Palladium catalyzed alkynylation of aryl halides (Sonogashira reaction) in water

Article abstract of DOI:10.1016/j.tetlet.2004.09.131

The palladium catalyzed alkynylation of aryl halides (Sonogashira reaction) has been achieved in pure water without any additives or phase transfer catalysts. The reaction, which requires only 0.5 mol % of Pd(PPh ₃)₄ catalyst, is rem

Full text of DOI:10.1016/j.tetlet.2004.09.131

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8733–8736
Palladium catalyzed alkynylation of aryl halides
(Sonogashira reaction) in water
Santanu Bhattacharyaa,* and Saumitra Senguptab,*
aDepartment of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
bDepartment of Chemistry, Jadavpur University, Kolkata 700 032, India
Received 5 July 2004; revised 13 September 2004; accepted 20 September 2004
Available online 7 October 2004
Abstract—The palladium catalyzed alkynylation of aryl halides (Sonogashira reaction) has been achieved in pure water without any
additives or phase transfer catalysts. The reaction, which requires only 0.5mol% of Pd(PPh3)4 catalyst, is remarkably fast (30min at
70°C) producing high yields of the aryl alkyne products.
Ó 2004 Elsevier Ltd. All rights reserved.
The palladium catalyzed coupling of vinyl or aryl ha-
lides with terminal acetylenes (the Sonogashira reaction)
is a powerful synthetic tool for the preparation of substi-
tuted acetylenes.1 The reaction which normally requires
a co-catalyst such as CuI has found widespread applica-
tion in natural product synthesis, organic materials
science and in the construction of various functional
macromolecules including dendrimers and conducting
polymers.2 Several modifications of the original Sono-
gashira protocol have been developed during the last
few years, prominent among which are the phase trans-
fer3 and copper-free conditions,4 and the use of more
active catalyst systems, including those having N-
heterocyclic carbene (NHC) ligands for reaction with
the less reactive bromo- and chloroarenes.5 The effect
of different solvents has also been probed6 including
aqueous–organic solvent mixtures in the presence of
water soluble phosphine ligands7 and ionic liquids.8
effect9a resulting in faster and cleaner reactions. Con-
trary to earlier belief, a number of Pd-catalyzed reac-
tions have been successfully carried out in pure water,
some of which even showed rate accelerating effects.
Although there are a few reports of Sonogashira cou-
plings in aqueous–organic solvent mixtures using Pd-
catalysts ligated with water soluble sulfonated phos-
phines,7 there are no reports on Sonogashira reactions
being carried out in pure water.10 Arecent paper, how-
ever, has described the alkynyl coupling and subsequent
cyclization of ortho-iodophenols to benzofurans in
water,11 perhaps aided by the enhanced solubility of
the phenolic substrates in water in the presence of base.
In continuation of our interest in aqueous Pd-catalyzed
reactions,12 we now report that Sonogashira reactions of
aryl iodides and bromides can indeed be carried out in
pure water without the need of any organic co-solvent
or additives such as phase transfer catalysts or water sol-
uble phosphine ligands.
Driven by environmental concerns, in recent years,
much attention has been paid towards using water as
solvent for organic and organometallic reactions.9 Apart
from being cheap, safe and environmentally benign,
water has a high dielectric constant and density so that
reactions involving water insoluble substrates when car-
ried out in water often benefit from the hydrophobic
Initial screening of the reaction conditions using iodo-
benzene and phenyl acetylene as the coupling partners
revealed that Pd(PPh3)4 was the best catalyst for this
reaction. Only 0.5mol% of this catalyst was sufficient
to induce the coupling reaction. PdCl2(PPh3)2 was less
effective in this regard whereas PdCl2 did not produce
any coupling product at all. Various bases, for example,
Et3N, DIEAor even aqueous ammonia can be used in
this reaction. However, the reaction is much cleaner in
the presence of the former two organic bases, of which
we chose DIEAfor its low volatility. The reaction rate
was found to be temperature dependent. While it took
2.5h for completion at room temperature (90% yield
Keywords: Sonogashira reaction; Palladium; Water; Aryl halides;
Alkynylation.
*
Corresponding authors. Tel.: +91 033 4734266; fax: +91 033
24146266; e-mail addresses: sb@orgchem.iisc.ernet.in; jusaumitra@
yahoo.co.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.131

