Improved procedures for the palladium-catalyzed coupling of terminal alkynes with aryl bromides (Sonogashira coupling)

Full text of DOI:10.1021/jo9808021

J . Org. Chem. 1998, 63, 8551-8553
8551
Sch em e 2
Im p r oved P r oced u r es for th e
P a lla d iu m -Ca ta lyzed Cou p lin g of Ter m in a l
Alk yn es w ith Ar yl Br om id es (Son oga sh ir a
Cou p lin g)†
Stephan Thorand and Norbert Krause*
some of the excellent yields reported in the literature.
Careful examination of the published procedures reveals
several difficulties which can affect the efficiency and
practicability of the Sonogashira coupling: (i) The reac-
tivity of the coupling of aryl bromides is often rather low,
so that harsh conditions have to be used; alternatively,
more reactive aryl iodides are employed which, however,
are more expensive and difficult to prepare. (ii) In some
cases, acceptable yields are only obtained after cumber-
some purification of the reactants and with strict exclu-
sion of oxygen,5 diminishing the practical value of the
method. (iii) Under the conditions of the Sonogashira
coupling, the oxidative homocoupling (Glaser coupling)
of the alkyne to the corresponding symmetrical diyne is
also catalyzed if oxygen is not excluded completely.6
Therefore, a large excess of the (sometimes expensive)
alkyne is usually employed, and the separation of the
diyne from the desired product may be difficult.
Kekule´-Institut fu¨r Organische Chemie und Biochemie,
Universita¨t Bonn, Gerhard-Domagk-Strasse 1,
D-53121 Bonn, Germany
Received April 28, 1998
One of the most straightforward methods for the
preparation of arylalkynes and conjugated enynes is the
palladium-catalyzed coupling of terminal alkynes with
aryl or alkenyl halides which was described for the first
time by Sonogashira et al. in 1975.1 Usually, the Sono-
gashira coupling is carried out in the presence of catalytic
amounts of a palladium(II) complex as well as copper(I)
iodide in an amine as solvent.2 Numerous applications
in natural product synthesis have been reported,2 for
example in the construction of the complex unsaturated
framework of the enediyne antibiotics (Scheme 1).3
Sch em e 1
To solve these problems, we varied the reaction condi-
tions and found that the desired products 2 are formed
with good-to-excellent yields when the coupling is carried
out with THF as solvent (Scheme 2). For example,
4-bromobenzaldehyde (1a ) and 4-bromoacetophenone
(1b) gave the products 2a and 2b with yields of 99% and
92%, respectively (Table 1), when trimethylsilylacetylene
(1.05 equiv) was added to a mixture of the aryl bromide,
2 mol % of Pd(PPh3)2Cl2, 4 mol % of CuI, and 1.5 equiv
of triethylamine in THF (method A). These yields are
equal to or higher than those reported in the literature4,5
(see Table 1) and were obtained after only 1 h of reaction
time at room temperature with ordinary, nondegassed
reagent-grade reactants.
In the course of a current research program directed
toward the synthesis of functionalized arylalkynes, we
required a reliable and operationally simple procedure
for the Sonogashira coupling of aryl bromides with
terminal alkynes. Typically, the aryl bromide is mixed
with the alkyne in an amine (normally di- or triethy-
lamine), and the mixture is either stirred at room
temperature or heated under reflux for varying amounts
of time.3-5 However, the experimental conditions for the
preparation of some compounds vary considerably, es-
pecially with respect to reaction time and temperature,
and in our hands, it turned out to be difficult to reproduce
The use of solvents such as THF7 or DMF8 in Sono-
gashira couplings has been reported occasionally but
without emphasizing a possible solvent effect on the rate
of the transformation.9 Our results suggest a remarkable
increase of reactivity when the coupling is performed in
THF instead of an amine as solvent. Analysis of the
crude products by GC-MS showed that only traces (<5%)
of the diyne are formed by homocoupling of the alkyne
under our conditions; thus, this side reaction is prevented
almost completely by slow addition of the alkyne, which
keeps its concentration in the reaction mixture low (it
seems that this dilution technique has not yet been used
in Sonogashira couplings). Additionally, workup of the
reaction mixture is simple, and the crude product is often
analytically pure.
* New address: Universita¨t Dortmund, Organische Chemie II,
D-44221 Dortmund, Germany. Phone: 49-231-7553882. Fax: 49-231-
7553884. E-mail: nkrause@pop.uni-dortmund.de.
† Presented at the Ninth International Symposium on Novel Aro-
matic Compounds (ISNA-9), Hong Kong, Aug 2-7, 1998; Poster PP18.
