Arylsilane oxidation - New routes to hydroxylated aromatics

Article abstract of DOI:10.1039/b924135c

An efficient route to hydroxylated aromatics has been developed, via the oxidation of aryl organosilanes under functional group-tolerant and relatively mild conditions, using sub-stoichiometric amounts of fluoride promoters.

Full text of DOI:10.1039/b924135c

Chemical Communications
www.rsc.org/chemcomm
Volume 46 | Number 20 | 28 May 2010 | Pages 3405–3616
ISSN 1359-7345
FEATURE ARTICLE
Nakanishi
COMMUNICATION
Bracegirdle and Anderson
Arylsilane oxidation—new routes to
hydroxylated aromatics
Supramolecular soft and hard materials
based on self-assembly algorithms
of alkyl-conjugated fullerenes
1359-7345(2010)46:20;1-M

View Article Online
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Arylsilane oxidation—new routes to hydroxylated aromaticsw
Sonia Bracegirdle and Edward A. Anderson*
Received (in Cambridge, UK) 18th November 2009, Accepted 21st December 2009
First published as an Advance Article on the web 13th January 2010
DOI: 10.1039/b924135c
An efficient route to hydroxylated aromatics has been developed,
via the oxidation of aryl organosilanes under functional group-
tolerant and relatively mild conditions, using sub-stoichiometric
amounts of fluoride promoters.
Phenols are ubiquitous in medicinal and natural product
chemistry, being synthetically fundamental in aromatic ring
functionalisation, and possessing bioactivity against numerous
diseases.1 Despite their importance, classical phenolation
Scheme 1
methods can be limited by harsh reaction conditions which
are incompatible with sensitive functionality.1,2 As a result, a
phenol might traditionally be installed in the early stages of a
synthesis, potentially leading to regiocontrol issues in further
arene functionalisation, or to instability towards oxidation.
Late-stage phenolation is therefore an attractive prospect,
to which recently reported transition metal-catalysed aryl
halide hydroxylation3 or direct C–H activation–oxidation4
offers one solution. We envisaged an alternative strategy,
whereby a ‘‘masked phenol’’ could be introduced onto an
aromatic ring, to be revealed at a suitable juncture under
conditions tolerant of other functional groups. In previous
work, we had planned to install the aryl ether of the natural
product rubriflordilactone A using this principle, via Tamao
oxidation of an alkoxyarylsilane.5 To our surprise, although
this oxidation is well-known in aliphatic systems,6 it has rarely
been applied to aromatic silanes,7 with the exception of
Dudley’s elegant work on arylsiletanes.8 In the event, this
oxidation proved successful,5 and provided a base upon which
to build this silicon-based phenolation methodology (Fig. 1).
The non-toxic and inexpensive nature of silicon reagents
further increased the appeal of this approach, and we report
here the optimisation of this transformation, and its application
in one-pot, or two-step phenolation reactions.9
aryllithium species 3 which could then be trapped with an
appropriate silylating agent. Diethylaminochlorodimethylsilane
410 was selected for this purpose, as it is known to selectively
undergo a single addition of carbon nucleophiles at low
temperatures.10,11 Following addition of 4 to aryllithium 3,
the resulting aminosilane 5 was treated with iso-propanol to
provide the more stable iso-propoxyarylsilane 6, which we
expected to display the optimum balance between oxidative
reactivity and silane stability.
The use of ortho-lithiation methodology was investigated
first, for which extensive precedent12 enabled the selection of
appropriate deprotonation conditions (ESIw), and the desired
arylsilanes 6a–e were isolated in excellent yields (Table 1,
entries 1–5). We next examined the bromine–lithium exchange/
silylation route, which led to a second series of arylsilanes 6f–q
(entries 6–18) (ESIw). These two approaches are complementary,
in that the first does not require pre-functionalisation of the arene
with a halide (but does require a directing group), whilst the
second gives access to a wider range of meta- and para-substituted
arylsilanes. Notably, both procedures afforded the corresponding
silanes in uniformly high yields, and with good tolerance of an
array of arene functionality.
With a variety of arylsilanes in hand, our attention now
turned to the oxidation itself. We selected carbamate 6a as our
test substrate, and found that under Tamao’s ‘‘classical’’
conditions6 (2 equiv. KF or TBAF, KHCO3, H2O2,
40–60 1C in THF–methanol), this silane underwent smooth
oxidation to phenol 7a (Table 2, entries 1 and 2). The reaction
was next conducted at room temperature, which led to equally
efficient conversion (entries 3 and 4), although in the case of the
TBAF-promoted oxidation, a significant amount of fluorosilane
8 was isolated (7a :8 3.4 : 1, 99% combined yield). In an attempt
to avoid this competitive side-reaction, we reduced the
fluoride loading to one equivalent; surprisingly this led to an
increase in the amount of fluorosilane (entries 5 and 6). Finally,
on lowering the equivalents of fluoride to 10 mol% (entries 7 and 8),
we were delighted to find that only trace amounts of fluoro-
silane were now detected, and that the reaction still proceeded
in quantitative yield. Removing the fluoride source altogether
(entry 9) maintained some conversion of the arylsilane to the
Two routes were explored towards the regiocontrolled
synthesis of suitable arylsilanes (Scheme 1): directed ortho-
lithiation (1), or bromine–lithium exchange (2), leading to an
Fig. 1
Chemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, UK OX1 3TA.
E-mail: edward.anderson@chem.ox.ac.uk;
Fax: +44 (0)1865 285002; Tel: +44 (0)1865 285000
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation of silanes 5 and phenols 7, and copies of
1
selected H and 13C NMR spectra. See DOI: 10.1039/b924135c
ꢀc
This journal is The Royal Society of Chemistry 2010
3454 | Chem. Commun., 2010, 46, 3454–3456

