Bis(2-thienyl)silanes: new, versatile precursors to arylsilanediols

Article abstract of DOI:10.1016/j.tetlet.2006.03.095

Silanediols have been shown to be effective bioisosteres for the hydrated carbonyl group. Current methods for the formation of silanediols place a number of constraints on how and where this functionality may be used. A range of arylsilanes that would allow both the formation of arylsilanediols and that are also compatible with multi-step synthetic routes, have been investigated as possible precursors to silanediols. Through this study bis(2-furyl)silanes and, in particular, bis(2-thienyl)silanes have been identified as practical precursors to arylsilanediols.

Full text of DOI:10.1016/j.tetlet.2006.03.095

Tetrahedron Letters 47 (2006) 3353–3355
Bis(2-thienyl)silanes: new, versatile precursors to arylsilanediols
Thomas F. Anderson, Matthew A. J. Statham and Michael A. Carroll*
School of Natural Sciences-Chemistry, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
Received 20 December 2005; revised 8 March 2006; accepted 15 March 2006
Abstract—Silanediols have been shown to be effective bioisosteres for the hydrated carbonyl group. Current methods for the for-
mation of silanediols place a number of constraints on how and where this functionality may be used. A range of arylsilanes that
would allow both the formation of arylsilanediols and that are also compatible with multi-step synthetic routes, have been inves-
tigated as possible precursors to silanediols. Through this study bis(2-furyl)silanes and, in particular, bis(2-thienyl)silanes have been
identified as practical precursors to arylsilanediols.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Silicon has a rich chemistry, however this has largely
O
HO OH
been restricted to its use as a controlling element in
the formation of conventional carbon based structures.1
The use of silicon-containing groups in biological
research, and in particular drug discovery, has been
known for some time. Enhanced lipophilicity, pro-drug
development or as alternatives for tetrahedral carbon/
nitrogen atoms have all provided potential avenues for
the inclusion of silicon (e.g., see Fig. 1).2–4
HO OH
H2O
R2
R2
R1
N
H
Si
R2
R1
N
H
R1
3
4
5
Figure 2. Silanediols as mimics for the hydrated amido group.
Included in this effort has been the recent application of
silicon based groups as isosteres of transient functional-
ity when it is associated with functional groups respon-
sible for biological activity.5,6 The most notable example
of this is the application of silanediols as bioisosteres of
the hydrated carbonyl group. To date this has largely
been restricted to species such as 5 as mimics of the
hydrated amido group, 4 (Fig. 2) and their application
in the development of peptidomimetics as protease
inhibitors.7–11
Our interest in silicon bioisosteres, as alternatives to aro-
matic carbonyl species, required a precursor for silanedi-
ols that was stable to conventional synthetic procedures
and purification techniques yet may be removed under
mild conditions when required. A range of silicon based
functionality has successfully been employed as precur-
sors to silanols (SiOR, Si–halogen, SiH) however, the
corresponding reactivity profile is not compatible with
a multi-step total synthesis. Phenylsilanes are the one
precursor that has received widespread use, has demon-
strated the desired stability, yet may liberate silanols
under appropriate conditions. The nature of other
functionalities present in these increasingly complex
systems has highlighted some limitations of this
approach6,12 and during the course of this work an
alternative has been developed to address some of these
concerns.13,14
F
N
Me
N
Si
N
O
F3C
O
SiMe3
2, Zifrosilone
1, Flusilazole
F
Aromatic amides are a common motif found in both
synthetic and naturally occurring biologically active
compounds (e.g., see Fig. 3).15–20 The corresponding
silanediol bioisosteres represent an important class of
target for both the discovery of new bioactive structures
Figure 1. Silicon-containing bioactive compounds.
*
Corresponding author. Tel.: +44 0 191 2227074; fax: +44 0 191
2226929; e-mail: m.a.carroll@ncl.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.095