(1) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(2) For reviews, see: (a) Sonogashira, K. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 3, pp 521-549. (b) Rossi, R.; Carpita, A.; Bellina, F. Org.
Prep. Proced. Int. 1995, 27, 129-160. (c) Tsuji, J . Palladium Reagents
and Catalysts; Wiley: Chichester, 1995; pp 168-171. (d) Nicolaou, K.
C.; Sorensen, E. J . Classics in Total Synthesis; VCH: Weinheim,
Germany, 1996; pp 582-586. (e) Brandsma, L.; Vasilevsky, S. F.;
Verkruijsse, H. D. Application of Transition Metal Catalysts in Organic
Synthesis; Springer: Berlin, 1998; pp 179-225. (f) Sonogashira, K. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J .,
Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 203-229.
(3) (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem. 1991, 103, 1453-
1481; Angew. Chem., Int. Ed. Engl. 1991, 30, 1387-1416. (b) Maier,
M. E. Synlett 1995, 13-26. (c) Grissom, J . W.; Gunawardena, G. U.;
Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453-6518.
(4) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627-630.
(6) Niedballa, U. In Methoden der Organischen Chemie (Houben-
Weyl); Mu¨ller, E., Ed.; Thieme: Stuttgart, 1977; Vol. 5/2a, pp 925-
937.
(7) (a) Buszek, K. R.; Yeong, J . Synth. Commun. 1994, 24, 2461-
2472. (b) Miller, M. W.; J ohnson, C. R. J . Org. Chem. 1997, 62, 1582-
1583.
(8) Saito, I.; Yamaguchi, K.; Nagata, R.; Murahashi, E. Tetrahedron
Lett. 1990, 31, 7469-7472.
(9) In some cases, the choice of the amine also affects the yield of
Sonogashira coupling products. For example, see: McGaffin, G.; De
Meijere, A. Synthesis 1994, 583-591 and references therein.
(5) Austin, W. B.; Bilow, N.; Kelleghan, W. J .; Lau, K. S. Y. J . Org.
Chem. 1981, 46, 2280-2286.
10.1021/jo9808021 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8552 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
Ta ble 1. Yield s of Ar yla lk yn es 2 Obta in ed by Son oga sh ir a Cou p lin g of Ar yl Br om id es 1 w ith Ter m in a l Alk yn es
this work (solvent: THF)
conditions
literature (solvent: Et3N)
arylalkyne
R1
R2
method
yield (%)
conditions
yield (%)
2a
2b
2c
2d
2e
2f
4-CHO
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
n-Bu
Ph
A
A
B
B
B
B
B
B
25 °C, 1 h
25 °C, 1 h
25 °C, 16 h
25 °C, 16 h
25 °C, 16 h
25 °C, 16 h
25 °C, 16 h
25 °C, 16 h
99
92
88
87
88
91
87
82
refl, 2 h
99a
4-COMe
2-CO2Me
3-CO2Me
4-CO2Me
4-COMe
4-COMe
4-CHO
25 °C, 4 h
80 °C, 3 h
100 °C, 16 h
100 °C, 4 h
140 °C, 2 h
refl., 3 h
804
81b
705
695
73c
2g
2h
8312
6613
6414
Ph
100 °C, 1 h
refl, 3 h
a
Reference 5; the authors used triethylamine that had been distilled over phenylisocyanate and degassed. We obtained similar yields
b
under these conditions; however with triethylamine which was distilled from CaH2 under argon, our yield was only 44%. Reference 10;
an autoclave was employed with acetontrile as solvent. c Reference 11; 1:1 mixture of 2f and other products, using an autoclave and
microwave irradiation.
Compared with substrates 1a ,b methyl bromoben-
zoates are known to be less reactive in Sonogashira
couplings; for example, the reaction of methyl 2-bro-
mobenzoate (1c) with trimethylsilylacetylene was only
achieved until now with 81% yield under high pressure
in an autoclave.10 Accordingly, this reaction proceeded
only sluggishly at room temperature when method A was
applied; at elevated temperatures, the catalyst decom-
posed rapidly with formation of a black precipitation.
However, careful optimization of the reaction conditions
enabled us to convert even the very unreactive aryl
bromide 1c into the corresponding arylalkyne 2c. Here,
larger amounts of trimethylsilylacetylene (1.5 equiv) and
the palladium catalyst (5 mol %) were used, and the
presence of triphenylphosphine improved the stability of
the catalyst. In particular, it turned out to be favorable
to employ a very small amount (ca. 1 mol %) of copper
iodide and to add this as the last component to the
reaction mixture (method B).2e Under these conditions,
2c was isolated with 88% yield after stirring for 16 h at
room temperature. The analogous reactions of methyl
3- and 4-bromobenzoate (1d ,e) with trimethylsilylacety-
lene gave the arylalkynes 2d ,e with 87% and 88% yield,
respectively. Previously, harsh conditions (heating to 100
°C for 4-16 h) had to be employed with triethylamine
as solvent (boiling point: 89 °C) in order to obtain inferior
yields of these products (see Table 1).5
To demonstrate the scope of our new procedures, we
also examined Sonogashira couplings of aryl bromides
1a,b with less reactive alkyl- and aryl-substituted alkynes.