View Article Online
Table 1 Synthesis of iso-propoxyaryldimethylsilanes 6a–qa
Table 2 Optimisation of iso-propoxyarylsilane oxidation using 6aa
Silane,
yield (%) Entry
Silane,
yield (%)
Substrate
Substrate
Entry
1
6a, 88
10
6i, 99
Entry FÀ Source Equiv. Temp/1C Yield (%) Ratio (7a : 8)b
1
2
3
4
5
6
7
8
9
KF
TBAF
KF
TBAF
KF
TBAF
KF
TBAF
no FÀ
2.0
2.0
2.0
2.0
1.0
1.0
0.1
0.1
—
60
60
rt
rt
rt
rt
rt
rt
rt
99
99
99
—
—
—
3.4 : 1
1.9 : 1
1.7 : 1
—
—
1.5 : 1c
99d
97d
99d
99
2
3
6b, 92
6c, 98
11
12
6j, 97
99
99d
6k, 90
a
Conditions: KHCO3 (2.0 equiv.), H2O2 (6.0 equiv.), MeOH–THF
b
(1 : 1), 16 h. Ratio obtained from 1H NMR. Ratio of 7a : 6a.
d
c
Combined yield.
4
5
6
6d, 99
6e, 81
6f, 99
13
14
15
6l, 83
6m, 95
6n, 99
Scheme 2
aminosilane 5a showed that this one-pot oxidation13 was equally
effective (85%), and set the stage for screening of our iso-propoxy-
silane collection 6a–q, and their intermediate aminosilanes.
7
8
6g, 99
6h, 99
6b, 94
16
17
18
6o, 63
6p, 99
6q, 99
Our results show that oxidation can be achieved for a wide
variety of iso-propoxy- and aminosilane substrates (Table 3).
Of particular note are the range of halogenated phenols we
could prepare, products which might not be readily accessed
using alternative methods. The observation that both primary
and secondary benzylic TBS ethers are stable to either oxidation
procedure (entries 16 and 17) highlights the potential utility of
this transformation in the context of multistep synthesis, in
which the aliphatic TBS protecting group is among the most
common. Intriguingly, whilst the aryl TBS ether of 6o was
cleaved in the two-step iso-propoxysilane procedure
(entry 15A, indicating that trialkylaryloxysilane deprotections
can be achieved under oxidative–catalytic fluoride conditions),
it was retained in the one-pot aminosilane route (entry 15B).
These results serve to emphasise the delicate balance between
the reactivity of the various silicon species towards fluoride.
Certain aminosilane oxidations did not proceed smoothly
under the optimised conditions (entries 2A, 9B, 10B and 14A/B),
despite the apparent contrasting efficiency of two of these
substrates in the iso-propoxysilane series. In these cases,
stoichiometric amounts of fluoride restored reactivity,
and this discrepancy again points to the subtle interplay of
electronic factors (aryl substituents) and leaving group ability
(iso-propoxy, methoxy, or diethylamino) which can clearly
affect the reaction mechanism.14 Calculations by Mader and
9
a
Conditions (entries 1–5): s-BuLi, TMEDA, THF, À78 1C; ClSiMe2-
h; i-PrOH, DMAP, rt, 12 h. Conditions
(NEt2), À78 1C,
2
(entries 6–18): n-BuLi (1.2 equiv.) or t-BuLi (2.0 equiv.), THF or
Et2O, À78 1C; ClSiMe2(NEt2), À78 1C, 2 h; i-PrOH, DMAP, rt, 12 h.
phenol,13 although significant quantities of 6a remained after 16 h.
This suggests that the sub-stoichiometric amount of fluoride ion is
not only accelerating the oxidation, but is also recycled at some
point in the reaction pathway. The optimised conditions for
oxidation of 6a thus employed 0.1 equiv. of fluoride source at
room temperature, for which we used TBAF (1 M solution in
THF) in subsequent oxidations for ease of quantification.
In addition to the isolation and oxidation of the stable
iso-propoxysilanes 6 from the intermediate aminosilanes 5
(route A, Scheme 2) we also envisaged a direct oxidation of
5 (route B), giving rise to a one-pot phenolation protocol
which avoids the need for isolation of an intermediate.
Application of the optimised oxidation conditions to carbamate
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 3454–3456 | 3455

