First microwave-accelerated Hiyama coupling of aryl- and vinylsiloxane derivatives: Clean cross-coupling of aryl chlorides within minutes

Article abstract of DOI:10.1002/adsc.200404196

The first microwave-accelerated Hiyama cross-coupling reactions are reported. The reactions of aryl bromides and activated aryl chlorides with PhSi(OMe)₃ [or C₂H₃Si(OMe)₃] are complete within minutes using a modified catalyst system that can be prepared from commercially available reagents in situ. The microwave-accelerated reactions proceed under relatively mild conditions (110-115°C).

Full text of DOI:10.1002/adsc.200404196

UPDATES
First Microwave-Accelerated Hiyama Coupling of Aryl- and
Vinylsiloxane Derivatives: Clean Cross-Coupling of Aryl
Chlorides within Minutes
Matthew L Clarke
School of Chemistry, University of St Andrews, St Andrews, Fife, Scotland, UK
Fax: (þ44)-1334-463-808, e-mail: mc28@st-andrews.ac.uk
Received: June 23, 2004; Accepted: November 22, 2004
Abstract: The first microwave-accelerated Hiyama
cross-coupling reactions are reported. The reactions
of aryl bromides and activated aryl chlorides with
PhSi(OMe)3 [or C2H3Si(OMe)3] are complete within
minutes using a modified catalyst system that can be
prepared from commercially available reagents in
situ. The microwave-accelerated reactions proceed
under relatively mild conditions (110–1158C)
of the considerably cheaper, more widely available aryl
chlorides with organosilicon compounds.
Hiyama and co-workers made significant progress
back in 1996 by showing that aryl(ethyl)dichlorosilanes
could be coupled with activated aryl chlorides to give
good yields after 24–48 hours at 1208C in DMF.[4b] De-
shong and Mowery developed a useful protocol for the
coupling of aryl bromides and iodides with siloxane de-
rivatives, which have been toutedas the most convenient
organosilane for Hiyama cross-coupling.[4c] They en-
countered considerable difficulty with aryl chloride sub-
strates. Thus many ligands [PPh3, (t-Bu)3P, t-Bu2P-bi-
phenyl] were completely ineffective. Even the most ef-
fective catalyst, (Cy2P-biphenyl/Pd2dba3), originally de-
veloped by Buchwald and co-workers and efficient for a
range of aryl chloride cross-coupling processes,[1c] only
Keywords: cross-coupling; homogeneous catalysis;
microwave heating; palladium; phosphane ligands
Introduction
ꢀ
Palladium-catalysed C C bond forming reactions are an produced a 47% yield in the cross-coupling of
extremely useful tool in modern organic synthesis. The PhSi(OMe)3 with 4-chloroacetophenone (10 mol %
synthesis of biaryls which are constituent parts of aro- Pd2dba3; TON<3). Nolan and co-workers reported
matic polymers, liquid crystals, natural products and that an imadazolium chloride/Pd(OAc)2 catalyst
medicines can be accomplished using either palladi- (3 mol %) was a more useful catalyst for three activated
um-catalysed Suzuki (organoboron reagents),[1] Negishi aryl chlorides, but the unactivated substrates gave unsat-
(organozinc reagents),[2] Kumada (organomagnesium isfactory yields.[4f] Before the organosilicon methodolo-
reagents),[3] Hiyama (organosilicon)[4] or Stille (organo- gy sees widespread use there are clearly some challenges
tin reagents)[5] cross-coupling reactions. The latter two to be overcome. Indeed, in a very recent review article,
reactions are especially useful in the preparation of alky- Denmark and co-workers concluded that one of the
larenes, arylalkenes, and dienes. The Stille reaction is key challenges in this area was developing new methods
disadvantaged by the high toxicity and high expense of of activating the organosilicon cross-coupling process.[6]
the organotin reagent. However, it remains in use to
this day, perhaps because it is very useful in the stereose-
lective coupling of vinyl- and alkenylstannanes.