Application of method B, i.e., treatment of 4-bromo-
acetophenone (1b) with 1-hexyne or phenylacetylene in
THF in the presence of Pd(PPh3)2Cl2, PPh3, Et3N, and
CuI for 16 h at room temperature, gave coupling products
2f,g with high yields (91% and 87%, respectively). Again,
the conditions are much milder than those employed
previously,11,12 and our yields are higher (see Table 1).
Likewise, coupling of 4-bromobenzaldehyde (1a ) with
phenylacetylene in THF as solvent gave arylalkyne 2h
with 82% yield, compared to 64-66% obtained after
heating in triethylamine for 1-3 h.13,14 Additionally, our
improved procedures can also be utilized for the synthesis
of conjugated enynes by coupling alkenyl bromides with
terminal alkynes. For example, the coupling of methyl
(Z)-3-bromo-2-propenoate with 3,3-dimethylbutyne ac-
cording to method A gave methyl (Z)-6,6-dimethyl-2-
hexen-4-ynoate with 67% yield.15
In summary, reliable and practical procedures for the
synthesis of arylacetylenes by Sonogashira coupling of
aryl bromides with terminal alkynes were developed
which involve the use of THF as solvent. By careful
choice of the composition of the reaction mixture and the
mode of addition of the reactants, even very unreactive
substrates were converted into the products with good-
to-excellent yields at room temperature with ordinary,
reagent-grade starting materials. Currently, we are
further exploring the scope of our procedures in order to
extend them to other substrate types.
Ack n ow led gm en t. Financial support of this work
by the Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
Exp er im en ta l Section
Gen er a l In for m a tion . THF was distilled from potassium/
benzophenone prior to use. All other chemicals were of reagent
grade and were used without further purification.
4-(Tr im et h ylsilylet h in yl)b en za ld eh yd e (2a )5 (Met h od
A). To a stirred mixture of 9.25 g (50.0 mmol) of 4-bromoben-
zaldehyde (1a ), 380 mg (2.0 mmol) of CuI, and 700 mg (1.0 mmol)
of Pd(PPh3)2Cl2 in 50 mL of THF was added 10.1 g (75.0 mmol)
of triethylamine. A solution of 5.15 g (52.5 mmol) of trimeth-
ylsilylacetylene in 10 mL of THF was then added over 1 h. The
solvent was evaporated, and the residue was treated with
pentane. Filtration through Celite and evaporation of the
solvent yielded 10.02 g (99%) of analytically pure 2a [mp: 66
°C (lit.5 66-67 °C)]. 1H NMR (400 MHz, CDCl3): δ 9.99 (s, 1H),
7.81 (dm, J ) 8.4 Hz, 2H), 7.59 (dm, J ) 8.4 Hz, 2H), 0.26 (s,
9H).
4-(Tr im eth ylsilyleth in yl)a cetop h en on e (2b)4 was pre-
pared according to the preparation of 2a from 39.8 g (0.20 mol)
of 4-bromoacetophenone (1b). Yield: 39.65 g (92%) of 2b after
distillation of the crude product (bp0.7: 97 °C) as an oil which
solidified upon standing [mp: 36 °C (lit.4 36-37 °C)]. 1H NMR
(400 MHz, CDCl3): δ 7.87 (dm, J ) 8.4 Hz, 2H), 7.52 (dm, J )
8.4 Hz, 2H), 2.57 (s, 3H), 0.25 (s, 9H).
Meth yl 2-(Tr im eth ylsilyleth in yl)ben zoate (2c)10 (Meth od
B). A mixture of 1.08 g (5.0 mmol) of methyl 2-bromobenzoate
(1c), 175 mg (0.25 mmol) of Pd(PPh3)2Cl2, 33 mg (0.125 mmol)
of PPh3, 736 mg (7.5 mmol) of trimethylsilylacetylene, and 1.01
g (7.5 mmol) of triethylamine in 20 mL of THF was stirred for
(10) Campbell, I. B. In Organocopper Reagents. A Practical Ap-
proach; Taylor, R. J . K., Ed.; Oxford University Press: Oxford, 1994;
p 224.
(11) Li, J .; Mau, A. W.-H.; Strauss, C. R. Chem. Commun. 1997,
1275-1276.