View Article Online
Table 3 Oxidations of iso-propoxyarylsilanes 6 (route A, Scheme 2)
and diethylaminoarylsilanes 5 (route B, Scheme 2)a
Yield (%)
A: from 6
B: from 5 Entry
Yield (%)
A: from 6
B: from 5
Product
Product
Entry
1
A: 99
10
A: 90
B: 82e
B: 85
Scheme 3
functional group-tolerant, thus allowing this late-stage
phenolation protocol to be readily factored into a synthetic
pathway. Further studies into the reaction mechanism, and its
application in synthesis, will be reported in due course.
We thank the EPSRC (Advanced Research Fellowship to
E.A.A.; EP/E055273/1), the Clarendon Trust and Merton
College (S.B.), and the Royal Society for financial support.
A: 35
B: 99b
B: 90c
A: 74
B: 78
2
3
11
A: 99
B: 77
A: 52
B: 43
12
13
14
Notes and references
A: 94
B: 99
A: 87
B: 59
1 J. H. P. Tyman, Synthetic and Natural Phenols, Elsevier,
New York, 1996; Z. Rappoport, The Chemistry of Phenols,
Wiley-VCH, Weinheim, 2003.
2 P. Hanson, J. R. Jones, A. B. Taylor, P. H. Walton and
A. W. Timms, J. Chem. Soc., Perkin Trans. 2, 2002, 1135.
3 K. W. Anderson, T. Ikawa, R. E. Tundel and S. L. Buchwald,
J. Am. Chem. Soc., 2006, 128, 10694; B. J. Gallon, R. W. Kojima,
R. B. Kaner and P. L. Diaconescu, Angew. Chem., Int. Ed., 2007, 46,
4
5
6
A: 61d
B: 89d
A: 68f
B: 75f
7251; T. Schulz, C. Torborg, B. Schaffner, J. Huang, A. Zapf,
¨
¨
R. Kadyrov, A. Borner and M. Beller, Angew. Chem., Int. Ed., 2009,
A: 90
B: 87
A: —g
B: 76
48, 918; A. G. Sergeev, T. Schulz, C. Torborg, A. Spannenberg,
H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2009, 48, 7595;
A. Tlili, N. Xia, F. Monnier and M. Taillefer, Angew. Chem., Int.
Ed., 2009, 48, 8725; D. Zhao, N. Wu, S. Zhang, P. Xi, X. Su, J. Lan
and J. You, Angew. Chem., Int. Ed., 2009, 48, 8729; For a review,
see: M. C. Willis, Angew. Chem., Int. Ed., 2007, 46, 3402.
4 R. E. Maleczka, F. Shi, D. Holmes and M. R. Smith, J. Am. Chem.
Soc., 2003, 125, 7792; For a recent example and leading references,
see: Y.-H. Zhang and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 14654.
5 M.-C. A. Cordonnier, S. B. J. Kan and E. A. Anderson, Chem.
Commun., 2008, 5818.
6 K. Tamao, T. Kakui, M. Akita, T. Iwahara, R. Kanatani, J. Yoshida
and M. Kumada, Tetrahedron, 1983, 39, 983; K. Tamao, M. Kumada
and K. Maeda, Tetrahedron Lett., 1984, 25, 321; K. Tamao,
N. Ishida, T. Tanaka and M. Kumada, Organometallics, 1983, 2,
1694; G. R. Jones and Y. Landais, Tetrahedron, 1996, 52, 7599;
See also: I. Fleming, Chemtracts: Org. Chem., 1996, 9, 1.
7 For recent non-general examples, see: C. Huang and
V. Gevorgyan, J. Am. Chem. Soc., 2009, 131, 10844; H. Ihara
