH (2.0)
rt
rt
5
Et
H
120
H2N
a) Unless noted, the reaction was carried out using 1 mol% of PdCl2(PPh3)2 and 2 mol% of CuI in THF. b) The yield was
estimated by 1H NMR using trichloroethylene as an internal standard. c) PdCl2(PPh3)2 (3 mol%) was used. d) PdCl2{P(o-
tol)3}2 (3 mol%) was used.
Sonogashira reactions are reported to proceed at room showed that the TBAF-promoted reaction was far superi-
temperature when the reaction is carried out with excess or as shown in Scheme 1. Although the Sonogashira reac-
amine,1,4 however, decreasing the amount of amine con- tion using a substrate bearing an electron-withdrawing
siderably retards the reaction. Indeed, comparison of the substituent with a smaller amount of Et3N (1.5 equiv) has
reaction of 1-octyne and 4-methoxy-1-iodobenzene under been shown to proceed under mild conditions,5,6 aryl ha-
TBAF-promoted conditions with the reaction employing lides bearing an electron-donating substituent should ob-
1.5 equivalents of several amines at room temperature viously be reacted under our TBAF-promoted conditions.
Synlett 2001, No. 5, 649–651 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Highly Effective Pd/Cu-Catalyzed Coupling Reaction of Terminal Alkynes
651
References and Notes
+
I
OMe
C6H13
H
(1) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; Chapter 5, pp 203-229. (b) Sonogashira, K.;
Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
(2) (a) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu. G. C.
Org. Lett. 2000, 2, 1729. (b) See also: Böhm, V. P. W.;
Hermann, W. A. Eur. J. Org. Chem. 2000, 3679.
(3) (a) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.;
Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
(b) Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.;
Nishihara, Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342.
(c) Mori, A.; Kondo, T.; Kato, T.; Nishihara, Y. Chem. Lett.
2001, 286. See also: (d) Koseki, Y.; Omino, K.; Anzai, S.;
Nagasaka, T. Tetrahedron Lett. 2000, 41, 2377.
PdCl2(PPh3) 2 (1 mol%),
CuI (2 mol%)
nC6H13
OMe
activator (1.5 mol)
THF, rt, 6 h
Scheme 1 Activator; TBAF (77%), Et3N (14%), piperidine (20%),
Et2NH (33%), iPr2NH (15%)
(4) Studies on the effect of amine in the Sonogashira coupling,
where piperidine and diisopropylamine were, in general,
superior solvents: Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403.
(5) Krause recently showed that the reaction with an aryl halide
with an electron-withdrawing substituent proceeded with 1.5
equivalents of tertiary amine in THF. Thorand, S.; Krause, N.
J. Org. Chem. 1998, 63, 8551.
(6) Recent works on the Sonogashira coupling, see: (a) Kabalka,
G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M. Tetrahedron
Lett. 2000, 41, 5151. (b) Nakamura, K.; Okubo, H.;
Yamaguchi, M. Synlett 1999, 549. (c) Bumagin, N. A.;
Sukhomlinova, L. I.; Luzikova, E. V.; Tolastaya, T. P.;
Beletskaya, I. P. Tetrahedron Lett. 1996, 37, 897.
The present coupling conditions were successfully ap-
plied to the polycondensation of a bifunctional alkyne and
a dihalogenated aromatic compound.7 The reaction of
1,7-octadiyne with 1,4-diiodobenzene was carried out in
the presence of catalytic PdCl2(PPh3)2/CuI and TBAOH to
afford the corresponding polymer in good yield (eq 3).
Such a polymerization has not been achieved at room tem-
perature without CuI.3c
+
(CH2)4
I
I
(7) Polycondensation with Sonogashira coupling: (a) Yamamoto,
T.; Honda, K.; Ooba, N.; Tomaru, S. Macromolecules 1998,
31, 7. (b) Pang, Y.; Li, J.; Hu, B.; Karasz, F. E.
PdCl2(PPh3) 2 (1 mol%),
CuI (2 mol%)
(CH2)4
Macromolecules 1998, 31, 6730. (c) Sato, T.; Jiang, D.-L.;
Aida, T. J. Am. Chem. Soc. 1999, 121, 10658. (d) Wagner, R.
W.; Johnson, T. E.; Lindsey, J. S. J. Am. Chem. Soc. 1996,
118, 11166. Sanechika, K.; Yamamoto, T.; Yamamoto, A.
Bull. Chem. Soc. Jpn. 1984, 57, 572. For reviews: (e) Bunz, U.
H. F. Chem. Rev. 2000, 100, 1605. (f) Yamamoto, T. Bull.
Chem. Soc. Jpn. 1999, 72, 621.
TBAOH (2.4 mol)
THF, rt, 6 h
Equation 3 55%, Mn = 7800, Mw/Mn = 3.7
A typical experimental procedure for the reaction of 1-oc-
tyne and iodobenzene is as follows: 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 was added successively iodoben-
zene (0.056 mL, 0.5 mmol), 1-octyne (0.089 mL, 0.6
mmol), and TBAF (1 mL, as 1 M THF solution, 1.0
mmol) under argon atmosphere. Stirring was continued at
room temperature for 3 h and the resulting mixture was
passed through a Celite pad. The filtrate was concentrated
and subjected to column chromatography on silica gel
(hexane-ethyl acetate, 50:1) to afford 87 mg of 1-phenyl-
1-octyne (93%).
Article Identifier:
1437-2096,E;2001,0,05,0649,0651,ftx,en;Y06301ST.pdf
Synlett 2001, No. 5, 649–651 ISSN 0936-5214 © Thieme Stuttgart · New York