Palladium-phosphinous acid-catalyzed Sonogashira cross-coupling reactions in water

Article abstract of DOI:10.1039/b407773c

A palladium-phosphinous acid-catalyzed Sonogashira cross-coupling reaction that proceeds in water under air atmosphere in the absence of organic co-solvents has been developed. Disubstituted alkynes have been prepared in up to 91% yield by POPd-catalyzed

Full text of DOI:10.1039/b407773c

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C O M M U N I C A T I O N
Palladium–phosphinous acid-catalyzed Sonogashira cross-
coupling reactions in water†
Christian Wolf* and Rachel Lerebours
Department of Chemistry, Georgetown University, Washington, DC 20057, USA.
E-mail: cw27@georgetown.edu; Fax: (+1) 202 687 6209; Tel: (+1) 202 687 3468
Received 25thꢀM yyꢁ0ꢂcceA5edpy5tꢃ1ꢄe yyꢁ
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A palladium–phosphinous acid-catalyzed Sonogashira cross-
coupling reaction that proceeds in water under air atmosphere
in the absence of organic co-solvents has been developed.
Disubstituted alkynes have been prepared in up to 91% yield
by POPd-catalyzed coupling of various aryl halides including
chlorides in the presence of tetrabutylammonium bromide and
pyrrolidine or ꢀaOꢁ.
ployment of water-soluble palladium(II) acetate and sulfonated
triphenylphosphine in a water–acetonitrile solution enabled Am-
atore and co-workers to conduct Sonogashira couplings of aryl
iodides under homogeneous conditions.16 It is noteworthy that the
presence of water has been found to be essential to the coupling
reaction of aryl iodides and various alkynoates when using an
amphiphilic polystyrene–poly(ethylene glycol) resin-supported
palladium–phosphine complex.17 Dibowski and co-workers uti-
lized palladium–guanidinophosphane catalysts for the coupling
of water-soluble aryl iodides and terminal alkynes under mild and
Palladium-catalyzed Suzuki, Stille, Hiyama, Negishi, Buchwald–
Hartwig, Kumada and Heck coupling reactions are among the most
1
18
powerful carbon–carbon bond forming reactions. The recent devel-
biocompatible aqueous conditions. Their procedure allowed
opment of highly active palladium complexes bearing bulky, elec-
tron-rich phosphane ligands has allowed chemists to extend these
methods from reactive substrates such as aryl iodides, bromides,
and triflates, to less reactive but inexpensive and readily available
the bioconjugation of peptide derivatives without compromising
their native structure and biological activity. A similar strategy has
recently been employed in the chemoselective coupling of aryl
iodide-functionalized peptides to a trialkyne nucleus under both
2
19
chlorides. Because of the instability of most catalysts and coupling
acidic and basic aqueous conditions.
reagents, cross-coupling reactions are usually carried out in polar
organic solvents under inert and anhydrous conditions. However,
from an environmental and economic standpoint, it is desirable to
avoid any use of hazardous and expensive organic solvents. Water
or aqueous solutions have been recognized as a very attractive me-
dium for organic reactions because solvents do not have to be dried
prior to use, and products can easily be isolated after completion
of the reaction by extraction which greatly facilitates operation.3
Recent efforts to introduce water into cross-coupling reactions
Recently, palladium–phosphinous acid complexes have
been introduced to a variety of C–C bond forming reactions
by us and others.20 We have reported the use of these electron-
rich Pd-complexes in Heck, Stille, and Hiyama couplings and
also in amination and thiation reactions of aryl chlorides and
bromides.21 We also found that palladium–phosphinous acid
complexes exhibit high stability to air and water and afford
22
high yields in Stille coupling reactions in water. Herein, we de-
scribe the usefulness of palladium–phosphinous acid complexes
4
5
6
have resulted in aqueous Suzuki, Buchwald–Hartwig, Stille,
[(t-Bu)
2
P(OH)]
2
PdCl
2
(POPd), [[(t-Bu)
2 2 2
P(OH)(t-Bu) PO)]PdCl]
7
8
9
Hiyama-like, and Heck reactions. Leadbeater recently described
a microwave-assisted Suzuki coupling method using palladium
(POPd1) and [(t-Bu)
2
P(OH)PdCl (POPd2) in Sonogashira cross-
2 2
]
coupling reactions of aryl halides in water (Fig. 1).
1
0
acetate in water.
Sonogashira cross-coupling of terminal alkynes with aryl and
vinyl halides has attracted increasing attention. A variety of aryl
halides including electron-deficient heteroaryl chlorides has
been employed in palladium-catalyzed coupling reactions with
terminal alkynes to afford versatile precursors for the forma-
tion of fused aromatic heterocycles, whereas the coupling of
less reactive electron-rich aryl chlorides remains challenging.11
Typically, the Sonogashira reaction requires inert and anhydrous
reaction conditions and only a few studies using water as an
additive or co-solvent have been reported. Sub-stoichiometric
amounts of water have been found to promote the formation of
symmetrical and unsymmetrical bisarylethynylenes in a modi-
1
2
fied Sonogashira-type coupling reaction. The heterogeneous
cross-coupling of aryl iodides and alkynes using Pd-catalysts
immobilized on mesoporous silica under aqueous conditions has
1
3
been reported to suffer from significant leaching. Kotschy and
co-workers observed that catalyst leaching can be limited to less
than 2% using Pd(0) immobilized on charcoal in CuI-promoted
Sonogashira couplings of aryl halides in aqueous dimethyl
Fig. 1 Structures of POPd, POPd1 and POPd2.
1
4
acetamide. Palladium on carbon has successfully been used to
To investigate the feasibility of aqueous Sonogashira coupling,
we screened the catalytic performance of POPd, POPd1, and
POPd2 in the cross-coupling reaction of 3-bromopyridine, 1,
and phenylacetylene, 2, in the presence of pyrrolidine and tet-
rabutylammonium bromide, TBAB, in water under air without
any organic co-solvents or surfactant additives (Scheme 1). We
did not observe product formation using POPd1 and POPd2 but
obtained alkyne 3 in 80% yield with POPd as the catalyst (Table 1,
catalyze the arylation of N-propargylated amino acids at terminal
1
5
and nonterminal peptide positions in aqueous DMA. The em-
†
Electronic supplementary information (ESI) available: Experimental
procedures and characterization of Sonogashira coupling products.
See http://www.rsc.org/suppdata/ob/b4/b407773c/
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 6 1 – 2 1 6 4
2 1 6 1