and M. Suginome, J. Am. Chem. Soc., 2009, 131, 7502.
8 For excellent examples, see: J. D. Sunderhaus, H. Lam and
G. B. Dudley, Org. Lett., 2003, 5, 4571; H. Lam, S. E. House and
G. B. Dudley, Tetrahedron Lett., 2005, 46, 3283; S. F. Tlais, H. Lam,
S. E. House and G. B. Dudley, J. Org. Chem., 2009, 74, 1876.
9 For some alternative methods, see: M. Hawthorne, J. Org. Chem.,
1957, 22, 1001; P. Beak and R. A. Brown, J. Org. Chem., 1982, 47,
34; M. Iwao, T. Iihama, K. K. Mahalanabis, H. Perrier and
V. Snieckus, J. Org. Chem., 1989, 54, 24; K. A. Parker and
K. A. Koziski, J. Org. Chem., 1987, 52, 674; M. Julia, S.
Pfeuty-SaintJalmes, K. Ple, J. N. Verpeaux and G. Hollingworth,
15
16
A: 72
B: 88
A: 99
B: 99
7
8
A: 81
B: 99
A: 99
B: 99
17
—
A: 81
B: 99e
9
a
Conditions: TBAF (0.1 equiv.), KHCO3 (2.0 equiv.), H2O2
b
(6.0 equiv.), MeOH–THF (1 : 1), rt, 16 h. From 1b. From 2d.
c
d
NMR yield based on an internal standard, due to product volatility
f
(ESIw).e 1.0 equiv. of TBAF. 2.0 equiv. of KF, 60 1C. The aryl
TBS ether was also cleaved.
g
Norrby15 suggest that the reaction proceeds via a pentacoordinate
silicon ‘‘ate’’ complex 9 (Scheme 3), as originally proposed by
Tamao et al.14 At this point, productive nucleophilic attack by
peroxide anion (followed by aryl migration, 10-11) must be
balanced against competitive loss of alkoxide to give fluorosilane
12. The relative reactivity of such fluorosilanes towards oxidation
remains somewhat uncertain,14 although additional fluoride ion
could reactivate 12 towards oxidation (via 13) perhaps accounting
for the need for further fluoride in these cases.
´
Bull. Soc. Chim. Fr., 1996, 133, 15; F. Trecourt, M. Mallet,
O. Mongin and G. Queguiner, J. Org. Chem., 1994, 59, 6173.
´
10 K. Tamao, E. Nakajo and Y. Ito, Tetrahedron, 1988, 44, 3997.
11 G. Stork and P. F. Keitz, Tetrahedron Lett., 1989, 30, 6981.
12 V. Snieckus, Chem. Rev., 1990, 90, 879.
13 For seminal work on fluoride-free alkylsilane oxidations, see:
K. Tamao and N. Ishida, J. Organomet. Chem., 1984, 269, c37.
14 K. Tamao, T. Hayashi and Y. Ito, Frontiers of Organosilicon
Chemistry, The Royal Society of Chemistry, Cambridge, 1991.
15 M. M. Mader and P.-O. Norrby, J. Am. Chem. Soc., 2001, 123, 1970.
In conclusion, we have developed a phenolation strategy
which provides access to a variety of hydroxylated aromatics
from the corresponding aryl bromides, or directing group-
substituted species. The oxidation has been shown to be
ꢀc
This journal is The Royal Society of Chemistry 2010
3456 | Chem. Commun., 2010, 46, 3454–3456