Fluorous synthesis of allylic fluorides: C-F bond formation as the detagging process

Article abstract of DOI:10.1039/b804484h

A novel fluorous tagging-detagging strategy has been developed featuring a fluorination as the detagging process; fluorous allylsilanes were prepared by cross-metathesis and subsequently subjected to electrophilic fluorodesilylation; Selectfluor was used as the detagging reagent; the resulting allylic fluorides were successfully purified by fluorous solid phase extraction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b804484h

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Chemical Communications
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Number 31 | 21 August 2008 | Pages 3585–3692
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
Véronique Gouverneuret al.
Fluorous synthesis of allylic fluorides:
C–F bond formation as the detagging
process
Martin Albrecht
C4-bound imidazolylidenes: from
curiosities to high-impact carbene
ligands
1359-7345(2008)31;1-2

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Fluorous synthesis of allylic fluorides: C–F bond formation
as the detagging processwz
Sophie Boldon, Jane E. Moore and Veronique Gouverneur*
a
b
a
´
Received (in Cambridge, UK) 17th March 2008, Accepted 2nd May 2008
First published as an Advance Article on the web 4th June 2008
DOI: 10.1039/b804484h
A novel fluorous tagging–detagging strategy has been developed
featuring a fluorination as the detagging process; fluorous
allylsilanes were prepared by cross-metathesis and subsequently
subjected to electrophilic fluorodesilylation; Selectfluor was used
as the detagging reagent; the resulting allylic fluorides were
successfully purified by fluorous solid phase extraction.
Scheme 1 C–F Bond formation, a new detagging process.
The ability of fluorine to alter the physical and chemical
properties of organic molecules has been used in the design
of fluorine-containing bioactive compounds.1 Rapid and effi-
cient protocols for the purification of fluorinated compounds
are therefore in high demand. Radiochemists working in the
area of positron emission tomography would also greatly
benefit from the availability of fast purification strategies for
the production of short half-life fluorinated 18F-radiotracers.
Fluorous chemistry emerges as a particularly attractive tech-
nology since the unique separation properties of molecules
containing a highly perfluorinated domain allows for the rapid
purification of crude reaction mixtures using fluorous solid
phase extraction (FSPE).2,3 This technique has proved to be
valuable in the context of medicinal chemistry. Surprisingly,
radiolabelling strategies relying on the use of fluorous soluble
supports are extremely scarce, notable exceptions being the
preparation of 125I-labelled benzamides and 35S-labelled
sulfonamides.4,5 In recognition of the importance of fluori-
nated pharmaceuticals, the need to develop rapid purification
protocols for 18F-radiotracers, and the advantages of fluorous
chemistry, fluorous-tagged precursors should be regarded as
highly valuable for the preparation and purification of fluori-
nated products. Examples of functional manipulation of
fluorinated fluorous reactants followed by a conventional
detagging process were reported in the literature.6 A more
challenging approach is the detagging of a fluorous-tagged
precursor based on a fluorination process. In the context of
18F-radiochemistry, this approach is potentially very powerful
as it allows for the FSPE separation of the 18F-labelled
radiotracers from the large excess of fluorous starting material,
the fluorination conveniently taking place late in the radio-
synthetic sequence (Scheme 1).
In this paper, we report the first detagging process relying
on a C–F bond forming event. For proof of concept, we
validated the feasibility of this unprecedented strategy with
the electrophilic fluorination of allylsilanes, a well-documen-
ted reaction for the preparation of allylic fluorides.7
We opted for a light fluorous approach as it advantageously
requires minimal optimisation and allows for the use of FSPE
for the purification protocol. We reasoned that tagged allyl-
trimethylsilanes may be amenable to cross-metathesis (CM)
and subsequent detagging upon fluorination with Selectfluor.
This reaction sequence raised two main points of interest, the
feasibility of cross-metathesis reactions involving a fluorous
olefin and the validation of the key fluorination-detagging
process (Scheme 2).
As no light fluorous allylsilanes are reported in the litera-
ture,8 our study began with the preparation of a model light
fluorous allylsilane. Allylsilane 1 was selected for further
functional manipulation as the incorporation of the ethylene
spacer insulates the silicon from the tag, thereby minimising
any electronic perturbation that could otherwise affect the
reactivity of the fluorous allylsilane for the cross-metathesis
reaction and subsequent electrophilic substitution. The reac-
tion of the commercially available fluorous-tagged dimethyl-
chlorosilane 2 with allyl magnesium bromide afforded the
fluorous-tagged allylsilane 1 in an isolated yield of 79%
(Scheme 3).9
a Chemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, UK OX1 3TA. E-mail:
veronique.gouverneur@chem.ox.ac.uk; Fax: +44 (0)1865 275644
b AstraZeneca UK, Alderley Park, Cheshire, UK SK10 4TG
w Dedicated to Professor Andrew B. Holmes on the occasion of his
65th birthday.
z Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b804484h
Scheme 2 Fluorous approach to allylic fluorides.
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This journal is The Royal Society of Chemistry 2008
3622 | Chem. Commun., 2008, 3622–3624

