Solvent-less and fluoride-free Hiyama reaction of arylsiloxanes with aryl bromides and chlorides promoted by sodium hydroxide: A useful protocol for palladium recycling and product isolation

Article abstract of DOI:10.1002/adsc.200505494

Palladium salts and oxime-derived pallada-cycles catalyze the cross-coupling reaction of arylsiloxanes with aryl bromides and chlorides in low catalyst loading (0.001-0.1 mol % of Pd) under fluoride-free conditions to provide biaryls and heterobiaryls. For some deactivated aryl bromides and for aryl chlorides, the corresponding cross-couplings need TBAB as additive. Concentrated aqueous sodium hydroxide (50%) promoted this Hiyama reaction in practically the absence of solvents under air in good yields. The process can be performed at 120°C either under heating in a pressure tube or under microwave irradiation. This protocol allows palladium recycling and facilitates the final isolation of the products simply by ether extraction.

Full text of DOI:10.1002/adsc.200505494

FULL PAPERS
DOI: 10.1002/adsc.200505494
Solvent-Less and Fluoride-Free Hiyama Reaction of
Arylsiloxanes with Aryl Bromides and Chlorides Promoted by
SodiumHydroxide: A Useful Protocol for PalladiumRecycling
and Product Isolation
´
Emilio Alacid, Carmen Najera*
´
´
Departamento de Química Organica , Facultad de Ciencias and Instituto de Síntesis Organica (ISO),
Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Fax: (þ34)-965-903-549, e-mail: cnajera@ua.es
Received: December 27, 2005; Accepted: March 23, 2006
Abstract: Palladium salts and oxime-derived pallada- practically the absence of solvents under air in good
cycles catalyze the cross-coupling reaction of arylsil- yields. The process can be performed at 1208C either
oxanes with aryl bromides and chlorides in low cata- under heating in a pressure tube or under microwave
lyst loading (0.001–0.1 mol % of Pd)under fluoride-
irradiation. This protocol allows palladium recycling
free conditions to provide biaryls and heterobiaryls. and facilitates the final isolation of the products sim-
For some deactivated aryl bromides and for aryl ply by ether extraction.
chlorides, the corresponding cross-couplings need
TBAB as additive. Concentrated aqueous sodium hy- Keywords: arylsiloxanes; biaryls; cross-coupling; mi-
droxide (50%)promoted this Hiyama reaction in
crowave heating; palladacycles
Introduction
ble and accessible compounds, being inexpensive and
commercially available. In general, all the couplings
Aryl-aryl cross-coupling reactions catalyzed by transi- with organosilicon compounds are promoted by fluoride
tion metals constitute fundamental transformations in anion, usually TBAF, by formation of the corresponding
organic chemistry. Several reactions, such as the Kuma- hypervalent fluorosilicate. Recently, it has been found
da, Negishi, Stille, Suzuki and Hiyama couplings can be that arylhalosilanes,[9] silicone,[10] and aryltrimethoxysi-
used for this carbon-carbon bond forming process.[1] lane[11] can be coupled with aryl halides using inorganic
This strategy gives rise to biaryls and heterobiaryls, moi- bases, such as KOH, NaOH, and K2CO3 in water as sol-
eties widely present in numerous classes of organic com- vent under fluoride-free conditions. However, under
pounds, such as natural products, pharmaceuticals, agro- these reaction conditions high catalyst loadings are usu-
chemicals and ligands for asymmetric synthesis and in ally required and in our hands the in situ polymerization
new materials, such as liquid crystals.[2] The palladium- of alkoxysilanes complicates the isolation of the final
catalyzed cross-coupling of organosilicon compounds product.
with organic halides has become the best alternative to
The oxime-derived palladacycles 1 and 2 have shown
the use of tin reagents from an environmental point of high catalytic activity in carbon-carbon bond forming
view. In addition, silicon compounds are more stable reactions either in organic or in aqueous solvents.[12–14]
than organomagnesium and organozinc reagents. Orga- The 4-hydroxyacetophenone oxime-derived palladacy-
nosilanes are becoming popular for industrial purposes, cle (1)has shown a good catalytic activity in aqueous
whereas organoboron compounds are difficult to purify media for Heck[12] and Suzuki[12] reactions in aqueous
and some are unstable, losing boron readily to give ho- media. The 4,4’-dichlorobenzophenone oxime-derived
mocoupling products.