Potentially the most attractive of all these methodolo-
Results and Discussion
gies is the cross-coupling of organosilicon compounds In 2001, the Pd2dba3 ·CHCl3/ligand 1 catalyst system was
(Hiyama reaction). These reagents are available at low reported to give good yields in Suzuki coupling of a
cost or very easily prepared, non-toxic, and are very sta- range of aryl chlorides.[7] In this update, the use of a
ble to other functionalities and reaction conditions. new catalyst system derived from this ligand in the Hiya-
However, this reaction has not yet superseded the Stille ma cross-coupling is reported. The use of this catalyst
and Suzuki reactions because the organosilanes are with microwave heating seems to go some way to over-
rather unreactive nucleophiles. There are frequent re- coming the problems with this methodology.
ports where certain aryl electrophiles fail to react, and
One advantage to the system developed in St An-
the scope of the reaction has not been fully evaluated. drews was that ligand 1 could be rapidly prepared in
Thus, in contrast to Suzuki, Kumada and Stille couplings, quantitative yield with no purification steps. Conse-
there is at present no general method for cross-coupling quently, the development of an in situ ligand synthesis
Adv. Synth. Catal. 2005, 347, 303–307
DOI: 10.1002/adsc.200404196
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303

Matthew L Clarke
UPDATES
and pre-catalyst activation procedure was attempted.
Adding an excess of N-methylpiperazine/triethylamine
to a toluene solution of commercially available chloro-
dicyclohexylphosphine gave after 10 hours a solution
of ligand and amines (þEt3N·HCl precipitate). This li-
gand solution can then be conveniently stored in a
Youngꢁs flask, and used when required. In this work, li-
gand solutions that were several months old performed
equally well as freshly prepared material. The ligand sol-
ution was then added to commercially available
Scheme 2. Hiyama reaction under conventional conditions.
[Pd(allyl)Cl]2 and the aryl halide being studied directly However, there does not appear to be any report of mi-
before the cross-coupling reactions. This catalyst system crowave-accelerated Hiyama cross-coupling.
seems to work at least as well as the original system in
The results presented in Tables 1 and 2 show that mi-
Suzuki cross-coupling reactions (Scheme 1). It is pro- crowaves do indeed show a pronounced accelerating ef-
posed that the desired reactive palladium-monophos- fect on Hiyama cross-couplings (Scheme 3). Table 1
phine catalyst is formed by the reaction sequence shown shows the effect of different additives and catalysts in
in Scheme 1 (co-ordination of phosphine, followed by this reaction. The substrate meta-chlorofluorobenzene
allylic amination).
was subjected to cross-coupling using a variety of activa-
A preliminary experiment suggested that this catalyst tion methods (Entries 1 to 5). The results show that the
could be useful for the cross-coupling of arylsiloxane de- use of 1.25% [Pd(allyl)Cl)]2/3.75% ligand 1/N-mepip
rivatives with aryl bromides under mild conditions. A and an excess of TBAF as activator are the best condi-
commercially available THF solution of TBAF was tions (at present) for this cross-coupling process. The
used as activator and solvent for these reactions for con- use of unmodified [Pd(OAc)2] or a combination of the
venience. However, the aryl chloride tested gave lower electron-donating, bulky, bidentate phosphine dtbpx
yields (TON¼15) under these mild conditions (bis-di-tert-butylphosphinoxylene) with [Pd(OAc)2]
(Scheme 2).
gave very low conversions to the desired product (En-
The simple catalyst preparation and use of widely tries 6 and 7). An initial attempt to carry out the reac-
available commercial reagents seemed to lend itself to tions of an activated aryl bromide with PhSi(OMe)3 us-
a rapid cross-coupling procedure using microwave heat- ing [Pd(OAc)2/PPh3] as catalyst also proved unsuccess-
ing. Microwave-assisted cross-coupling reactions are ful, providing mainly reduced arene products (Table 1;
currently making a significant impact in organic syn- Entry 8). The use of the catalyst derived from ligand 1
thesis as high yields can be produced within minutes.[8] appears to be significant in obtaining the desired prod-
ucts.
Scheme 3. Microwave-assisted Hiyama reaction.
