A robust method for the Hiyama-type coupling of arylsiloxanes and disiloxanes with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.04.048

Palladium catalysed Hiyama-type coupling of aryl disiloxanes or aryl silanols with aryl halides in the presence of stoichiometric silver(I) oxide and catalytic TBAF allows the rapid preparation of biaryls in moderate to high yield under mild thermal or microwave irradiation conditions.

Full text of DOI:10.1016/j.tetlet.2008.04.048

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3939–3942
A robust method for the Hiyama-type coupling of arylsiloxanes
and disiloxanes with aryl halides
a
b
a,
a
*
Spencer Napier , Sebastian M. Marcuccio , Heather Tye , Mark Whittaker
a Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK
b Advanced Molecular Technologies Pty Ltd, 11 Duerdin St., Clayton, Victoria 3168, Australia
Received 11 February 2008; revised 26 March 2008; accepted 9 April 2008
Available online 12 April 2008
Abstract
Palladium catalysed Hiyama-type coupling of aryl disiloxanes or aryl silanols with aryl halides in the presence of stoichiometric
silver(I) oxide and catalytic TBAF allows the rapid preparation of biaryls in moderate to high yield under mild thermal or microwave
irradiation conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Recent developments in the field of palladium catalysed
cross-coupling reactions of organosilanes (Hiyama cou-
plings) from the laboratories of Denmark and Hiyama
amongst others have resulted in the emergence of valuable
alternatives to the more commonly used Suzuki cross-cou-
pling reactions.1–9 The organosilicon group can be intro-
duced using a wide variety of methods to provide
compounds possessing a high degree of functionality. The
reagents required to introduce the organosilicon function-
ality are generally available in bulk and are inexpensive.
Alkene dimethylsilanols, dimethylsiloxanes and tetrame-
thyldisiloxanes give the desired products in good to excel-
lent yields under a variety of cross-coupling conditions.
Although there are some excellent protocols available,
there is no one universal cross-coupling procedure which
works well for aryldimethylsilanols, dimethylsiloxanes
and tetramethyldisiloxanes. Hiyama and co-workers8 have
developed a silver(I) oxide mediated reaction for coupling
aryl dimethylsilanols with aryl iodides; however, the reac-
tion fails when aryl bromides are employed. They have also
demonstrated that cross-coupling of such species fails when
TBAF is used as an activator in place of silver(I) oxide. In
this case, the dimethylsilanol condenses in situ to give the
1,3-di(aryl)-1,1,3,3-tetramethyldisiloxane, which is not a
competent cross-coupling partner under the reaction condi-
tions. Denmark and Ober9 observed that di(aryl)-1,1,3,3-
tetramethyldisiloxanes fail to react under their standard
cross-coupling conditions, which work very well for di-
methylsilanols, using cesium carbonate as the base. Addi-
tional water in the reaction mixture gives the desired
product in low yield, while the use of cesium hydroxide
in place of cesium carbonate results in a higher yield but
at the expense of competing homocoupling and reduced
functional group compatibility.
A variety of dimethylsilanols, dimethylsiloxanes and
tetramethyldisiloxanes have recently become commercially
available through several catalog suppliers10 making the
reagents readily accessible. With this in mind, we thought
it timely to re-investigate the arylsilicon cross-coupling
reaction with a view to developing a general, high yielding
and practically expedient reaction protocol, which would
hopefully address the shortcomings of existing meth-
odologies.
Herein, we report a mild and efficient method for the
cross-coupling of aryl silanols, silanes and disiloxanes with
aryl iodides and aryl bromides, using palladium tetrakistri-
phenylphosphine, relatively inexpensive silver(I) oxide11
and catalytic quantities of tetra-n-butylammonium fluoride
*
Corresponding author. Tel.: +44 (0) 1235 441341; fax: +44 (0) 1235
441351.
E-mail address: heather.tye@evotec.com (H. Tye).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.048

3940
S. Napier et al. / Tetrahedron Letters 49 (2008) 3939–3942
Table 1
(TBAF), which gives good conversion to the desired prod-
ucts after only 30 min for most cases and does not lead to
the formation of homocoupled by-products.