3354
T. F. Anderson et al. / Tetrahedron Letters 47 (2006) 3353–3355
aryl groups have also been shown to be susceptible to
O
O
hydrolysis22 the generation of dimesitylsilanes by the
addition of 2 equiv of mesityllithium (generated from
bromomesitylene and n-butyllithium) proved problem-
atic in our hands24 and exploitation of this form of con-
trol was discontinued.
NMe
N
N
N
N
H
N
N
Me
6, Granisetron
7, CX516
The susceptibility of the diarylsilanes to acid hydrolysis
was then investigated (Table 2). The acids studied were
triflic acid, which is currently used in the hydrolysis of
Si–Ph bonds, TFA, as this is used routinely to remove
protecting groups (e.g., Boc) and silica gel to establish
the stability to chromatography. As expected the Ph–
Si bond was hydrolysed in the presence of triflic acid
but was found to be stable to both TFA and silica gel.
The electron-rich aromatic rings (Table 2: entries 2
and 4) were extremely sensitive and gave the silanediol
(as a mixture, by ESI mass spectrometry, with a range
of siloxanes) under all of the conditions examined. Sur-
prisingly the 3-methoxyphenyl group was only removed
by the action of triflic acid. Both heteroaromatic exam-
ples (Table 2: entries 5 and 6) exhibited the desired pro-
file of being stable to silica gel yet could be removed
under mild acidic conditions. These results coupled with
the increased ease of synthesis and purification led to the
2-thienyl derivative being selected as the precursor of
choice.
Figure 3. Biologically active aryl amides.
and as potential derivatives of current products to com-
bat the observed increasing levels of resistance. As a
result, aromatic amides, and more generally aromatic
carbonyl compounds, highlight a major obstacle in the
use of diphenylsilanes as silanediol precursors—the
preparation of arylsilanediols using this methodology
is therefore extremely limited.
Eaborn21,22 and others23 have demonstrated that the
rate of hydrolysis of aryl–silicon bonds was dependent
on the nature of the aromatic substituents. On this basis,
and in light of our practical constraints, we now wish to
report the synthesis of a range of diarylsilanes, subse-
quent hydrolysis of the aryl–silicon bonds and hence
their potential as precursors to silanediols.
The desired diaryldialkylsilanes were prepared in good
yields (typically > 80%) by the addition of a slight
excess of the appropriate aryllithium reagent to the
dialkyldichlorosilane. Purification by short-path
distillation led to much reduced yields of analytically
pure material (Table 1). Although sterically demanding
To confirm that this approach would allow the forma-
tion of phenylsilanediols by the selective hydrolysis of
the silicon-2-thienyl bond the silanes 17 and 18 were pre-
pared25 and treated with TFA.26 This led to the desired
phenylsilanols being produced with no evidence, by
NMR, for the 2-thienylsilicon bond remaining intact
(Scheme 1).
Table 1. Formation of diarylmethyloctylsilanesa
Me
ArX
In conclusion, bis(2-thienyl)silanes and bis(2-furyl)sil-
anes have been shown to be stable to chromatography
yet undergo hydrolysis under mild acidic conditions
and are therefore suitable precursors to silanediols,
and in particular phenylsilanediols. Application to the
preparation of biologically active materials bearing aryl-
silandiol bioisosteres will be reported elsewhere.
Me
Si
Ar Ar
Entry
1
ArX
Ar
Yieldb (%)
Br
8, 44
9, 31
10, 52
OMe
I
OMe
2
3
Table 2. Hydrolysis of diarylmethyloctylsilanesa
MeO
MeO
MeO
MeO
I
I
Me
Me
Acid
C5H11
Si
HO OH
C5H11
Si
Ar Ar
8 - 13
14
4
5
6
11, 24
12, 36
13, 77
Entry
Substrate
Acidb
Silica (%)
TFA (%)
TfOH (%)
O
S
O
S
b
b
1
2
3
4
5
6
8
9
85
91
87
85
82
84
84
b
90
b
10
11
12
13
88
b
85
80
85
b
a ArX (3.0 equiv), nBuLi (2.5 equiv), THF, ꢀ78 ꢁC, 30 min then
dichloromethyloctylsilane (1.0 equiv).
b Yield after short-path distillation.
a Formation of 14 using silica (500 mg), TFA (5.0 equiv) or TfOH
(2.5 equiv), DCM, 0 ꢁC, 2 h then NH4OH (aq).
b Refers to complete recovery of starting material.