palladacycle (2)shows an excellent catalytic activity in
Several types of silicon reagents have been used, such Heck, Suzuki, Rossi, Sonogashira, Glaser, and sila-So-
as arylhalosilanes,[3] aryl(halo)silacyclobutanes,[4] aryl- nogashira reactions and also for the acylation of alkynes
(triallyl)silanes,[5] aryl(dimethyl)silanols,[6] arylbis(cate- in organic solvents. The catalytic activity of 1 and 2 is
[7]
chol)silicates,
and aryl(trialkoxy)silanes.[8] Among based on the slow generation of palladium nanoparticles
these types of organosilanes, alkoxysilanes are very sta- which are the real catalyst, these complexes acting as a
Adv. Synth. Catal. 2006, 348, 945 – 952
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Emilio Alacid, Carmen Najera
FULL PAPERS
these reaction conditions the isolation of the product
was rather troublesome due to the formation of emul-
sions complicating the extractive work-up. Therefore
the reaction was performed without solvent, just with
2.5 equivs. of 50% NaOH in a pressure tube at 1208C
(Table 1). Under these reaction conditions the efficien-
cy of Pd(OAc)2, PdCl2, Pd on carbon, and palladacycles
1 and 2 with a loading of 0.1 mol % of Pd was evaluated
(Table 1, entries 1–5). The two former salts were effi-
cient catalysts for the cross-coupling reaction, whereas
Figure 1. Oxime-derived palladacycles 1 and 2.
source of very active Pd(0).[15] We report the develop- in the case of Pd/C only the homocoupling products of
ment of a simple and practical protocol which allows 4-bromoanisole and anisole were obtained even with
the cross-coupling of aryltrimethoxysilanes with aryl 0.5 mol % of Pd. Palladacycle 2 gave the highest yield
bromides and chlorides promoted by concentrated (95%)of compound 5aa, which was isolated by adding
NaOH using a very low loading of palladacycles and li- ether to the reaction mixture. The polar phase could
gand-free Pd salts as catalysts under solvent-less and flu- be reused several times for new coupling reactions as de-
oride-free conditions. This procedure allows not only an scribed below. This coupling was also performed under
easy isolation of the final product but also the reuse of an argon atmosphere giving product 5aa in similar yield
the catalyst.
after 3 h reaction time (Table 1, compare entries 5 and
6). The loading of palladacycle 2 could be reduced until
0.005 mol % to provide product 5aa in 91% yield in the
Results and Discussion
same reaction time with an estimated TOF of 3033 hꢀ1
.
The same process was carried out under microwave irra-
Initial studies were performed with the deactivated aryl diation to afford product 5aa in 86% yield in 10 min with
bromide, 4-methoxybromobenzene (3a, 1 mmol)and
phenyltrimethoxysilane (4a, 1.5 mmol)in water
(2 mL)with NaOH (2.5 mmol)under microwave heat-
an estimated TOF up to 51600 hꢀ1 (Table 1, entries 7
and 8). Some inorganic bases including KOH and K2
CO3, which were active for the Suzuki couplings,[12c, d]
ing.[16] In the presence of palladacycle 1 or Pd(OAc)2 were investigated and only KOH gave similar results
(0.1 mol % Pd)as catalysts, 4-methoxybiphenyl ( 5aa) than NaOH (Table 1, entries 9 and 10). In addition, oth-