Examination of the conditions applied previously by
other groups2–9 led to the selection of a set of hybrid con-
ditions in which the effect of different fluoride sources in
addition to silver(I) oxide was explored (Scheme 1 and
Table 1).
Fluoride source screen for 4-iodoacetophenone coupling using 1 equiv-
Ag2O and 5 mol %Pd(PPh3)4 in THF
Entry
Additive
Time
Temp(°C)
Conv.a (%)
1
2
3
4
5
6
7
a
—
—
18 h
70
70
70
120
70
70
47
14
56
66
88
81
94
30 min
30 min
30 min
30 min
30 min
30 min
1 equiv TBAF
1 equiv TBAF
1 equiv TBAT
0.12 equiv TBAF
0.12 equiv TBAT
For the reaction of phenyldimethylsilanol with 4-iodo-
acetophenone, improved conversions were observed when
using palladium tetrakistriphenylphosphine and silver(I)
oxide in combination with tetra-n-butyl ammonium fluo-
ride (TBAF) or tetra-n-butylammonium difluorotriphenyl
silicate (TBAT) as activators (Table 1, entries 3 and 5).
Furthermore, when catalytic amounts of the fluoride
source were used, the conversion to product was found to
be greatly enhanced (Table 1, entries 6 and 7) with TBAT
giving the best results. Clearly, the addition of a fluoride
source leads to increased reactivity allowing for the signif-
icantly reduced reaction times to be employed. Whilst some
mechanistic aspects of the coupling reaction have been dis-
cussed previously,8,9 the combination of silver(I) oxide and
fluoride may behave differently to either additive alone.
Further mechanistic analysis will be required to determine
the role of fluoride in this reaction, and indeed why the use
of catalytic quantities is beneficial.
A further observation was that under these reaction con-
ditions, no homocoupled side products were detected,
which is in contrast to the literature observations where
the addition of fluoride or base (in the absence of silver(I)
oxide) can lead to varying amounts of homocoupling.5,9
Conducting the reactions under thermal conditions in pres-
sure tubes resulted in similar reaction profiles and yields to
those observed when using microwave irradiation.
The utility of these reaction conditions was further dem-
onstrated for a range of aryl halides as shown in Table 2,
enabling the formation of the desired biaryl products in
good to excellent isolated yields. Applying these conditions
to the reaction of 4-bromoacetophenone gave a 38% con-
version after 30 min (Table 2, entry 8). This result is in con-
trast to the use of silver(I) oxide alone, which fails to give
significant cross-coupling when aryl bromides are
employed.8
70
Conversion calculated from product peak versus4-iodoacetophenone
peak in the LCMS UV trace after 30 min microwave irradiation using a
CEM Explorer focused reactor.
Table 2
Phenyldimethylsilanol coupling with aryl halides
Entry
R
X
Product
Yielda (%)
1
2
3
4
5
6
7
8
a
COMe
NO2
Me
OMe
NH2
I
I
I
I
I
I
I
Br
1a
1b
1c
1d
1e
1f
98 (75)b
78
100
85
52
86
CF3
5-Iodoindolec
COMe
1g
1a
50
38
Isolated yield from reactions carried out on 0.25 mmol scale with 1
equiv Ag2O, 1.2 equiv silanol, 5 mol % Pd(PPh3)4 and 0.12 equiv TBAT
(tetra-n-butylammonium difluorotriphenyl silicate) in THF with heating
for 30 min under thermal conditions.
b
Yield in brackets using TBAF as the fluoride source.
5-Iodoindole coupling partner not pendant R group.
c
nol with 4-bromoacetophenone was conducted (see
Scheme 2, Tables 3 and 4). The results confirmed silver(I)
oxide as the additive of choice (Table 3, entry 1), giving a
35% conversion in THF, although the use of silver(I) sul-
fate gave a similar reaction profile and conversion of 33%
(Table 3, entry 12).
