Palladium-catalysed synthesis of aryl-alkyl ethers using alkoxysilanes as nucleophiles

Article abstract of DOI:10.1039/b907784g

Changing the activator from tetrabutyl ammonium fluoride (TBAF) to sodium hydroxide unexpectedly switches the catalytic pathway of the Hiyama coupling reaction of vinyl trialkoxysilanes with aryl bromides into a Pd catalysed C-O bond forming reaction; if

Full text of DOI:10.1039/b907784g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Palladium-catalysed synthesis of aryl-alkyl ethers using alkoxysilanes
as nucleophiles†
Edward J. Milton, Jos e´ A. Fuentes and Matthew L. Clarke*
Received 17th April 2009, Accepted 17th April 2009
First published as an Advance Article on the web 15th May 2009
DOI: 10.1039/b907784g
Changing the activator from tetrabutyl ammonium fluoride (TBAF) to sodium hydroxide unexpectedly
switches the catalytic pathway of the Hiyama coupling reaction of vinyl trialkoxysilanes with aryl
bromides into a Pd catalysed C–O bond forming reaction; if the correct conditions are used, high yields
of aryl-alkyl ethers are observed. In addition, coupling between readily available tetraalkoxysilanes and
aryl bromides can also be realised with NaOH or TBAF activation. The reactions take place in only
2
0 minutes if microwave heating is employed.
5
Introduction
arylation of alkenyl trialkoxysilanes. Although we have observed
quite efficient reactions between certain aryl chlorides using
TBAF as activator, swapping TBAF for other activators had
Aryl ethers are a widespread motif in a wide range of natural prod-
ucts, pharmaceuticals, agrochemicals and organic materials, and
consequently there has been a considerable amount of research
5e,f
a highly negative effect on the yield of aryl alkene. When vinyl
trimethoxysilane was used in combination with sodium hydroxide
as activator, the methoxy group of vinyl trimethoxysilane was
unexpectedly coupled to the aryl halide to give an aryl-methyl ether
in moderate yield (Scheme 1). This type of reactivity has not, to
the best of our knowledge, been reported before. Our efforts were
therefore focused on investigating if reaction conditions could be
devised that allowed a high-yielding ether synthesis.
1
into their synthesis. Nucleophilic aromatic substitution reactions
can be a useful procedure for electron deficient aryl chlorides and
fluorides under basic conditions. The Cu-promoted Ullman ether
synthesis can be a useful method but is limited to certain reactive
2
substrates and only takes place in high boiling polar solvents.
Palladium-catalysed C–O bond forming reactions potentially have
several advantages, including high functional group tolerance,
the use of common, relatively benign solvents, and the use of
some less-reactive aryl halide electrophiles under mild conditions.
However, in contrast to Pd-catalysed C–N bond forming reactions,
developments in Pd-catalysed C–O bond formation have been
slow, with many limitations still to overcome. The Pd-catalysed
synthesis of diaryl ethers using phenols as nucleophiles has been
improved markedly providing that specific bi-aryl phosphines
3
are used. Good results have also been readily obtained using
Scheme 1
3f
tertiary alkoxides as nucleophiles, since Pd-tertiary alkoxides
cannot undergo b-hydride elimination during the catalytic cycle. A
sustained effort has seen some examples of effective cross-coupling
to give aryl-alkyl ethers with specific aryl halide substrates, but no
general method has been discovered to date, making this one of
the least developed Pd-catalysed cross-coupling reactions. Iron-
catalysed ether synthesis using aryl iodides is an important recent
discovery, but needs significant further research to extend the
6
A ligand screen revealed that this reaction is highly sensitive
to ligand structure. Electron-donating, larger bite angle diphos-
phines seem to perform best, and the commercially available
ligand, 1-di-tert-butylphosphino-1¢-diphenylphosphino-ferrocene
dtbdppf), was selected for further development. A study on the
effect of Pd precursor, and the L/Pd ratio demonstrated that
Pd(OAc) in combination with two equivalents of the ligand gave
(
4,2d
reaction to aryl bromides and chlorides under mild conditions.