was obtained in 55 or 40% yield, respectively (1208C, er siloxanes, such as phenyltriethoxysilane (4b)and sili-
80 W, 10 min irradiation time).[17] The same reaction cone (4c)could alternatively be used, although in the
was performed under conventional heating during 4 h, case of silicone only moderate yield of product 5aa
affording product 5aa in similar yields. However, under was obtained (Table 1, entries 11 and 12). The formation
Table 1. Hiyama coupling of arylsiloxanes with 4-bromoanisole: reaction conditions study.[a]
[c]
Entry
Arylsiloxane
Cat. [mol% Pd]
Base
t
Yield [%][b]
TON
TOF [hꢀ1
]
1
2
3
4
5
6
7
8
9
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OMe)3
PhSi(OEt)3
Ph(MeSiO)n
Pd(OAc)2 (0.1)50% NaOH
PdCl2 (0.1)50% NaOH
Pd/C (0.5)50% NaOH
3 h
57
570
190
3 h
3 h
57
–
570
190
–
[d]
–
1 (0.1)50% NaOH
2 (0.1)50% NaOH
2 (0.1)50% NaOH
2 (0.01)50% NaOH
2 (0.01)50% NaOH
2 (0.1)50% KOH
2 (0.1)K
3 h
3 h
3 h
3 h
10 min
3 h
78
95
780
950
96
3033
86
260
316
960
[e]
320
51600
–
91 (98130)0
[f]
8600
260
72
3 h
93
61
720
–
10
11
12
2CO3
3 h
–
2 (0.1)50% NaOH
2 (0.1)50% NaOH
930
610
310
203
3 h
[a]
Reaction conditions: 4-bromoanisole (1 mmol), siloxane (1.5 mmol), cat. (see column), and base (2.5 mmol) were heated in
a pressure tube at 1208C.
[b]
Of compound 5aa, determined by 1H NMR using N,N-diphenylformamide as internal standard. In parenthesis isolated yield
after flash chromatography.
Estimated values.
42% of the homocoupled product 4,4’-dimethoxybiphenyl was obtained.
Under argon.
Under microwave heating at 1208C (80 W).
[c]
[d]
[e]
[f]
946
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Solvent-Less and Fluoride-Free Hiyama Reaction of Arylsiloxanes
FULL PAPERS
vated aryl bromides, such as 2-bromotoluene (3 g)and
2-bromothiophene (3 h), the presence of TBAB im-
proved the conversions and the reaction rates either un-
der heating or under microwave irradiation using
0.1 mol % of Pd to afford products 5ga and 5ha in
good yields (Table 2, entries 15–18). Under similar re-
action conditions (E)-styryl bromide gave stereospecifi-
cally (E)-stilbene in good yields (Table 2, entries 19 and
20).
The stability of complex 2 during the Hiyama cross-
coupling reaction and the reusing of the active catalytic
species was studied in the arylations of phenyltrime-
Scheme 1.
of Pd black in the reaction mixture was observed in all thoxysilane with 4-bromoanisole and 4-bromoaceto-
these experiments. A 3% leaching of palladium in the phenone using palladacycle 2 (0.05 mol %)at 120 8C
crude product 5aa was found by ICP-OES analysis in during 3 h and 1 h, respectively (Table 3). After extrac-
the case of the cross-coupling catalyzed by palladacycle tion of the corresponding products, fresh reagents were
2 (Table 1, entry 5).
added to the residue and the catalytic cycle was run for
The optimized reaction conditions were chosen for 3 h and 1 h, respectively, and in general good conver-
the Hiyama cross-coupling reactions of different aryl sions were obtained during 5 consecutive catalytic cy-
and vinyl bromides 3 with aryltrimethoxysilanes 4. cles.