When the solvent was altered to 1,4-dioxane or N,N-
dimethylformamide, conversions increased to 48% and
46%, respectively (Table 4, entries 3 and 7), whereas alter-
ing the palladium species to palladium(II) acetate bis-tri-
phenylphosphine gave a conversion of 67% (Table 4,
entry 13). Under the optimised conditions (1 equiv Ag2O,
0.12 equiv TBAF, 5 mol % Pd(OAc)2(PPh3)2, 1,4-diox-
ane), after 6 h of heating, the conversion increased to
80% resulting in a 67% isolated yield of 4-phenylacetophe-
none. This result demonstrates that it is feasible to employ
aryl bromides in place of iodide; however, longer reaction
As a wider array of aryl bromide building blocks is com-
mercially available compared to aryl iodides, we thought it
useful to optimise the procedure further. A screen of the
reaction conditions varying the additive, solvent and palla-
dium species for the cross-coupling of phenyldimethylsila-
R
Pd(PPh3)4, Ag2O
additive
R
Si
O
O
PhSiMe2OH,
TBAF, additive,
OH
+
X
THF, 70 O
C
palladium catalyst,
solvent, 70 OC
Ph
Br
1a-g
X = Br, I
Scheme 1.
Scheme 2. For conversions see Tables 3 and 4.

S. Napier et al. / Tetrahedron Letters 49 (2008) 3939–3942
3941
Table 3
Table 5
Varying the additive in THF with Pd(PPh3)4
Coupling of 4-iodoacetophenone with a range of aromatic silicon reagents
Entry
Additive
Conv.a (%)
Entry
Additive
Conv.a (%)
Entry
Ar
R
Yielda (%)
1
2
3
4
5
6
a
Ag2O
35
0
0
0
13
0
7
8
9
10
11
12
Me3SiOK
BaO
CuI
PhCO2Ag
Ag2CO3
Ag2SO4
0
0
0
0
26
33
1
2
3
4
a
C6H5
C6H5
C6H5
C6H5
OH
OMe
ONa
OSiMe2Ph
75
73
0
CsCO3
K2CO3
NaOtBu
AgNO3
DIPEA
88
Isolated yield from the reactions carried out on a 0.2 mmol scale with
1.2 equivsilicon reagent, 1 equivAg2O, 0.12 equivTBAF (1 Min THF) and
5 mol %Pd(PPh3)4 for 30 min under thermal conditions.
Conversion calculated from product peak versus4-iodoacetophenone
peak in the LCMS UV trace after 30 min microwave irradiation. Thermal
conditions gave similar results.
The use of the methyl ether derivative of phenyldimeth-
ylsilanol was well tolerated giving a similar result to the sil-
anol, although the sodium salt gave no cross-coupling
using these conditions (Table 5, entries 2 and 3).
Table 4
Varying the solvent and palladium catalysta
Entry
Solvent
Catalyst
Conv.b (%)
Of significant interest was the reaction of 1,3-diphenyl-
1,1,3,3-tetramethyl-disiloxane which gave an 88% yield of
the desired biaryl product (Table 5, entry 4). This was par-
ticularly intriguing as the formation of a dimeric species
previously presumed to be the disiloxane had been observed
as a side reaction when phenyldimethylsilanol was used.
The exact nature of this side product has not yet been deter-
mined. This result is significant as other literature methods
employing silver(I) oxide alone or base fail to give good lev-
els of conversion to the desired cross-coupled product.8,9 As
the disiloxane species could in theory be capable of donat-
ing both of its aryl groups during the cross-coupling reac-
tion, experiments were conducted with reduced
equivalents of this reagent. The reaction using 0.5 equiv
of the disiloxane resulted in the formation of the biaryl
product in 47% yield. This would suggest that the enhanced
yield when using 1.2 equiv of the reagent (Table 5, entry 4)
was as a result of having two aryl groups available for the
reaction. This observation is consistent with a recent exam-
ple of the reaction of hexaarylcyclotrisiloxanes in Hiyama-
type cross-couplings reported by Endo et al.5
1
2
3
4
5
6
7
8
THF
Bu2O
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
38
0
48
17
8
22
46
7
1,4-Dioxane
Toluene
DCM
MeCN
DMF
Water
9
10
11
12
13
a
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
PdCl2(PPh3)2
PdSO4(PPh3)2
allyl-PdCl(PPh3)2
Pd(dba)2(PPh3)2
Pd(OAc)2(PPh3)2
0
6
42
32
67
Reactions carried out on 0.2 mmol scale with 5 mol % catalyst, 0.12
equivTBAF (1 Min THF), 1 equivAg2O and 1.2 equiv phenyldimethyl-
silanolfor 30 min under thermal conditions.