2
In this paper, we report an alternative method for Pd-catalysed
ether formation that makes use of alkoxysilanes and an activator.
the best results. A solvent screen (see ESI†) demonstrated that
useful yields could be obtained using toluene as solvent, which
is cheaper and of lower environmental impact than THF. The
reaction takes place very conveniently in a short time using
microwave heating, but in many of the cases studied, good yields
could still be obtained using conventional heating. Experiments
in which the NaOH to silane ratio was varied revealed that the
reaction is sensitive to this parameter, although for the model
reaction used in Table 1, a variety of ratios between 1 and 2.5 gave
good results. The control experiments of reaction without catalyst,
Results and discussion
The background to this serendipitous discovery was a project
focused on developing genuinely practical conditions for the
School of Chemistry, University of St Andrews, EaStCHEM, St Andrews,
Fife, UK. E-mail: mc28@st-andrews.ac.uk; Fax: (44) 1334 463808;
Tel: (44) 1334 463850
or with [Pd(OAc) ] used without ligand did not give any significant
2
†
Electronic supplementary information (ESI) available: Full experimental
details and further results. See DOI: 10.1039/b907784g
amounts of product with any of the substrates described here. For
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Table 1 Effect of different pre-catalysts and conditions on the coupling reaction of vinyl trimethoxysilane with para-bromoacetophenone
◦
a
Entry
Pd pre-catalyst
Ligand (mol%)
Temp. / C
Conversion to methyl ether (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
PPh
PCy
S-Phos (2)
dppe (1)
dppb (1)
dcype (1)
dppf (1)
3
(2)
(2)
75
75
75
75
75
75
75
75
75
75
75
75
75
105
75
130
120
105
120
120
16
10
8
16
9
3
21
20
38
42
9
17
29
59
77
80
84
95
85
0
dippf (1)
dtbdppf (1)
dtbdppf (1)
dtbdppf (1)
dtbdppf (3)
dtbdppf (2)
dtbdppf (2)
dtbdppf (2)
dtbdppf (2)
dtbdppf (2)
dtbdppf (2)
none
1
1
1
1
1
1
1
1
1
1
2
Pd(OTfac)
Pd(dba)
2
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
none
2
2
2
2
2
2
2
b
b
bc
d
be
d
d
Pd(OAc)
2
none
0
a
Reagents and conditions: 1 mol% Pd precursor, ligand as described in column 3, 1.5 equiv. vinyl trimethoxysilane, 2.5 equiv. NaOH unless otherwise
b
indicated, 0.5 mmol p-xylene internal standard, stirred at the temperature indicated in THF for 16 hours unless otherwise indicated. Toluene used as
solvent at temperature indicated. Reaction carried out in a sealed tube; 74% yield after chromatography. Toluene used as solvent and microwave heating
for 20 minutes. 1.25 equiv. of NaOH, 8 hours reaction time.
c
d
e
comparison, sodium methoxide did not give any ether product
under these reaction conditions.
Table 2 Coupling of vinyl trimethoxysilane or vinyl triethoxysilane with
a
aryl halides
Our working hypothesis is that the hydroxide, once in solution
binds to Si to form a hypervalent silicon species that can transfer
alkoxide to palladium, or alternatively gradually release alkoxides
as the reaction proceeded. We felt that this alternative method
could potentially be adapted for synthetic use, and therefore
a number of other aryl halides were investigated under these
reactions conditions. It was therefore pleasing to find that the
reaction can indeed be extended to other aryl halides, including
the activated aryl chlorides in Table 2, entries 1 and 6.
Conversion
[yield] (%)
Entry
1
Aryl halide
Product
84 [74]
2
85 [77]
b
3
4
5
81 [80]
The reactions shown do generally proceed well under the
original conditions, but can also be carried out in only 20 minutes
◦
c
if microwave heating is used at 120 C.