Thus, heating these reagents and palladacycle 2 at
Cross-couplings of different chloroarenes 6 with silox-
1208C in the presence of 2.5 equivs. of 50% aqueous anes 4 to give biphenyls 5 were performed with catalyst 2
NaOH afforded products 5 which were isolated by ex- in the presence of TBAB (0.5 equivs.)and aqueous 50%
traction with ether (Scheme 2 and Table 2). The cou- NaOH as base (Scheme 3 and Table 4). Initial studies
pling of activated 4-bromoacetophenone (3b)with phe-
nyltrimethoxysilane (4a)was carried out similarly as
about the loading of Pd for the coupling between phe-
nyltrimethoxysilane (4a)and 4-chloroanisole ( 6a)
with 4-bromoanisole, either under heating in a pressure showed that higher yields could be obtained with
tube during 1 h or under microwave irradiation during 1 mol % of Pd under thermal conditions (Table 4, en-
10 min (Table 2, entries 1–4). This coupling could also tries 1 and 2). However, under microwave irradiation
be performed with
(0.001 mol %)to give 4-acetylbiphenyl ( 5ba)in quanti-
a
lower loading of Pd with 0.1 mol % of Pd high conversions were observed
(Table 4, entries 3 and 4). The use of PdCl2 as catalyst
tative yield in 4 h with a TON of 99000 and a TOF of gave lower yield than with palladacycle 2 (Table 4, com-
24750 hꢀ1 (Table 2, entry 5). 4-Tolyltriethoxysilane pare entries 4 and 5). Good yields were obtained with
(4d)was coupled with 4-bromoacetophenone with
activated 4-chloroacetophenone (6b)and siloxanes 4a
0.1 mol % Pd in 3 h to provide biphenyl 5bd in good and 4d either under thermal or microwave conditions
yield (Table 2, entry 6). Deactivated 3- and 4-bromo- (Table 4, entries 6–8). Heterocyclic chlorides, such as
phenols, (3c)and ( 3d), were arylated with phenyltrime- 3-chloropyridine (6f), were coupled with different silox-
thoxysilane (4a)using 0.1 mol % of Pd to give biaryls
anes, such as phenyltrimethoxysilane (4a), (4-methoxy-
5ca and 5da, respectively in good yields (Table 2, en- phenyl)triethoxysilane (4e)and (4-trifluorophenyl)trie-
tries 7 and 8). The anti-inflammatory 4-biphenylacetic thoxysilane (4f)to afford products 5fa, 5fe, and 5ff,[21] re-
acid (5ea)[18] was obtained in 84% yield by reaction of spectively, in good yields under both reaction conditions
p-bromophenylacetic acid (3e)with phenyltrimethoxy-
(Table 4, entries 9–15). The presence of 0.5 equivs. of
silane (4a)(Table 2, entry 9.) 3-Bromopyridine ( 3f) TBAB as additive was crucial in order to obtain good
was coupled in 2.5 to 3 h with different siloxanes 4a, yields, because when the reaction of 3-chloropyridine
4d, and 4e to afford the corresponding 3-arylpyridines (6f)and phenyltrimethoxysilane ( 4a)was performed in
5fa, 5fd,[20] 5fe, respectively, in high yields (Table 2, en- the absence of TBAB only a 16% yield of product 5fa
tries 10–14). The presence of tetra-n-butylammonium was obtained (Table 4, compare entries 9 and 10). In
bromide (TBAB)[19] was important only for the coupling the coupling between 4a and other chloroarenes, such
of 3-bromopyridine (3f)with (4-methoxyphenylt)rie-
thoxysilane (4e)under conventional thermal conditions
as 4-chloroquinaldine (6j), 4-(trifluoromethyl)chloro-
benzene (6k), and 3-chloroaniline (6l), products 5ja,
(Table 2, entries 13 and 14). For the arylation of deacti- 5ka, and 5la were obtained in good yields although the
Scheme 2.
Scheme 3.
Adv. Synth. Catal. 2006, 348, 945 – 952
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Solvent-Less and Fluoride-Free Hiyama Reaction of Arylsiloxanes
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Table 3. Recycling experiments for the Hiyama reaction of aryl bromides with phenyltrimethoxysilane catalyzed by pallada-
cycle 2.[a]
Run ArBr
Siloxane (equivs.)Mol % Pd Additive
t
Product
No
Yield [%][b]
[c]
1
2
3
4
5
PhSi(OMe)3 (2)0.2
PhSi(OMe)3 (1.5)0.1
TBAB
3 h 5aa
3 h 5aa
3 h 5aa
3 h 5aa
3 h 5aa
98
94
73
70
70
[d]
1
2
3
4
5
TBAB
1 h 5ba
1 h 5ba
1 h 5ba
1 h 5ba
1 h 5ba
90
90
96
83
82
TBAB[d]
TBAB[d]
TBAB[d]
TBAB[d]
[a]
Reaction conditions: aryl bromide (1 mmol), phenyltrimethoxysilane (see column), 2 (see column), aqueous 50% NaOH
(2.5 mmol), 120 8C in a pressure tube.
Yield determined by H NMR, by using diphenylmethane as internal standard.
