A copper- and amine-free Sonogashira-type coupling procedure catalyzed by oxime palladacycles

Article abstract of DOI:10.1016/S0040-4039(02)02335-3

Oxime palladacycle derived from 4,4′-dichlorobenzophenone was found to promote the Sonogashira reaction of aryl iodides and aryl bromides with terminal acetylenes using 1 equivalent of tetrabutylammonium acetate in organic solvents generally in 1 h at 110

Full text of DOI:10.1016/S0040-4039(02)02335-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9365–9368
A copper- and amine-free Sonogashira-type coupling procedure
catalyzed by oxime palladacycles
Diego A. Alonso, Carmen Na´jera* and Ma6 Carmen Pacheco
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 24 September 2002; revised 14 October 2002; accepted 16 October 2002
Abstract—Oxime palladacycle derived from 4,4%-dichlorobenzophenone was found to promote the Sonogashira reaction of aryl
iodides and aryl bromides with terminal acetylenes using 1 equivalent of tetrabutylammonium acetate in organic solvents generally
in 1 h at 110°C and in high TONs (up to 72000). © 2002 Elsevier Science Ltd. All rights reserved.
Cross-coupling reactions of acetylenes with aryl or
alkenyl halides or triflates in the presence of a palla-
dium salt or complex, copper iodide and an amine, are
extensively used in organic chemistry and materials
science for the preparation of internal alkynes and
enynes.1 Thus, the Sonogashira reaction is used in
numerous syntheses of natural products, for instance,
enediyne antibiotics,2 as well as in the preparation of
liquid crystals, conducting polymers and other engi-
neering materials.3 In order to simplify the Sonogashira
reaction protocol, several important aspects have to be
improved. First, to eliminate the use of copper(I) iodide
as co-catalyst, because it induces homocoupling reac-
tions (Glaser-type reactions) of terminal alkynes to
diynes in the presence of oxygen.4 Second to also avoid,
is the use of the amine. Its presence, either as solvent or
in stoichiometric amounts for the elimination of the
HX formed in the reaction, seems vital but largely
depends on the type of substrates to be coupled. Fur-
thermore, and from an economical point of view, to
employ lower catalyst loadings, which is a very impor-
tant feature because of the high loadings (1–5 mol%)
usually required when typical catalysts such as
Pd(PPh3)2Cl2, Pd(PPh3)4 or Pd2(dba)3 are employed.
Another facet to improve is the ability to perform this
reaction in air using reagent-grade chemicals and
solvents.
Copper-free methodologies have recently been
described employing amines as solvents as in the case of
palladium(0) complexes such as Pd(PPh3)4 in piperidine
or pyrrolidine.5 The only example using a palladacycle6
in a copper-free protocol, is Herrmann%s phospha-pal-
ladacycle which is performed in triethylamine and only
worked with phenylacetylene as sp counterpart.7 On the
8
other hand, the catalytic system Pd2(dba)3 promotes
the copper-free Sonogashira reaction of aryl bromides
at room temperature,9 but the air-unstable tris-tert-
butylphosphane has to be used as co-catalyst. Stoichio-
metric amounts of silver(I) oxide for aryl iodides, and
tetrabutylammonium fluoride (TBAF) or tetra-
butylammonium hydroxide (TBAOH)10 for aryl bro-
mides, have been used as activators in the first
described copper- and amine-free procedure.11 Very
recently, phenylacetylene has been coupled with aryl
chlorides under harsh conditions in the presence of
ZnCl2 as additive and Cs2CO3 as base, employing 5
mol% of the phosphinito palladium pincer complex
PdCl[C6H3(OPPri2)2-2,6].12
Scheme 1.
Keywords: alkynes; coupling reactions; palladium catalysis.
* Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02335-3

