LETTER
549
Low Temperature Sonogashira Coupling Reaction
Keiichi Nakamura, Hitoshi Okubo, Masahiko Yamaguchi*
Faculty of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan
Fax +81 (22) 2176811; E-mail: yama@mail.pharm.tohoku.ac.jp
Received 4 February 1999
Methyl p-iodobenzoate was treated with 1.1 mole equiva-
lents of m-methoxyphenylacetylene in DMF/i-Pr2NEt
(20:1) in the presence of 2.5 mol% of Pd2(dba)3
(dba = dibenzylideneacetone), 30 mol% of CuI, 200
mol% of n-Bu4NI, and 20 mol% of additives at -20 °C for
20 min (Table 1). While 41% yield of the coupling prod-
uct was obtained under the conditions (entry 1) no reac-
tion occurred in the absence of n-Bu4NI (entry 2). Thus,
the ammonium salt turned out to be essential for the low
temperature coupling reaction.3 Other iodides such as (n-
C8H17)4NI, Et4NI, or BnEt3NI were less effective. Effect
of ligands which are capable to coordinate with palladium
metal was then examined for the further acceleration.
While triphenylphosphine was not effective (entry 3), in-
troduction of methyl group at the ortho-position improved
the yield (entries 4 and 5). It was finally found that the use
of 20 mol% of a hindered triarylphosphine, tris(2,4,6-tri-
methylphenyl)phosphine, gave the product in quantitative
yields in 20 min (entry 6). The yield decreased when 10
mol% of the phosphine was used (entry 7). Phosphine ox-
ide was another good promoter (entry 8). It may be inter-
esting to note that phenols also effectively promoted the
coupling reaction (entries 9-14).5 The substituent effect on
the phenol ring appeared to be relatively unimportant. In
all these reactions, purification of CuI6 was critical to ob-
tain reproducible results.
Abstract: A low temperature Sonogashira reaction was developed,
which coupled equimolar amount of aryl iodide possessing elec-
tron-withdrawing groups with aromatic acetylene at -20 °C in quan-
titative yield.
Key words: Sonogashira coupling reaction, n-Bu4NI,
tris(2,4,6trimethylphenyl)phosphine, aryl iodide
Sonogashira coupling reaction is a well-established meth-
od which couples terminal acetylene and aromatic halides
or triflates.1 The reaction is catalyzed by palladium/cop-
per complex in the presence of amine base, and is gener-
ally conducted at room temperature or higher
temperature.2,3 During our investigations on the synthesis
of macrocyclic acetylenic compounds possessing helicene
unit4 we needed a rapid Sonogashira coupling reaction
which can be used for the effective macrocyclization. De-
scribed here is a new protocol, which gives diarylacet-
ylenes quantitatively at -20 °C.
Table 1. Effect of Additives on the Sonogashira Coupling Reaction.
OMe
+
HC
C
MeO2C
1.0 mol eq
I
1.1 mol eq
2.5 mol% Pd2(dba)3, 20 mol% CuI
20 mol% additive, 200 mol% n-Bu4NI
DMF/i-Pr2NEt (20:1), -20 °C, 20 min
The coupling reaction of several aryl iodides possessing
electron-withdrawing groups and arylacetylene either un-
der the phosphine conditions (Method A) or phenol con-
ditions (Method B) gave the corresponding
diarylacetylene in quantitative yield (Table 2). The orga-
nopalladium species appeared to be more stabilized under
the Method A conditions than under the Method B condi-
tions, and formation of palladium black was suppressed in
the former. In some cases, however, the coupling reaction
proceeded more rapidly under the phenol conditions. The
reaction completed in most cases within 60 min at -20 °C
using approximately equimolar amounts of the substrates.
The reaction of several reactive aryl iodides took place
even at -50 °C. The catalysts load could be decreased as
much as 0.1 mol%. Dimeric acetylene which was often
the serious byproduct in the Sonogashira reaction was not
detected under the present conditions. Biscoupling reac-
tion of decyl 3,5-diiodobenzoate using 2.1 mol equiva-
lents of an arylacetylene is shown in Scheme 1, which also
demonstrated the effectiveness of the present coupling
method. Effect of the substituents on the arylacetylene
was small, and those with electron-withdrawing and elec-
tron-donating groups gave the product in high yields. In
OMe
MeO2C
C
C
Synlett 1999, No. 5, 549–550 ISSN 0936-5214 © Thieme Stuttgart · New York