(12) Lindeman, S. V.; Struchkov, Y. T.; Khotina, I. A.; Mikhailov,
V. N.; Rusanov, A. L. Russ. Chem. Bull. 1994, 43, 1873-1879.
(13) Dieck, H. A.; Heck, F. R. J . Organomet. Chem. 1975, 93, 259-
263.
(14) De la Rosa, M. A.; Velarde, E.; Guzman, A. Synth. Commun.
1990, 20, 2059-2064.
(15) Gerold, A. Ph.D. Thesis, Universita¨t Bonn, Bonn, 1997.

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8553
20 min at room temperature, and 12 mg (0.06 mmol) of CuI was
then added. After being stirred for 16 h, the mixture was worked
up as in method A. Column chromatography of the crude
product (SiO2; cyclohexane/ethyl acetate, 15:1) yielded 1.02 g
(88%) of 2c as an orange oil. 1H NMR (400 MHz, CDCl3): δ
7.89 (ddd, J ) 7.9/1.5/0.5 Hz, 1H), 7.57 (ddd, J ) 7.6/1.5/0.5 Hz,
1H), 7.43 (td, J ) 7.5/1.5 Hz, 1H), 7.35 (td, J ) 7.6/1.4 Hz, 1H),
3.91 (s, 3H), 0.25 (s, 9H).
4-bromoacetophenone (1b) and 616 mg (7.5 mmol) of 1-hexyne.
Yield: 909 mg (91%) of 2f. 1H NMR (400 MHz, CDCl3): δ 7.63
(dm, J ) 8.6 Hz, 2H), 7.37 (dm, J ) 8.6 Hz, 2H), 2.20 (t, J ) 7.0
Hz, 2H), 2.02 (s, 3H), 1.46-1.26 (m, 4H), 0.80 (t, J ) 7.1 Hz,
3H).
4-(P h en yleth in yl)a cetop h en on e (2g)12 was prepared ac-
cording to the preparation of 2c from 995 mg (5.0 mmol) of
4-bromoacetophenone (1b) and 766 mg (7.5 mmol) of phenyl-
acetylene. Yield: 957 mg (87%) of 2g [mp: 98-99 °C (lit.12 99-
100 °C)]. 1H NMR (400 MHz, CDCl3): δ 7.63 (dm, J ) 8.6 Hz,
2H), 7.54-7.49 (m, 2H), 7.41 (dm, J ) 8.6 Hz, 2H), 7.04-6.97
(m, 3H), 2.02 (s, 3H).
4-(P h en yleth in yl)ben za ld eh yd e (2h )13,14 was prepared ac-
cording to the preparation of 2c from 925 mg (5.0 mmol) of
4-bromobenzaldehyde (1a ) and 562 mg (5.5 mmol) of phenyl-
acetylene. Yield: 840 mg (82%) of 2h [mp: 96-97 °C (lit.13 98-
98.5 °C, lit.14 98-99 °C)]. 1H NMR (400 MHz, CDCl3): δ 9.55
(s, 1H), 7.52-7.43 (m, 2H), 7.37 (dm, J ) 8.6 Hz, 2H), 7.37 (dm,
J ) 8.4 Hz, 2H), 7.04-6.97 (m, 3H).
Meth yl 3-(tr im eth ylsilyleth in yl)ben zoa te (2d )5 was pre-
pared according to the preparation of 2c from 1.08 g (5.0 mmol)
of methyl 3-bromobenzoate (1d ). Yield: 1.01 g (87%) of 2d
(mp: 49-50 °C). 1H NMR (400 MHz, CDCl3): δ 8.13 (t, J ) 1.4
Hz, 1H), 7.96 (dt, J ) 7.9/1.6 Hz, 1H), 7.62 (dt, J ) 7.7/1.5 Hz,
1H), 7.36 (td, J ) 7.8/0.5 Hz, 1H), 3.90 (s, 3H), 0.25 (s, 9H).
Meth yl 4-(tr im eth ylsilyleth in yl)ben zoa te (2e)5 was pre-
pared according to the preparation of 2c from 1.08 g (5.0 mmol)
of methyl 4-bromobenzoate (1e). Yield: 1.02 g (88%) of 2d [mp:
56-57 °C (lit.4 57-59 °C, lit.5 55 °C)]. 1H NMR (400 MHz,
CDCl3): δ 7.96 (dm, J ) 8.6 Hz, 2H), 7.51 (dm, J ) 8.6 Hz, 2H),
3.90 (s, 3H), 0.25 (s, 9H).
4-(1-Hexyn -1-yl)a cetop h en on e (2f)11 was prepared accord-
ing to the preparation of 2c from 995 mg (5.0 mmol) of
J O9808021