The reactions of an activated and deactivated aryl bro-
mide with PhSi(OMe)3 (Table 2; Entries 2 and 3) are
complete within sixteen minutes at 105–1158C. The ac-
tivated aryl chlorides shown also give the desired biaryl
with high yields on a similar time scale (Table 2; En-
tries 1 and 5). The side products from these reactions
(if any) are small amounts of the reduced arene. Micro-
wave heating seems to be especially well suited to cross-
coupling reactions: it is noteworthy that although the re-
action temperature is significantly above the boiling
point of THF, these are moderate temperatures for a
cross-coupling of aryl chlorides, and would be compati-
ble with mildly heat sensitive functionality. Thus, we
have opted for slightly longer reactions times, but with
milder conditions than some microwave-accelerated re-
Scheme 1. In situ synthesis of the palladium catalyst, and its
application in the Suzuki cross-coupling reaction.
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Microwave-Accelerated Hiyama Coupling of Aryl- and Vinylsiloxanes
Table 1. Microwave-accelerated cross-coupling of aryl halides with PhSi(OMe)3: influence of catalysts and additives.[a]
UPDATES
Entry
Substrate
Catalyst
Promoter
Conversion
(GC Yield) [%]
1
2
3
4
5
6
7
8
3-chlorofluorobenzene
3-chlorofluorobenzene
3-chlorofluorobenzene
3-chlorofluorobenzene
3-chlorofluorobenzene
3-chlorofluorobenzene
3-chlorofluorobenzene
3-bromobenzonitrile
1.25% in situ catalyst from ligand 1
0.4% in situ catalyst from ligand 1
1.25% in situ catalyst from ligand 1
1.25% in situ catalyst from ligand 1
1.25% in situ catalyst from ligand 1
2.5% [Pd(OAc)2]
TBAF
TBAF
0.1 equiv. TBAF
CsF
K3PO4
TBAF
TBAF
TBAF
>99 (95)[b]
58 (58)[c]
<10 (<10)[c]
25 (25)[c]
40 (0)[b]
<10 (<10)[c]
<10 (<10)[c]
>95 (<10)[b]
2.5% [Pd(OAc)2], 4% dtbpx
2.5% [Pd(OAc)2], 5% PPh3
[a]
Reaction conditions: 1158C, 2 min warm-up time, 16 min hold-time; power controlled by temperature and pressure setting
(~60–80 Watt). Conversions refer to starting material consumed, yields refer to conversion to desired biaryl as determined
by GCMS and 19F NMR where appropriate.
Remaining mass balance is reduced arene.
Remaining mass is starting material (3-chlorofluorobenzene).
[b]
[c]
Table 2. Microwave accelerated cross-coupling of aryl ha- actions, which are often conducted above 1508C. One
lides with PhSi(OMe)3.[a]
limitation of this methodology seems to be cross-cou-
pling of deactivated aryl chlorides as illustrated by 4-
Entry
1
Substrate
Conversion
(GC Yield) [%]
chlorotoluene (Table 2; Entry 4). The aryl chloride was
converted into a mixture of biphenyl, benzene, toluene,
4-tolyltoluene and the desired product. Nonetheless,
these results suggest that microwave-assisted Hiyama
cross-coupling could be a very useful methodology in
laboratory-scale synthesis.
The repeated failure of unactivated aryl chlorides to
participate in organosilicon cross-coupling warrants fur-
ther discussion: there are now several reports in the lit-
erature in which Suzuki, Negishi and Kumada coupling
reactions take place with substrates such as 4-chloroto-
luene (also compare Schemes 1 and 2). The contrasting
results with organosilicon nucleophiles suggest one of
the following:
>99 (95)[b]
>99 (90)[b]
>99 (>95)
2
3
a) the organosilicon compounds retard oxidative addi-
tion of aryl chlorides to palladium(0) species;
b) transmetallation of the organosilicon species is rate
limiting and that the nature of the aryl substituents
in the electrophile (and [Pd(L)Ar(Cl)] intermedi-
ate) has an effect on this process;
4
5
>99 (trace)[c]
>99 (90)[b]
c) transmetallation and oxidative addition are finely
balanced in the catalytic cycle, and if oxidative ad-
dition and transmetallation are slow, a pathway for
catalyst degradation exists which lowers the overall
productivity of the reaction;
d) a final alternative is that the organosilicon cross-
coupling does not proceed through the commonly
accepted cross-coupling mechanism; mechanistic
studies to shed light on this intriguing reactivity
are underway.