8734
S. Bhattacharya, S. Sengupta / Tetrahedron Letters 45 (2004) 8733–8736
detected by TLC analysis. Under the optimized condi-
0.5% Pd(PPh3)4, 1% CuI
base, H2O, 70oC, 30 min
tions [0.5% Pd(PPh3)4, 1% CuI, DIEA(1.5equiv),
H2O, 70°C, 30min] (Scheme 1), a number of terminal
acetylenes reacted with iodobenzene to produce excel-
lent yields of the substituted phenyl acetylene derivatives
(Table 1, entries 1, 3 and 4). Interestingly, the coupling
reaction between iodobenzene and phenyl acetylene
can also be carried out without CuI. However, this
resulted in a reduced product yield (entry 2). It is worthy
of note that 1-hexyne, a water insoluble and less reactive
acetylene, reacted efficiently under these conditions to
produce the coupling product 2 in an excellent yield
(entry 3).
Ar
R
Ar-X +
X = I, Br
R
(75-92%)
Base = DIEA (for X = I)
pyrrolidine (for X = Br)
Scheme 1. Sonogashira reaction of aryl halides in water.
of diphenyl acetylene 1), the reaction time can be
shortened (20–30min) by raising the reaction tempera-
ture to 70°C without any compromise in product yield.
At this temperature, the reaction is so facile that it does
not even require strict adherence to anaerobic
conditions.
However, the reaction of bromobenzene with phenyl
acetylene under the above conditions was not efficient
and afforded only an 18% yield of diphenyl acetylene
even after 3h at 70°C (Table 1, entry 5). Since bromo-
arenes are cheaper and more readily available than
iodoarenes and hence are synthetically more useful as
educts, we explored a variety of reaction conditions in
order to induce bromobenzene into this coupling mani-
fold. Increased catalyst loading (up to 5mol%), higher
reaction temperatures (reflux) or the use of excess phe-
nyl acetylene did not lead to any significant improve-
The reaction is truly heterogeneous since two distinct
layers could be observed throughout the course of the
reaction. Hence, hydrophobic effects9a appear to be
quite pronounced in this reaction and could be the
major contributing factor to its facile reaction rate.
Notably, the addition of an organic co-solvent such as
DMF (DMF/H2O 9:1) greatly retarded the rate of the
reaction and led to the appearance of side products as
Table 1. Sonogashira reaction of aryl halides in water (Scheme 1)
Entry
1
ArX
Acetylene
Basea
A
Product
Yield (%)
92
I
I
Ph
1
1
2
A
62b
Ph
C4H9-n
OH
3
4
A
A
87
88
I
I
C4H9-n
OH
2
3
5
6
A
B
18c
82
Br
Br
Ph
Ph
1
1
CH2OH
(CH2)2OH
C4H9-n
7
8
CH2OH
B
B
80
75
Br
4
Me
Me
Br
(CH2)2OH
5
CHO
CHO
Br
C4H9-n
(CH2)4OH
Ph
9
B
B
B
85
6
(CH ) OH
2 4
Br
10
11
80
7
MeO
MeO
Br
20c
8
a A: diisopropylethylamine, B: pyrrolidine.
b Without CuI.
c A t 70°C for 3h.

S. Bhattacharya, S. Sengupta / Tetrahedron Letters 45 (2004) 8733–8736
8735
ment in the coupling yield. Addition of a cationic
References and notes
surfactant such as cetyltrimethylammonium bromide
(20mol%) to the reaction mixture did not show any
beneficial effect.10b,c However, by changing the base to
pyrrolidine,6a bromobenzene could be smoothly coupled
with phenyl acetylene resulting in a high yield of diphe-
nyl acetylene 1 (82%, entry 6). Under these modified
conditions, a number of different bromoarenes and
terminal acetylenes reacted smoothly to produce the
coupling products 4–7 in high yields (entries 7–10).
Apparently, there is not much of a steric effect in these
reactions since o-bromotoluene easily coupled with
homopropargylic alcohol to produce the corresponding
coupling product 5 in 75% yield (entry 8). The reaction
also showed excellent functional group tolerance as evi-
dent from the successful coupling of o-bromobenzalde-
hyde with 1-hexyne to give 6 in high yield (entry 9).
This particular result is quite significant since aqueous
organometallic reactions of aldehyde bearing educts
are usually problematic due to the competing Cannizaro
reaction of such substrates in water.10a However, with a
highly electron rich substrate such as p-bromoanisole,
only a 20% yield of the coupling product 8 could be iso-
lated after 3h at 70°C (entry 11). Apart from unreacted
starting materials, no other side products (Glaser-type
homocoupling products) could be detected in these reac-
tions. Evidently, as observed by others,13 the strong
electron donating effect of the p-OMe group greatly
retarded the rate of this reaction.
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In conclusion, we have shown that Sonogashira reac-
tions of water insoluble aryl iodides and bromides
can be carried out in water alone with as low as
0.5mol% of Pd(PPh3)4 as the catalyst. The reaction is
facile at 70°C requiring only 30min for completion
and produced high to excellent yields of the coupling
products. We have also shown that steric effects are
minimum in these reactions and sensitive functionalities
like an aldehyde group can be tolerated. The choice of
the base is crucial, especially in the case of aryl
bromides.
Representative experimental procedure: Around bottom
flask fitted with a reflux condenser was charged with the
aryl halide (1.0mmol), terminal acetylene (1.5–2mmol),
DIEA(for aryl iodides) or pyrrolidine (for aryl bro-
mides) (1.5mmol), Pd(PPh3)4 (0.5mol%) and CuI
(1mol%) in water (5mL). It was then immersed in an
oil bath kept at 70°C. After vigorous stirring for
30min (the reaction darkened in colour), it was cooled
to room temperature and extracted with ether. The com-
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under reduced pressure. Silica-gel chromatography of
the residue produced the coupling products.14
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Acknowledgements
S.S. thanks the Department of Organic Chemistry,
Indian Institute of Science, Bangalore for an OC-ICOS
Visiting Fellowship and Professor A. Srikrishna and
Dr. K. R. Prasad for laboratory facilities.