2.5 equivs.
0.5 equivs.
[b]
[c]
[d]
1
amount of TBAB was increased to 1 equiv. with a load- irradiation in only 10 to15 min. In general, aryl chlorides
ing of Pd between 1–1.5 mol % (Table 4, entries 16–19, needed the presence of 0.5 to 1 equiv. of TBAB as addi-
21 and 22). The use of silicone (4c)instead of 4a for the tive for good conversions and higher Pd loadings than
arylation of 6k provided product 5ka in lower yield than aryl bromides. No differences have been found in the re-
phenyltrimethoxysilane (Table 4, compare entries 18 activity of different siloxanes, although silicone was the
and 20). 2-Chlorobenzaldehyde diethyl acetal (6m) less reactive. These reaction conditions allow the easy
could be arylated with 4a at the ortho-position to afford extractive recovery of the final product, and the solid
2-phenylbenzaldehyde (5ma)in good yield after acidic
hydrolysis (Table 4, entry 23).
residue showing catalytic activity can be reused several
times. So far this phosphine-free protocol can be consid-
For the reuse of the catalyst the coupling of 3-chloro- ered as the most simple and efficient method described
pyridine (6f)and phenyltrimethoxysilane ( 4a)to pro-
vide 3-phenylpyridine (5fa)was chosen as a model reac-
tion (Table 5). Under thermal conditions three runs of
20 h were performed, the yield being lowered only to
73% after the third experiment (Table 5, entries 1–3).
Similar results were observed under microwave heating
during 15 min, the yield decreasing to 52% after the
third run (Table 5, entries 4–6).
to perform these type of couplings.
Experimental Section
General
The reagents and solvents were obtained from commercial
sources and were generally used without further purification.
Flash chromatography was performed on silica gel 60 (0.040–
0.063 mm, Merck). Thin layer chromatography was performed
on Polygramꢁ SIL G/UV254 plates. Melting points were deter-
mined on a Reichert Thermovar apparatus. Gas chromato-
graphic analyses were performed on a HP-6890 instrument
equipped with a WCOT HP-1 fused silica capillary column.
IR data were collected on a Nicolet Impact-400D-FT spec-
trophometer in cmꢀ1. 1H NMR spectra were recorded on Bruk-
er AC-300 (300 MHz)and when specified on Bruker Advance-
DRX-500 (500 MHz)spectrometers. Chemical shifts are re-
ported in ppm using tetramethylsilane (TMS, 0.00 ppm)as in-
ternal standard. 13C NMR spectra were recorded at 75 MHz
with CDCl3 as the internal reference. EI-MS were measured
Conclusion
In conclusion, we have developed a straightforward pro-
cedure for the cross-coupling reaction between silox-
anes and aryl bromides and chlorides using a very low
loading of catalyst under solvent-less and fluoride-free
conditions, only promoted by concentrated NaOH.
Pd(OAc)2, PdCl2 or oxime-derived palladacycles can
be used as catalyst, the 4,4’-dichlorobenzophenone ox-
ime-derived palladacycle 2 being the catalyst of choice.
These process can be performed at 1208C either under
normal heating in a pressure tube or under microwave on a Mass Selective Detector G2579A from Agilent Technolo-
Adv. Synth. Catal. 2006, 348, 945 – 952
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Emilio Alacid, Carmen Najera
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950
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Adv. Synth. Catal. 2006, 348, 945 – 952

Solvent-Less and Fluoride-Free Hiyama Reaction of Arylsiloxanes
FULL PAPERS
Table 5. Recycling experiments for the Hiyama reaction of 3-
chloropyridine with phenyltrimethoxysilane catalyzed by pal-
ladacycle 2.[a]
Typical Experimental Work-Up for Hiyama Coupling
of Aromatic and Heteroaromatic Bromides and
Chlorides with Arylsiloxanes. Recycling Experiments
Entry Run Reaction conditions
T
Yield [%][b]
Whenthe reaction under thermal or MW conditions was finish-
ed, the mixture was cooled to room temperature and AcOEt
was added (3ꢁ10 mL). The organic solution was dried and
evaporated as described above to give the corresponding crude
product 5. The solid residue was dried under vacuum and the
new reagents (except the catalysts)were added again (see Ta-
bles 3 and 5).