b
Conversion calculated from product peak versus4-iodoacetophenone
peak in the LCMS UV trace.
times are generally required to achieve similar levels of
conversion.
The next phase of the investigation was to determine
whether other silicon reagents could be used in place of
the more traditional aryldimethylsilanol for the coupling
with 4-iodoacetophenone (Scheme 3, Table 5). For these
reactions, we switched to using TBAF as the activator. A
drawback of using TBAT is that it can act as a phenyl
group donor, which leads to the formation of trace
amounts of side products in reactions where silanols other
than phenyldimethylsilanol are used.12 This is not the case
for TBAF and thus our preference was to use this as the
activating agent.
The reproducibility of these reactions was found to be
highly dependent on the quality of the Pd catalyst and
the TBAF source. TBAF was employed as a solution in
THF, which needed to be refrigerated on storage to avoid
loss of activity in the reaction. The TBAF solution
contained trace quantities of water (ꢀ5 wt %) which may
be important for the reaction;13 however, this was not
explored as part of the current study.
To demonstrate the utility of this new methodology, the
coupling of differing aryl iodides and bromides with vari-
ous disiloxanes was examined (Scheme 4, Table 6).
The phenyl disiloxane reacted well with both electron
rich and electron poor aryl iodides (Table 6, entries 1–3)
to give the desired products in excellent yield. As expected
the aryl bromides gave reduced yields when compared to
the iodides after the same reaction period although p-nitro
bromobenzene (Table 6, entry 6) proved to be an exception
suggesting that electron deficient bromides are good cou-
pling partners for this type of reaction.
Si
Ar
R
Ac
Ag2O, 5 mol% Pd(PPh3)4,
+
Ar
Ac
0.12 eq TBAF, THF, 70 O
C
1
I
The presence of electron donating groups on the disilox-
ane resulted in lower yields under these reaction conditions
Scheme 3.

3942
S. Napier et al. / Tetrahedron Letters 49 (2008) 3939–3942
Acknowledgement
R
Si
Si
O
Ar
Ar
R
Ag2O, 5 mol% Pd(PPh3)4,
We are grateful to Advanced Molecular Technologies
Pty Ltd for the generous supply of the various silicon
reagents employed in this study.
+
Ar
0.1 eq TBAF, THF, 70 O
C
X
References and notes
Scheme 4.
1. Hiyama, T.; Shirakawa, E. Organosilicon Compounds. In Cross-
Coupling Reactions a Practical Guide; Miyaura, N., Ed.; Topics in
Current Chemistry; Springer: Berlin, 2002; Vol. 219, p 61.
2. Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531–1541.
3. Spivey, A. C.; Cripton, C. G. G.; Hanna, J. P. Curr. Org. Synth. 2004,
1, 211–226.
4. Denmark, S. E.; Baird, J. D. Chem. Eur. J. 2006, 12, 4954–4963.
5. Endo, M.; Sakurai, T.; Ojima, S.; Katayama, T.; Unno, M.;
Matsumoto, H.; Kowase, S.; Sano, H.; Kosugi, M.; Fugami, K.
Synlett 2007, 749–752.
6. Seganish, W. M.; Deshong, P. Org. Lett. 2004, 6, 4379–4381.
7. Handy, C. J.; Manoso, A. S.; McElroy, W. T.; Seganish, W. M.;
Deshong, P. Tetrahedron 2005, 61, 12201–12225.
8. Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.; Nishihara,
Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342–5349.