Fig. 1 Side-product formed upon CM of 3d and 1 using catalyst A.
Scheme 3 Preparation of the fluorous allylsilane 1.
The electrophilic fluorination of the fluorous allylsilanes
4a–e were carried out in acetonitrile at room temperature in
the presence of 2 equivalents of Selectfluor (Scheme 5). The
results are summarised in Table 3.
All fluorous allylsilanes 4a–e underwent fluorodesilylation
and delivered the corresponding allylic fluorides 6a–e resulting
from clean transposition of the double bond. The allylic
fluorides were all purified by FSPE and using this purification
protocol, isolated in chemical yields ranging from 53 to 87%
(entries 1–5). The fluorous tag positioned two methylene
groups away from the silicon did not affect the reactivity of
the fluorous allylsilanes. Indeed, similar reaction times were
necessary for complete conversion using either the fluorous or
the corresponding non-fluorous allylsilanes.7a An additional
experiment revealed that the reaction time for the fluorination
of 4c can be significantly reduced from 24 h to only 30 min.
when the reaction was carried out at 80 1C. Using these
conditions, 6c was formed in 70% yield after FSPE (entry
3). Notably, when the fluorination of 4c was carried out with a
sub-stoichiometric amount of Selectfluor, the excess allylsilane
Scheme 4 Cross-metathesis of fluorous allylsilane 1 with 3a.
With allylsilane 1 in hand, we optimised the CM reaction
using N-allylphthalimide 3a as the olefinic partner (Scheme 4,
Table 1). The reaction conditions previously reported for this
transformation in non-fluorous series7a (5 mol% catalyst A,
DCM, reflux) led to the formation of the desired product 4a
along with a side-product not observed using non-fluorous
precursors (entry 1, Table 1). The structure of this side product
was unambiguously determined to be the truncated vinylsilane
5a (Scheme 4). This was confirmed through an independent
synthesis.9 Compound 5a is likely the result of an isomerisa-
tion process followed by alkene exchange. The formation of 5a
was eradicated when the reaction was performed in the pre-
sence of 0.5 eq. of 1,4-benzoquinone, the reaction time being
limited to 12 h.10 Under these conditions, 4a was isolated in
45% yield (entry 2, Table 1). Increasing the reaction time did
not improve conversion or E/Z selectivity but resulted in
detectable isomerisation (entry 3, Table 1).
Table 2 Cross-metathesis of 1 with various olefinsa
Entry
1
CM partner
Product
Yield (%) [E : Z ratio]
4a
45 [4 : 1]
With the initial studies completed, we prepared various
fluorous allylsilanes by cross-metathesis with a series of func-
tionalised olefinic partners including unsaturated esters and
ethers (Table 2). The reaction of the unsaturated ester 3b with
3 eq. of allylsilane 1 afforded the desired product 4b with an
isolated chemical yield of 40% (entry 2). Similar yields were
obtained when using as the olefinic partner, the benzylic ester
derivative 3c or the benzyl-protected allyl alcohol 3e (entries 3
and 5). When applying our standard conditions, the benzoyl-
protected allyl alcohol 3d delivered the product of cross-metath-
esis 4d as the major product along with up to 20% of the
undesired vinylsilane 5d (Fig. 1). Further optimisation of this
reaction was therefore required and revealed that the formation
of 5d was suppressed when the metathesis was carried out in the
presence of 5 mol% of the Hoveyda–Grubbs catalyst B instead
of catalyst A. All reactions delivered the product as mixtures of
E : Z isomers. The purification of all CM adducts was
performed using silica gel chromatography or FSPE.
2
4b
40b
3
4
4c
4d
39 [3 : 1]
36 [5 : 1]c
5
4e
42 [5 : 1]
a
3 eq. fluorous allylsilane 1, 5 mol% catalyst A, 0.5 eq. 1,4-
b
benzoquinone, DCM, reflux, 12 h. E : Z ratio could not be deter-
c
mined unambiguously from NMR. 5 mol% catalyst B.
Table 1 Optimisation of CM of allylsilane 1 with N-allylphthalimide 3a
Entry
Additive
Eq.
t/h
Ratio of 4a : 5a
Yield 4a (%) [E : Z ratio]
1
2
3
—
1,4-Benzoquinone
1,4-Benzoquinone
—
0.5
0.5
48
12
48
4 : 1
4a only
8 : 1
60 [3 : 1]
45 [4 : 1]
43 [4 : 1]
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This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3622–3624 | 3623