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Scheme 1 Aqueous Sonogashira coupling of 3-bromopyridine, 1, and
phenylacetylene, 2.
Table 1 Optimization of the Sonogashira coupling of 1 and 2
Entry
Catalyst
Base
Additives
Yield (%)a
80
1
2
3
4
5
6
7
8
9
POPd
POPd1
POPd2
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
TBAB
TBAB
TBAB
TBAB
TBAB
none
TBAB
TBAB
TBAB
TBAB
TBAB/CuI
TBAB/CuI
b
—
—
60
—
b
c
d
b
—
Cy
2
NMe
10
10
44
10
90
81
2,2,6,6-TMP
NaOAc
Cs CO
2 3
pyrrolidine
NaOH
1
0
1
1
1
2
a
General reaction conditions: 100 mg of 1, 2 equivalents of 2, 10 mol% Pd
Scheme 2 Proposed catalytic cycle of the POPd-catalyzed Sonogashira
coupling.
catalyst, 1.0 equivalent of TBAB in 5 mL of deionized water at 135–140 °C
b
c
for 5 h in a closed vessel. No product formation was observed. 1.5 equiva-
d
lents of 2. Reaction temperature was 100 °C.
the results of the Sonogashira coupling between phenylacetylene
and bromonaphthalenes 4 and 6 (entries 2 and 3). The pyrro-
lidine-promoted Sonogashira coupling reaction procedure did not
result in any alkyne formation with chloroquinolines 12 and 14.
Instead, we found that the amine undergoes nucleophilic aromatic
substitution to form the corresponding 4-pyrrolidinoquinolines.
However, the quinoline-derived alkynes 13 and 15 can be obtained
in 71% and 73% yields, respectively, using aqueous 0.5 M NaOH
entries 1–3). Optimization studies revealed that the coupling reac-
tion requires two equivalents of the terminal alkyne and does not
proceed in the absence of TBAB or at lower temperature (Table 1,
entries 4–6).
We then decided to screen various organic and inorganic bases. In
general, we obtained superior results with pyrrolidine. Replacement
23
2
of pyrrolidine by N-methyldicyclohexylamine (Cy NMe), 2,2,6,6-
(
entries 6 and 7).
tetramethylpiperidine (TMP), sodium acetate or caesium carbonate
resulted in significantly decreased yields of 3 (entries 7–10).
Employing other additives than TBAB in the reaction mixture
is not necessary albeit the yield of 3 further increased to 90% in
the presence of 10 mol% of CuI (entry 11). Interestingly, the CuI-
promoted POPd-catalyzed Sonogashira coupling of 1 and 2 affords
Formation of 5–10% butadiynes derived from terminal alkynes 2
and 17 was observed when CuI was used as a co-catalyst. This may
be attributed to oxidative Glaser coupling, which is a well known
side reaction of Cu(I)-promoted coupling reactions in the presence
of air. Recently, copper-free Sonogashira coupling methods using
24
aryl bromides and iodides have been introduced. We observed
3
in remarkable 81% yield in 0.5 M sodium hydroxide solution
that POPd-catalyzed Sonogashira coupling also proceeds with aryl
chlorides in the absence of CuI albeit with slightly decreased yields
entries 1 and 8).
(entry 12).
It is assumed that reduction and deprotonolysis of the palladium
(
phosphinous acid complex results in the formation of a highly active
anionic Pd(0) complex that undergoes oxidative addition with aryl
halides in water (Scheme 2). Complexation by the terminal acetylene
and subsequent deprotonation gives an intermediate complex that