8736
S. Bhattacharya, S. Sengupta / Tetrahedron Letters 45 (2004) 8733–8736
9. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b) Li, C.-J.
d7.32–7.38 (6H, m), 7.51–7.55 (4H, m); 13C NMR
(75MHz, CDCl3): d 89.3 (Cq), 123.2 (Cq), 128.2 (CH),
128.3 (CH), 131.5 (CH). 2: colourless oil; 1H NMR
(300MHz, CDCl3): d 0.94 (3H, t, J = 7.2Hz), 1.44–1.63
(4H, m), 2.40 (2H, t, J = 7Hz), 7.25–7.30 (3H, m), 7.37–
7.40 (2H, m); 13C NMR (75MHz, CDCl3): d 13.6 (CH3),
19.0 (CH2), 22.0 (CH2), 30.8 (CH2), 80.5 (Cq), 90.3 (Cq),
124.0 (Cq), 127.4 (CH), 128.1 (CH), 131.5 (CH). 5:
colourless oil; 1H NMR (300MHz, CDCl3): d 2.41 (3H,
s), 2.72 (2H, t, J = 6Hz), 3.81 (2H, t, J = 6Hz), 7.04–
7.20 (3H, m), 7.37 (1H, d, J = 7.2Hz); 13C NMR
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(75MHz, CDCl3):
d 20.6 (CH3), 23.8 (CH2), 61.2
(CH2), 81.2 (Cq), 90.1 (Cq), 123.0 (Cq), 125.4 (CH),
127.8 (CH), 129.3 (CH), 131.8 (CH), 139.9 (Cq). 6:
colourless oil; 1H NMR (300MHz, CDCl3): d 0.96 (3H,
t, J = 7Hz), 1.45–1.69 (4H, m), 2.49 (2H, t, J = 6.9Hz),
7.35–7.40 (1H, m), 7.50–7.52 (2H, m), 7.88 (1H, d,
J = 7.8Hz), 10.5 (1H, s); 13C NMR (75MHz, CDCl3): d
13.5 (CH3), 19.2 (CH2), 22.0 (CH2), 30.5 (CH2), 76.2
(Cq), 98.1 (Cq), 126.8 (CH), 127.8 (CH), 127.9 (Cq),
133.2 (CH), 133.6 (CH), 135.9 (Cq), 192.2 (CH). 7:
colourless oil; 1H NMR (300MHz, CDCl3): d 1.65–1.74
(4H, m), 2.23 (1H, s, OH), 2.45 (2H, t, J = 6.6Hz), 3.66
(2H, t, J = 6Hz), 7.37–7.45 (3H, m), 7.69–7.76 (3H, m),
7.89 (1H, s); 13C NMR (75MHz, CDCl3): d 19.1 (CH3),
24.9 (CH2), 31.7 (CH2), 62.1 (CH2), 81.1 (Cq), 90.2 (Cq),
121.0 (Cq), 126.1 (CH), 126.2 (CH), 127.4 (CH), 127.5
(CH), 127.7 (CH), 128.5 (CH), 130.9 (CH), 132.3 (Cq),
132.9 (Cq).
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14. Physical and spectral data of some selected coupling
1
products—1: mp 55–56°C; H NMR (300MHz, CDCl3):