We are currently developing other novel fluorination–detag-
ging processes for applications in medicinal chemistry and in
18F-radiochemistry.
This work was generously supported by AstraZeneca
(CASE award to S. B.). We thank Professor D. P. Curran
(University of Pittsburgh) for very helpful discussions and for
advice to S. B.
Scheme 5 Electrophilic fluorination of 4a–e with Selectfluor.
Table 3 Fluorodetagging of 4a–e with Selectfluor
Yield
(%)
Entry Allylsilane
1
Allylic fluoride
Notes and references
53a
1 (a) H.-J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Muller, U. Obst-Sander and M. Stahl, ChemBioChem, 2004, 5, 637;
(b) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013; (c) J.-P. Begue
and D. Bonnet-Delpon, J. Fluorine Chem., 2006, 127, 992; (d) D.
O’Hagan, Chem. Soc. Rev., 2008, 37, 308; (e) S. Purser, P. R.
Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37,
320.
2
79b
2 J. A. Gladsyz, D. P. Curran and I. T. Horvath, Handbook of
Fluorous Chemistry, Wiley-VCH, Weinheim, Germany, 2004.
3 W. Zhang and D. P. Curran, Tetrahedron, 2006, 62, 11837.
4 A. Donovan, J. Forbes, P. Dorff, P. Schaffer, J. Babich and J. F.
Valliant, J. Am. Chem. Soc., 2006, 128, 3536.
3
4
87
70c
5 A. S. Zhang, C. S. Elmore, M. A. Egan, D. G. Melillo and D. C.
Dean, J. Labelled Compd. Radiopharm., 2005, 48, 203.
6 (a) P. Wipf and J. T. Reeves, Tetrahedron Lett., 1999, 40, 5139;
(b) Z. Luo, J. Williams, R. W. Read and D. P. Curran, J. Org.
Chem., 2001, 66, 4261; (c) W. Zhang, Z. Luo, C. H.-T. Chen and
D. P. Curran, J. Am. Chem. Soc., 2002, 124, 10443; (d) W. Zhang,
Org. Lett., 2003, 5, 1011; (e) A.-L. Villard, B. H. Warrington and
M. Ladlow, J. Comb. Chem., 2004, 6, 611; (f) W. Zhang and Y. Lu,
Org. Lett., 2003, 5, 2555; (g) Y. Lu and W. Zhang, Mol. Diversity,
2005, 9, 91; (h) L. A. McAllister, R. A. McCormick, S. Brand and
D. J. Procter, Angew. Chem., Int. Ed., 2005, 44, 452; (i) S. Manku
and D. P. Curran, J. Org. Chem., 2005, 70, 4470; (j) S. Fustero, A.
G. Sancho, G. Chiva, J. F. Sanz-Cervera, C. del Pozo and J. L.
Acena, J. Org. Chem., 2006, 71, 3299; (k) A.-C. Le Lamer, N.
Gouault, M. David, J. Boustie and P. Uriac, J. Comb. Chem., 2006,
63
87
5
a
b
1 eq. Selectfluor. 6b contaminated with B5% of an unidentified
c
impurity. 1 eq. Selectfluor, MeCN, 80 1C, 30 min.
8, 643; (l) S. Fustero, S. Catala
´
Acena, J. F. Sanz-Cervera and S. Me
n, S. Flores, C. del Pozo, J. L.
rida, QSAR Comb. Sci., 2006,
´
25, 753; (m) A. C. Spivey, C.-C. Tseng, J. P. Hannah, C. J. G.
Gripton, P. de Fraine, N. J. Parr and J. J. Scicinski, Chem.
Commun., 2007, 2926; (n) S. G. Leach, C. J. Cordier, D. Morton,
G. J. McKiernan, S. Warriner and A. Nelson, J. Org. Chem., 2008,
73, 2752.
7 (a) S. Thibaudeau and V. Gouverneur, Org. Lett., 2003, 5, 4891;
(b) Y.-h. Lam, C. Bobbio, I. R. Cooper and V. Gouverneur,
Angew. Chem., Int. Ed., 2007, 46, 5106; (c) S. Purser, B. Odell, T.
D. W. Claridge, P. R. Moore and V. Gouverneur, Chem.–Eur. J.,
2006, 12, 9176; (d) M. Tredwell and V. Gouverneur, Org. Biomol.
Chem., 2006, 4, 26.
was easily separated by FSPE, a result further demonstrating
the potential of fluorous chemistry in radiochemistry.
In conclusion, we have applied light fluorous chemistry for
the preparation and manipulation of allylsilanes. Since allylsi-
lanes are widely used in organic synthesis through electrophi-
lic, radical or organometallic processes, numerous fluorous
variants are likely to appear in the near future. To the best of
our knowledge, this is the first reported example of light
fluorous olefins used in
a
cross-metathesis reaction.8,11
8 For a rare example of heavy fluorous allylsilanes, see: Y. Huang,
D. Chen and F.-L. Qing, Tetrahedron, 2003, 59, 7879.
9 For further details see ESIz.
Although a complete and rigorous study on the use of fluorous
olefins in cross-metathesis will be necessary, the results
reported herein validate the feasibility of such a process.
Significantly, this is also the first example of a fluorous
detagging process featuring a C–F bond forming reaction.
10 S. H. Hong, D. P. Sanders, C. W. Lee and R. H. Grubbs, J. Am.
Chem. Soc., 2005, 127, 17160.
11 For a rare example of solid-phase olefin CM, see: A. L. Garner and
K. Koide, Org. Lett., 2007, 9, 5235.
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3624 | Chem. Commun., 2008, 3622–3624