T. F. Anderson et al. / Tetrahedron Letters 47 (2006) 3353–3355
3355
Turcotte, N.; Drouin, A.; Alaoui-Ismaili, M. H.; Bethell,
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Ph
R
Ph
R
Ph
R
i
ii
Si
Cl Cl
Si
Si
S
HO OH
18. Lindgren, H.; Pero, R. W.; Ivars, F.; Leanderson, T. Mol.
Immunol. 2001, 38, 267–277.
S
19. Miao, S.; Bao, J.; Garcia, M. L.; Goulet, J. L.; Hong, X.
J.; Kaczorowski, G. J.; Kayser, F.; Koo, G. C.; Kotliar,
A.; Schmalhofer, W. A.; Shah, K.; Sinclair, P. J.;
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Bioorg. Med. Chem. Lett. 2003, 13, 1161–1164.
15
16
17
18
19
20
R=Me
R=Ph
R=Me, 55%
R=Ph, 84%
R=Me, 81%
R=Ph, 86%
Scheme 1. Reagents and conditions: (i) 2-thienyllithium, THF,
ꢀ78 ꢁC, 18 h; (ii) TFA, DCM, 0 ꢁC, 2 h then NH4OH (aq).
20. Carson, J. R.; Coats, S. J.; Codd, E. E.; Dax, S. L.; Lee, J.;
Martinez, R. P.; Neilson, L. A.; Pitis, P. M.; Zhang, S.-P.
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Acknowledgement
We thank the University of Newcastle for funding and
the EPSRC for provision of the Swansea Mass Spec-
trometry Service.
21. Eaborn, C. J. Organomet. Chem. 1975, 100, 43–57.
22. Eaborn, C. J. Chem. Soc. 1956, 4858–4864.
23. Meen, R. H.; Gilman, H. J. Org. Chem. 1955, 20, 73–
81.
24. Carroll, M. A.; Statham. M. A. J., unpublished results.
Dimesityldichlorosilane is available from Gelest (Cat. No.
SID3540.0).
References and notes
25. Bis(2-thienyl)diphenylsilane 18: 2-Thienyllithium (10.0 mL
of a 1.0 M solution in THF, 10.0 mmol) was added
dropwise over 10 min to a solution of dichlorodiphenyl-
silane (1.27 g, 5.0 mmol) in THF (50 mL) at ꢀ78 ꢁC. The
mixture was then allowed to warm to room temperature
overnight after which the solvent was removed in vacuo.
Dichloromethane (50 mL) was added and any precipitate
removed by filtration. The filtrate was washed with water
(3 · 30 mL), dried (MgSO4) and concentrated in vacuo to
give the crude product. Recrystallisation gave 18 as a
white crystalline solid (1.46 g, 4.2 mmol, 84%); mp 132–
134 ꢁC (from ethyl acetate); (found C, 69.14; H, 4.79.
C20H16S2Si requires C, 68.92; H, 4.63); silica gel TLC Rf
0.40 (petrol); mmax/cmꢀ1 (KBr) 3071, 2958, 2922, 1427,
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J
4 Hz), 7.68 (4H, d, H2/H6 J 8 Hz), 7.45 (8H, m, H3/H30/
H4/H5), 7.26 (2H, t, H40 J 4 Hz); dC (75 MHz; CDCl3)
138.86 (C50), 136.22 (C2/C6), 134.38 (C1), 133.89 (C20),
133.22 (C30), 130.53 (C4), 128.77 (C40), 128.37 (C3/C5);
m/z (EI) 348 (M+, 14%), 271(20), 105(37), 77(100). [Found
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26. Diphenylsilanediol 20: Trifluoroacetic acid (0.38 mL,
5.0 mmol) was added dropwise over 5 min to a solution
of 18 (0.35 g, 1.0 mmol) in dichloromethane (30 mL) at
0 ꢁC. After stirring for 2 h, ammonia (30% aq) was added
dropwise until the solution was neutral pH. The solvents
were removed in vacuo, to give the crude product as a
yellow/brown solid, which was purified by recrystallisation
to give 20 as a white crystalline solid (0.19 g, 0.86 mmol,
86%); mp 160–162 ꢁC (from benzene) lit.,27 160–162 ꢁC
(dec); silica gel TLC Rf 0.15 (1:9, acetone–petrol); mmax
/
cmꢀ1 (KBr) 3412, 2987, 1641, 1445, 1392, 1142; dH
(300 MHz; CDCl3); 2.20 (2H, br s, Si(OH)2), 7.36–7.47
(6H, m, H3/H4/H5), 7.65–7.68 (4H, m, H2/H6); dC
(75 MHz; CDCl3); 128.66 (C3/C5), 131.17 (C4), 133.73
(C2/C6), 136.32 (C1).
27. Diphenylsilanediol is commercially available. Gilman, H.;
Atwell, W. H. J. Am. Chem. Soc. 1964, 86, 5589–5593.