Table 6
Disiloxane couplings
Entry
Ar
X
R
Product
Yielda (%)
1
2
C6H5
C6H5
I
I
I
COMe
OMe
NO2
1a
1d
1b
1a
1d
1b
2a
3a
4a
5a
77
96
85
3
C6H5
4
C6H5
Br
Br
Br
I
COMe
OMe
NO2
COMe
COMe
COMe
COMe
55b
31b
92b
26c
5
C6H5
6
C6H5
7
8
9
10
a
4-(MeO)C6H4
4-MeC6H4
4-ClC6H4
2-Thiophene
I
I
I
59c
37c
9. Denmark, S. E.; Ober, M. H. Adv. Synth. Catal. 2004, 346, 1703–
1714.
38 (49)d
10. Suppliers include Advanced Molecular Technologies, Alfa Aesar,
Sigma–Aldrich and Wako.
11. A typical price for silver(I) oxide is £10 for 1 g from Sigma–Aldrich.
12. TBAT has previously been reported as a phenyl source see: McElroy,
W. T.; Deshong, P. Org. Lett. 2003, 5, 4779–4782.
Isolated yield from reactions carried out on a 1.0 mmol scale with 1.5
equivsilicon reagent, 0.1 equivTBAF (1 Min THF) and 5 mol %Pd(PPh3)4
for 60 min under thermal conditions.
b
Aryl bromide couplings performed in 1,4-dioxane.
Reactions heated for 18 h.
c
13. See Ref. 9 for a discussion on the role of water in similar base
mediated reactions.
d
Bracketed yield when the reaction was heated at 90 °C.
14. Example procedure—thermal reaction: To 1 mmol aryl iodide and 1
mmol silver(I) oxide in 7.5 ml anhydrous THF were added 1.5 mmol
1,1,3,3-tetramethyl 1,3-diphenyl disiloxane, 0.05 mmol tetrakis(tri-
phenylphosphine) palladium(0) and 0.1 mmol tetrabutylammonium
fluoride (1 M in THF). The resulting suspension was stirred in a
pressure tube at 70 °C for 1 h. The reaction was then filtered and
washed with EtOAc and then to the resulting filtrate was added 1.5 g
of silica, and the resultant suspension was concentrated to give the
silicated crude product, which was purified by column chromatogra-
phy (heptane + 0–5% EtOAc). Selected example: 4-acetylbiphenyl
(1a), 1H NMR (400 MHz, CDCl3) d 2.5 (s, 3H), 7.30–7.35 (m, 1H),
7.35–7.41 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 6.6 Hz, 2H),
7.90 (d, J = 6.6 Hz, 2H); m/z 197.16 (M+H)+. Example procedure—
msicrowave reaction: To 1 mmol aryl iodide and 1 mmol silver(I) oxide
in 7.5 ml anhydrous THF were added 1.5 mmol 1,1,3,3-tetramethyl
1,3-diphenyl disiloxane, 0.05 mmol tetrakis(triphenylphosphine) pal-
ladium(0) and 0.1 mmol tetrabutylammonium fluoride (1 M in THF).
The microwave tube was sealed and placed in the microwave cavity of
a CEM Explorer. The tube was irradiated with microwave energy for
30 min maintaining a temperature of 70 °C. Work-up was conducted
as for the thermal example.
(Table 6, entries 7 and 9), with longer heating times
required to achieve moderate conversions.
In conclusion, we have developed new reaction condi-
tions which enable the cross-coupling of a range of aryl sil-
icon reagents with aryl iodides or bromides.14 Under mild
conditions and shortened reaction times, only 30 min in
many cases, the desired biaryl products are afforded in
good yield with no evidence of competing homocoupling
occurring. More significantly, we have demonstrated the
utility of this methodology for the coupling of aryl disilox-
anes, which are simple to prepare and unlike their silanol
equivalents are not sensitive to trace amounts of acids
and bases. With the recent increase in commercial avail-
ability of aryl silicon reagents, this methodology offers a
valuable alternative to traditional methods for biaryl
formation such as Suzuki and Stille couplings.