[a]
Reaction conditions: 1158C, 2 min warm-up time, 16 min
hold-time; power controlled by temperature and pressure
setting (~60–80 Watt). Reactions were run with 1.25%
catalyst derived from [Pd(allyl)Cl)]2 and ligand 1, using
3 equivalents of TBAF solution in THF as promoter. Con-
versions refer to starting material consumed, yields refer
to conversion to desired biaryl as determined by GCMS
and 19F NMR where appropriate.
[b]
[c]
Remaining mass balance is reduced arene.
Complex mixture including reduced arene as major prod-
uct.
One of the useful applications of Stille and Hiyama
cross-coupling is the synthesis of arylalkenes. A proce-
dure used to produce styrene derivatives requires rela-
tively mild conditions in order to prevent polymerisa-
Adv. Synth. Catal. 2005, 347, 303–307
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Matthew L Clarke
UPDATES
tion of the products. It was pleasing to find that para- Experimental Section
chloroacetophenone could be smoothly coupled with vi-
nyltrimethoxysiloxane within 18 minutes at 1108C using
the new microwave procedure (Scheme 4). This product
General Remarks
Reactions were carried out under a nitrogen atmosphere in 10-
mL sealable glass tubes (available from CEM) in a CEM dis-
cover microwave apparatus. The power used was varied auto-
matically in order to maintain the desired temperature within
the specified pressure limit (250 psi). The reactions were stir-
red and carried out using the CEM cooling function which pre-
vents overheating of the reaction mixture and provides more
microwave radiation for a given temperature. 19F and
19F{1H} NMR spectroscopy was carried out using a Bruker Ad-
vance 300 in conventional solvents using C6D6 as an internal
standard. The reactions were monitored using a Hewlett Pack-
ard GC-MS machine equipped with an MDN-35 fused silica ca-
pillary column (30 m, 0.25 mm I. D.; 0.25 mm film). Tempera-
was isolated in pure form (95%) simply by pouring the
black reaction mixture onto a pad of silica and eluting
with petroleum ether/ether (4:1) to give a colourless sol-
ution of the desired alkene, which can be washed with
water to remove water-soluble impurities. This prelimi-
nary result suggests that the cheapest, most convenient
and environmentally benign method to prepare arylal-
kenes on research scale could prove to be the micro-
wave-assisted procedure being developed here. In
both styrene and biaryl syntheses, the ability of some
aryl chlorides to undergo cross-coupling is significant
as there are many more aryl chloride electrophiles com-
mercially available and at a fraction of the cost of aryl
bromides.
ture programme: 508C (2 min) up to 1308C at 208C minꢀ1
;
hold 2 min; up to 2308C (6 min). Spilt ratio¼100:1.
[Pd(Cl)(allyl)]2 was a generous gift from Johnson Matthey.
N-Methylpiperazine, chlorodicyclohexylphosphine, and the
aryl halides were obtained from Aldrich Chemical Company
and used as received. Tetrabutylammonium fluoride (1 M sol-
ution in THF), PhSi(OMe)3, and C2H3Si(OMe)3 were obtained
from Lancaster Chemical Company and used as received.
Hiyama Cross-Coupling using in situ Ligand-Catalyst
Synthesis; Preparation of 3-fluorophenylbenzene,
Typical Procedure
Scheme 4. Synthesis of a styrene derivative.