9366
D. A. Alonso et al. / Tetrahedron Letters 43 (2002) 9365–9368
Table 1. Sonogashira coupling: reaction conditions study
Entry
Solvent
Base
Additive (mol%)
T (°C)a
1 (mol% Pd)
tR (h)
Yield (%)b
TONc
1
2
3
4
5
6
7
8
Pyrrolidine
NMP
NMP
NMP
NMP
NMP
NMP
NMP/H2O: 95/5
THF
NMP
–
CuI (5)
–
–
–
TBAF (150)
TBAOH (150)
TBAOAc (150)
TBAOAc (110)
TBAOAc (110)
TBAOAc (110)
TBAOAc (110)
TBAOAc (110)
90
110
110
110
110
110
110
110
0.5
0.5
0.5
0.5
0.5
0.1
0.1
0.1
1
1
1
3.5
3
3
2
1
5
4
84
96
168
192
72
58
172
–
990
990
890
990
9700
72000
Pyrrolidine
NaOAc
NH4OAc
36d
29d
86d
0
–
–
–
–
–
–
–
–
\99
\99
89
\99
97
e
9
–
0.1
10
11
12
80
110
110
0.1
NMP
NMP
10−2
10−3
24
24
72
a Bath temperature.
b Conversion determined by GC using decane as internal stardard and based on starting 1-chloro-4-iodobenzene.
c TON (turnover number)=mol product mol Pd−1
.
d Several non-identified enyne by-products were also obtained in variable yields as a result of the addition of the terminal alkyne to the reaction
product.
e Under THF reflux.
We have recently reported that oxime-based palladacy-
cles are air and water stable precatalysts for a wide range
of cross-coupling processes such as Heck, Suzuki, Stille,
Sonogashira and Ullmann-type reactions in organic13
and aqueous14 solvents. In the preliminary studies of the
Sonogashira reaction,13a we performed the coupling of
phenylacetylene and iodobenzene in the presence of CuI
and pyrrolidine as solvent at 90°C. We have found that
this alkynylation process can be performed under very
convenient copper- and amine-free conditions in air and
using reagent-grade chemicals.
good yields could be obtained when the catalyst loading
was reduced to 10−3 mol% of Pd (Table 1, entry 12).
Using these conditions,16 complex 1 catalyzed the Sono-
gashira coupling of a wide variety of aryl iodides and
bromides and terminal acetylenes (Scheme 2, Table 2).
Yields were generally high after short reaction times for
all type of substrates. Activated substrates such as
1-chloro-4-iodobenzene and 1-chloro-4-bromobenzene
reacted with an array of aromatic and aliphatic alkynes
in good to excellent yields (Table 2, entries 1–5 and
10–11). As illustrated in entries 7, 8, 15 and 16, less
reactive electron-rich 4-iodoanisole, 4-bromotoluene and
4-bromoanisole, also coupled with fairly good efficiency.
Steric effects as in 2-iodotoluene and 2-bromobenzoni-
trile (Table 2, entries 9 and 14), did not influence the
yield. 9-Bromoanthracene, reacted with phenylacetylene
and (triisopropylsilyl)acetylene to afford, in high yields,
the corresponding 9-alkynylanthracenes with no observ-
able formation of aceanthrylenes.17
The alkynylation reaction of aryl halides was evaluated
with palladium complex 115 (Scheme 1). In order to
determine the optimum reaction conditions, we chose the
coupling between 1-chloro-4-iodobenzene and phenyl-
acetylene in the presence of catalyst 1 (0.1–0.5 mol% of
Pd) as a model reaction (Scheme 1, Table 1). As
previously reported,13a the coupling reaction between
1-chloro-4-iodobenzene and phenylacetylene, provided a
good yield when pyrrolidine was used as solvent in the
presence of CuI as co-catalyst (5 mol%) at 90°C under
air using 0.5 mol% of Pd (Table 1, entry 1). When using
N-methylpyrrolidinone (NMP) as solvent and 2 equiv. of
pyrrolidine as base in the absence of CuI at 110°C (Table
1, entry 2), an excellent yield was obtained. Because of
this result, we carried out a base study, which showed
that inorganic bases such as NaOAc and NH4OAc only
led to poor reaction yields. Other bases such as TBAF,
gave an acceptable 86% yield after 3 h. Aqueous TBAOH
did not promote the reaction coupling at all (Table 1,
entries 5 and 6). However, tetrabutylammonium acetate
(TBAOAc) showed the best activity even when the
catalyst loading was reduced to 0.1 mol% of Pd (Table
1, entry 7). The presence of small amounts of water did
not have a deleterious effect in the reaction yield (Table
1, entry 8). Changing the solvent from NMP to THF
under reflux, resulted in a lower yield and longer reaction
times (entry 9). The reaction could be carried out at lower
temperature (80°C) and using 1.1 equiv. of TBAOAc as
well (entry 10), and high TON accompanied with very
In summary, we have shown that the phosphane-free
oxime-derived palladacycle 1, is an efficient and versatile
catalyst for amine- and copper-free Sonogashira reac-
tions of aryl iodides and aryl bromides with a variety of
terminal acetylenes. The catalyst system is highly active
using very low loading conditions, under air and employ-
ing reagent-grade chemicals. Further studies to extent to
other substrates this reaction protocol and to understand
the mechanism of the process are currently under inves-
tigation in our group. This study provides further evi-
dence of the usefulness of oxime-derived palladacycles in
palladium-catalyzed reactions.
Scheme 2.

D. A. Alonso et al. / Tetrahedron Letters 43 (2002) 9365–9368
9367
Table 2. Sonogashira coupling or aryl halides catalyzed by 1
Acknowledgements
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This work has been supported by the Direccio´n Gen-
eral de Investigacio´n of the Ministerio de Ciencia y
Tecnolog´ıa (MCyT) (BQU2001-0724-CO2-01). D.A.A.
thanks MCyT for a contract under the program Ramo´n
y Cajal. M.C.P. thanks Generalitat Valenciana for a
predoctoral fellowship.
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15. Other palladacycles developed in our group derived from
benzophenone, acetophenone, pinacolone and 4,4%-
dimethoxybenzophenone, gave very similar results.
16. Typical experimental procedure: A solution containing
palladium catalyst 1 (0.1 mol% of Pd, 2.5×10−4 mmol,