76 [73]
Vinyl trimethoxy- and vinyl triethoxysilanes are actually cheap
fine chemicals and thus could be developed as nucleophiles
for the synthesis of methyl and ethyl ethers. However, for this
discovery to have a broader impact in the synthesis of aryl-alkyl
ethers the reactions needed to be extended to readily available
tetraalkoxysilanes; we were therefore delighted to find that simple
tetraalkoxysilanes would also undergo this reaction (even more)
readily. Choosing the appropriate alkoxysilanes allowed for the
transfer of ethoxy, n-propoxy and n-butoxy groups to aryl halides
using the new method (Scheme 2 and Table 3). The use of TBAF
has also been investigated as an alternative activator for the
tetraalkoxysilanes, and in some cases, improved results have been
obtained (Table 3, entries 6–9).
In these studies using these relatively unoptimised conditions
and simple commercially available diphosphine ligands, we have
found that several aryl halides gave lower yielding reactions
using both the vinyl trialkoxysilanes or tetraalkoxysilane
nucleophiles. For example, p-dimethylamino-bromobenzene gave
predominantly starting material with some reduced arene, whereas
o-chloro-anisole, a very deactivated substrate, returned only
84 [74]
86 [72]
6
d
7
75 [66]
a
Reagents and conditions: 1 mol% Pd precursor, 2 mol% dtbdppf as ligand,
1
.5 equiv. vinyl trimethoxysilane, 1.25 equiv. NaOH unless otherwise
◦
indicated, 0.5 mmol p-xylene internal standard, stirred at 120 C in
toluene using microwave heating for 20 min. Conversions are product
calibrated against internal standard, yields refer to pure compounds after
b
chromatography. 84% yield if heated at reflux in toluene for 16 hours (oil
bath). 86% yield if heated at reflux in toluene for 16 hours (oil bath).
c
d
2
.0 equiv. of vinyl trimethoxysilane.
2
646 | Org. Biomol. Chem., 2009, 7, 2645–2648
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Table 3 Pd-catalysed C–O bond formation between a variety of silanes
and para-bromoacetophenone
that alkoxysilanes are widely available, and sometimes produced
as intermediates in synthesis, the results reported here could lead
to useful procedures in the synthesis of ethers.
a
Entry
Silane
Activator
Conversion [yield] (%)
1
2
3
4
5
6
7
8
9
Si(OMe)
Si(OMe)
4
NaOH
TBAF
NaOH
NaOH
TBAF
NaOH
TBAF
NaOH
TBAF
80 [72]
78
Experimental
4
Si(OEt)
Si(OEt)
3
4
4
H
82 [73]
79 [67]
For full details, see ESI†: general procedure for reactions using
normal heating. The aryl halide (1 mmol) was added to a flame-
dried Schlenk tube containing a stirrer bead, followed by the silyl-
ether (1.5 mmol), p-xylene (0.5 mmol, 62 mL) and dry, degassed
toluene (5 mL). A H NMR spectra of this solution was taken
to calibrate the internal standard. To this, Pd(OAc)
b
Si(OEt)
68
n
Si(OPr )
4
4
70 [65]
80
50 [42]
86 [73]
n
Si(OPr )
n
Si(OBu )
4
4
1
n
Si(OBu )
2
(0.0023 g,
a
Reagents and conditions: 1 mol% Pd precursor, 2 mol% dtbdppf as ligand,
.5 equiv. tetraalkoxysilane, 1.25 equiv. NaOH or 3 equiv. of TBAF.
.5 mmol p-xylene as internal standard, stirred in refluxing toluene for
0
.1 mmol, 1 mol%), dtbdppf (0.0102 g, 0.2 mmol, 2 mol%) and
1
0
1
powdered NaOH (0.05 g, 1.25 mmol) were added to the tube that
was then sealed, flushed with nitrogen or argon and heated to
reflux (or other temperatures) for the time specified. The reactions
were analysed by H NMR and GCMS. The products were isolated
by removal of solvent followed by column chromatography (SiO
using hexane–diethyl ethers as eluent.