A dry Schlenk flask equipped with a rubber septum was evac-
uated and purged with nitrogen two or three times prior to the
addition of dry toluene (60 mL), N-methylpiperazine
(0.210 mL, 0.189 g, 1.895 mmol) and then triethylamine
(0.194 mL, 0.141 g, 1.389 mmol). Neat dicyclohexylchloro-
phosphine (0.294 g, 1.263 mmol) was added dropwise to this
solution via a syringe. This suspension was stirred overnight
and then left to settle giving a solution of ~6 mg of ligand/mL
Conclusion
In summary, the first examples of microwave-assisted
Hiyama cross-coupling reactions are reported. The mi-
crowaves have an amazing effect on the rate of this nor-
mally sluggish reaction. The reaction times (normally
24–48 hours in refluxing DMF) and catalyst loading concentration. This can then be used directly in reaction mix-
tures or transferred to a Youngꢁs flask via syringe and stored
as a solution for several weeks under a dry nitrogen atmos-
phere. The purity of the ligand can be checked by 31P{1H}
NMR if required (dP ¼75.8 ppm).
have been reduced significantly compared to using con-
ventional heating. At just 105–1158C, high yields of
biaryl can be produced in under twenty minutes. A
new in situ ligand and catalyst synthesis has been devel-
oped that can be prepared prior to each cross-coupling
reaction, or stored as the crude ligand 1/N-mepip solu-
tion. Using this catalyst, activated aryl chlorides can
also be coupled with PhSi(OMe)3 and vinyl-Si(OMe)3
within minutes under microwave heating. The proce-
A microwave tube containing allylpalladium chloride dimer
(5.0 mg, 1.367ꢁ10ꢀ5 mol, 1.25 mol %), 1-chloro-3-fluoroben-
zene (0.117 mL, 0.143 g, 1.09 mmol), and a magnetic stirring
bar was then placed under an inert atmosphere before the ad-
dition of the ligand solution (2 mL of 6 mg·mLꢀ1 solution,
~3.7 mol %) using a syringe. PhSi(OMe)3 (0.408 mL, 043 g,
dures are very easy to carry out and therefore should 2.186 mmol) and a THF solution of TBAF (4.3 mL of 1 M sol-
ution) were then added to the microwave tube using a syringe.
This microwave vessel was then heated at 1158C for 16 min
(with 2 minutes warm-up time). Yield and conversion for the
reactions carried out using fluoroarylbenzenes were deter-
find application in organic syntheses. Further studies
to thoroughly evaluate the scope of Hiyama cross-cou-
pling under both conventional and microwave heating
will be carried out in due course and reported in a full pa-
per. Mechanistic studies to gain better understanding of
the fundamental steps of this reaction and optimal phos-
phine ligand are also underway.
mined by 19F NMR (C6D6, internal standard) [dproduct
¼
ꢀ113.0 ppm; (dreactant ¼ ꢀ110 ppm)]. It is noted, however,
that the reduced arene product also comes at a similar chemical
shift to the product, so a close inspection of the expanded spec-
trum is required. The conversion and yield of these reactions
were also checked by GC-MS for accuracy. In all cases there
was good agreement between NMR and GC results. Yields
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Microwave-Accelerated Hiyama Coupling of Aryl- and Vinylsiloxanes
UPDATES
and conversion for the other aryl chlorides were determined by
GC-MS using naphthalene as internal standard.
[3] a) K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc.
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[5] a) D. Milstein, J. K. Stille, J. Am. Chem. Soc., 1979, 101,
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Acknowledgements
The author would like to thank Dr. Nick Westwood (University
of St Andrews) and Dr. Chris Mason (CEM) for the loan of a
CEM discover microwave apparatus, and Peter Pogorzelec for
carrying out GC-MS measurements. The generous gift of palla-
dium allyl chloride dimer from Johnson Matthey is also ac-
knowledged.
[6] S. E. Denmark, M. H. Ober, Aldrichima Acta 2003, 36, 75.
[7] a) M. L. Clarke, D. J. Cole-Hamilton, J. D. Woollins, J.
Chem. Soc. Dalton Trans. 2001, 2721; b) M. L. Clarke,
A. M. Z. Slawin, J. D. Woollins, Polyhedron 2003, 22, 19.
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References and Notes
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Adv. Synth. Catal. 2005, 347, 303–307
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