generates disubstituted alkynes via reductive elimination. Thus,
sodium hydroxide or pyrrolidine fulfil two fundamental functions,
i.e., activation of the catalyst for oxidative addition and alkyne
deprotonation during catalysis.
We applied our optimized coupling procedure to a variety of aryl
halides and alkynes to determine the scope of the POPd-catalyzed
Sonogashira reaction in water (Table 2). Aryl iodides and bromides
were converted to the corresponding alkynes in 70–91% yield (en-
tries 1–5, 9–11). It is noteworthy that nitrile and carbonyl functions
are tolerated under the reaction conditions employed in this study.
We obtained alkynes 9 and 20 from 2-bromobenzonitrile, 8, and
In summary, we have developed a Sonogashira coupling method
that utilizes a palladium–phosphinous acid catalyst in water and
avoids the use of hazardous organic co-solvents. Disubstituted
alkynes have been prepared in good to high yields from aryl chlo-
rides, bromides and iodides with POPd in the presence of TBAB.
Pyrrolidine was found to afford superior results over other organic
and inorganic bases but its use is limited to aryl halides that are not
susceptible to nucleophilic aromatic substitution. Replacement of
pyrrolidine by NaOH avoids amination of chloroquinolines and
thus allows conversion of these electron-deficient aryl chlorides to
alkynes in high yields. The present and previously reported stud-
ies from our laboratories show that POPd combines high catalytic
activity for Stille and Sonogashira cross-coupling reactions with
remarkable stability to air and water. We believe that this catalyst
is also a very promising candidate for developing other C–C bond
forming reactions that proceed in water and thus minimize waste
production and environmental pollution.
3
-bromoacetophenone, 19, in 81% and 70% yield, respectively
(
entries 4 and 10). As expected, 3-chloropyridine, 16, affords lower
yields than its bromo derivative 1 (entries 1 and 8). Introduction
of ortho-substituents to phenylacetylene does not result in lower
yields and we obtained alkyne 18 from 2-methylphenylacetylene,
Acknowledgements
1
7, and 1 in 90% (entry 9). As we had experienced with 3-bromo-
We thank Combiphos Catalysts, Inc., New Jersey
(www.combiphos.com) for POPd, POPd1 and POPd2.
pyridine, 1, replacement of pyrrolidine by NaOH slightly decreases
2
1 6 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 6 1 – 2 1 6 4

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Table 2 Aqueous Sonogashira cross-coupling reactions
Entry
Aryl halide
Alkyne
Product
Yield (%)a
90 (80c)
1
2
3
91(82b)
73(64b)
4
5
81
90(90b)
6
7
71b
73b
b
c
8
9
65 (51 )
90
1
0
70
11
81
a
General conditions: 100 mg of 1, 2 equivalents of the terminal alkyne, 10 mol% POPd, 1.0 equivalent of TBAB, 2 equivalents of pyrrolidine, 10 mol% of CuI
b
c
in 5 mL of deionized water at 135–140 °C for 5 h in a closed vessel. Pyrrolidine was replaced by 0.5 M NaOH. No CuI was added.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 6 1 – 2 1 6 4
2 1 6 3

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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 6 1 – 2 1 6 4