6 hours. Conversions are product calibrated against internal standard,
b
yields refer to pure compounds after chromatography. The coupling of
Si(OEt)
4
with p-bromonitrobenzene also gave a high isolated yield (81%)
1
using TBAF conditions in toluene.
2
)
Microwave heating conditions
The aryl halide (1 mmol) was added to a flame dried Schlenk tube
containing a stirrer bead, followed by the silyl-ether (1.5 mmol),
1
p-xylene (0.5 mmol, 62 mL) and dry, degassed toluene (5 mL). A H
NMR spectra of this solution was taken to calibrate the internal
Scheme 2
standard. This was then added via syringe to Pd(OAc)
2
(0.0023 g,
0
.1 mmol, 1 mol%), dtbdppf (0.0102 g, 0.2 mmol, 2 mol%)
starting material. Tetraisopropoxysilane and alkoxysilanes
derived from tertiary alcohols have proven rather unreactive
in these first studies; a contrast to the latter being easier
and powdered NaOH (0.05 g, 1.25 mmol) (or TBAF, 3 equiv.),
in a dry microwave tube flushed with nitrogen or argon. The
reaction mixture was heated by microwave irradiation at 120 C for
◦
3f
nucleophiles in the direct reaction that possibly reflects that
some of these reactions are limited by slow transmetalation
2
0 minutes, with analysis and isolation carried out as above.
7
using these relatively bulky catalysts. This reflects that a more
in-depth study developing new catalysts for this new variant
of C–O coupling is required before it is truly general in scope.
The results described here suggest considerable potential for
using alkoxysilanes as oxygen nucleophiles, and given that the
contrasting reactivity patterns (e.g. in the preferred choice of
catalyst) were seen to the direct coupling of alcohols, the new
procedure may prove to be complementary to the existing
Acknowledgements
The authors thank the EPSRC for funding and Johnson Matthey
for the loan of some of the palladium salts.
Notes and references
1
For example, see: (a) J. Zhu, Synlett, 1997, 133; (b) C. K.-F. Chiuy,
in Comprehensive Organic Functional Group Transformations, ed. A. R.
Katrizky, O. Meth-Cohn and C. W. Rees, Pergamon Press, New York,
8
methodology.
1
995, vol. 2, ch. 2.13; (c) Comprehensive Natural Products Chemistry,
Conclusions
ed. D. Barton, K. Nakanashi and O. Meth-Cohn, Elsevier Science,
Oxford, UK, 1999, vol. 1, 3 and 8; (d) T.-X. Metro, D. G. Pardo and J.
Cossy, J. Org. Chem., 2008, 73, 707; (e) E. J. Corey and G. A. Reichard,
Tetrahedron Lett., 1989, 30, 5207; (f) J. Deeter, J. Frazier, G. Staten,
M. Staszak and L. Weigel, Tetrahedron Lett., 1990, 31, 7101; (g) A. W.
Czarnik, Acc. Chem. Res., 1996, 29, 112.
2 (a) J. Lindley, Tetrahedron, 1984, 40, 1433; (b) M. A. Keegstra, T. H.
Peters and L. Brandsma, Tetrahedron, 1992, 48, 3633; (c) R. A. Altman,
A. Shafir, A. Choi, P. A. Lichor and S. L. Buchwald, J. Org. Chem., 2008,
In conclusion, the unexpected observation of alkoxy transfer from
vinyl trimethoxysilane in a Hiyama reaction is reported along with
the development into a procedure for Pd-catalysed C–O bond
formation. These results suggest that optimal ligands are electron-
donating bidentate ligands and that it is possible to couple to
a range of activated bromides and chlorides. It has also been
established that more widely available tetraalkoxysilanes can also
be coupled using either NaOH or TBAF activation. Although
this catalytic process is still in the early stages of development,
it is hoped that the use of custom-designed diphosphine ligands
could lead to quite a general process that may find a niche where
direct coupling of alcohols under basic conditions is not successful.