1
2
3
4
5
6
1
2
3
1
2
3
Thermal
Thermal
Thermal
Microwave
Microwave
Microwave
20 h
20 h
20 h
15 min 99
15 min 85
15 min 52
85
94
73
[a]
Reaction conditions: aryl chloride (1 mmol), phenyltrime-
thoxysilane (2 mmol), 2 (0.5 mol %), aqueous 50% NaOH
(2.5 mmol), TBAB (0.25 mmol), 120 8C in a pressure tube
or under microwave irradiation at 1208C and 80 W.
Acknowledgements
´
We thank DGES of the Spanish Ministerio de Educacion y
[b]
1
Yield determined by H NMR, by using diphenylmethane
Ciencia (MEC) (grant: CTQ2004-00808/BQU), the Generalitat
Valenciana (grants: GRUPOS05/11) and the University of Ali-
cante for financial support. E. A. thanks MEC for a predoctoral
fellowship.
as internal standard.
2.5 equivs.
0.5 equivs.
[c]
[d]
gies 5973N in m/z (rel. intensity in % of base peak). ICP-OES
analyses were performed with a Perkin Elmer Optima 4300.
The catalysts were weighed in an electronic microscale (Sartor-
ius, XM1000P)with a precision of 1 mg. Microwave reactions
were performed with a CEM Discover Synthesis Unit in glass
vessels (10 mL)sealed with a septum under magnetic stirring.
References and Notes
[1] For recent reviews, see: a) Handbook of Organopalladi-
um Chemistry for Organic Synthesis, (Eds.: E.-I. Negishi,
A. de Meijere), Wiley, New York, 2002; b) Cross-cou-
pling Reactions, (Ed.: N. Miyaura), Springer, Berlin,
2000; c) Metal-catalyzed Cross-coupling Reactions,
(Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Weinheim,
1998; d) Metal-catalyzed Cross-coupling Reactions, 2nd
edn, (Eds.: F. Diederich, A. de Meijere), Wiley-VCH,
Weinheim, 2004; e) Transition Metals for Organic Syn-
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Metals for Organic Synthesis; Building Block and Fine
Chemicals, 2nd edn, (Eds.: M. Beller; C. Bolm), Wiley-
VCH, Weinheim, 2004.
Typical Experimental Procedure for Hiyama Coupling
of Aromatic and Heteroaromatic Bromides and
Chlorides with Arylsiloxanes under Thermal
Conditions
A mixture of aryl halide (1 mmol), siloxane (1.5 mmol), TBAB
(0.5 to 1 mmol, see Tables 2–5 )and Pd salts or palladacycles 1
or 2 (see Tables 1–5)in a 15-mL Ace tube was stirred during
5 min. Then an aqueous 50% NaOH solution (0.1 mL,
2.5 mmol)was added and the reaction was heated at 120 8C
during the time indicated in Tables 1–5. After the reaction
was completed or stopped, the reaction mixture was poured
into ether (5 mL). The resulting suspension was filtered off
and the solid was washed with ether (8ꢁ5 mL). The ethereal
filtrates were dried and evaporated (15 mm Hg). The residue
was purified by recrystallization or by flash chromatography
on silica gel to give pure products 5. All compounds 5 are com-
mercially available.
´
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Typical Experimental Procedure for Hiyama Coupling
of Aromatic and Heteroaromatic Bromides and
Chlorides with Arylsiloxanes under Microwave
Irradiation
A glass tube (10 mL)was charged with the aryl halide
(0.5 mmol), siloxane (0.75 mmol), TBAB (0.25 to 0.5 mmol,
see Tables 2–5 ), aqueous 50% NaOH (0.05 mL, 1.25 mmol)
and palladacycle 2 (see Tables), sealed with a septum and heat-
ed at 1208C (80 W, 10 bar)during 10–15 min with air stream
cooling. The reaction mixture was cooled at room temperature
followed by extractive work up as above.
Adv. Synth. Catal. 2006, 348, 945 – 952
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Emilio Alacid, Carmen Najera
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