Further studies will also concentrate on elucidating if direct Si–OR
to Pd reactions occur or if the hypervalent silanes serve to release
low concentrations of alkoxide as the reaction proceeds. Given
7
3, 284; (d) An important recent development is the coupling of phenols
◦
with aryl chlorides at 135 C using 10 mol% Cu catalyst and 80 mol%
ligand: N. Xia and M. Taillefer, Chem.–Eur. J., 2008, 14, 6037.
(a) G. Mann and J. F. Hartwig, J. Am. Chem. Soc., 1996, 118, 13109;
3
(
b) K. E. Torraca, X. Huang, C. Parrish and S. L. Buchwald, J. Am.
Chem. Soc., 2001, 123, 10770; (c) Saturated oxygen heterocycles: K. E.
Torraca, S.-I. Kuwabe and S. L. Buchwald, J. Am. Chem. Soc., 2000,
122, 12907; (d) A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe, J. P.
Sadighi and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 4369; (e) G.
Mann, Q. Shelby, A. H. Roy and J. F. Hartwig, Organometallics, 2003,
2
2, 2775; (f) Tertiary alcohols: C. A. Parrish and S. L. Buchwald, J. Org.
Chem., 2001, 66, 2498; (g) O-enolates: M. C. Willis, D. Taylor and
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Org. Biomol. Chem., 2009, 7, 2645–2648 | 2647

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A. T. Gilmore, Tetrahedron, 2006, 62, 11513; (h) Enol ether synthesis:
M. C. Willis, D. Taylor and A. T. Gilmore, Chem. Commun., 2003,
reaction of aryl trialkoxysilanes:R. Lerebours and C. Wolf, J. Am. Chem.
Soc., 2006, 128, 13052.
2
222; (i) The best Pd procedure requires the careful matching of
6 All ligands in Table
1,2-bis-diphenylphosphino-ethane; dppb = 1,4-bis-diphenylphosphino-
butane; dippf 1,1-bis-diisopropylphosphino-ferrocene; dppf
1,1-bis-diphenylphosphino-ferrocene; dcype 1,2-bis-dicyclohexyl-
1
are commercially available: dppe
=
different ligands to the relatively small range of substrates studied: A. V.
Vorogushin, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127,
=
=
8
146.
=
4
5
(a) O. Bistri, A. Correa and C. Bolm, Angew. Chem., Int. Ed., 2008, 47,
5
phosphino-ethane; S-Phos = 2-dicyclohexylphosphino-2¢,6¢-dimethoxy-
86; (b) J. Bonnamour and C. Bolm, Org. Lett., 2008, 10, 2665.
1,1¢biphenyl.
(a) T. Hiyama and Y. Hatanaka, Pure Appl. Chem., 1994, 66, 1471; (b) For
one of the most practical examples:S. E. Denmark and J. M. Kallemeyn,
J. Am. Chem. Soc., 2006, 128, 16958; (c) M. E. Mowery and P. DeShong,
Org. Lett., 1999, 1, 2137; (d) E. Alacid and C. Najera, Adv. Synth. Catal.,
7 M. L. Clarke and M. Heydt, Organometallics, 2005, 24, 6475.
8 Another complementary approach aimed at side-stepping the sometimes
problematic direct formation of aryl-alkyl ethers is the Pd catalysed
C–O bond formation with hydroxide, followed by alkylation with alkyl
halides: (a) K. W. Anderson, T. Ikawa, R. E. Tundel and S. L. Buchwald,
J. Am. Chem. Soc., 2006, 128, 10694; (b) M. C. Willis, Angew. Chem.,
Int. Ed., 2007, 46, 3402.
2
006, 348, 2085; (e) M. L. Clarke, Adv. Synth. Catal., 2005, 347, 303;
(
(
f) M. L. Clarke, E. J. Milton, and J. A. Fuentes, unpublished results;
g) An interesting side product (aldehyde oxidation) in the addition
2
648 | Org. Biomol. Chem., 2009, 7, 2645–2648
This journal is © The Royal Society of Chemistry 2009