Sequential Cross-Metathesis/ Electrophilic Fluorodesilylation: A Novel Entry to Functionalized Allylic Fluorides

Article abstract of DOI:10.1021/ol035991a

(Equation Presented) Various allylic fluorides were prepared using a two-step process involving a cross-metathesis of allyltrimethylsilane with different olefinic partners followed by a fluorodesilylation of the corresponding functionalized allylsilanes w

Full text of DOI:10.1021/ol035991a

ORGANIC
LETTERS
2
003
Vol. 5, No. 25
891-4893
Sequential Cross-Metathesis/
Electrophilic Fluorodesilylation: A Novel
Entry to Functionalized Allylic Fluorides
4
S e´ bastien Thibaudeau and V e´ ronique Gouverneur*
UniVersity of Oxford, The Dyson Perrins Laboratory,
South Parks Road, OX1 3QY Oxford, U.K.
Veronique.gouVerneur@chem.ox.ac.uk
Received October 13, 2003
ABSTRACT
Various allylic fluorides were prepared using a two-step process involving a cross-metathesis of allyltrimethylsilane with different olefinic
partners followed by a fluorodesilylation of the corresponding functionalized allylsilanes with Selectfluor.
The ability of fluorine to alter the physical and chemical
properties of organic molecules has been used in the design
of fluorine-containing materials and bioactive compounds.
General methodologies to access fluorine-substituted targets
are still limited, probably because of the abnormal reactivity
often displayed by fluorine and fluorine-containing groups
when compared with other halo substituents. Surprisingly,
only a few methodologies are available for the preparation
of allylic fluorides despite the enormous synthetic potential
of this functional group.
to allylic fluorides, but this technology lacks generality and
requires starting materials that are not readily available.3
With the appearance of electrophilic sources of fluorine,
1
4
the concept of electrophilic fluorodesilylation has emerged
and our group has reported on how this concept can be
applied to vinylsilanes and allylsilanes as an entry to
5
fluoroolefins and enantioenriched non functionalized allylic
6
fluorides, respectively. This letter will further report on the
synthetic applications of electrophilic fluorodesilylation of
allylsilanes and will elaborate on the scope and limitations
of an improved strategy combining a cross-metathesis (CM)
reaction with a fluorodesilylation process as a direct entry
to various functionalized allylic fluorides.
Allylic fluorides are often prepared by nucleophilic
displacement of allylic alcohols with reagents such as
(diethylamino)sulfur trifluoride (DAST), but this transforma-
tion suffers from the formation of side products as a result
of allylic transposition. The ring opening of tertiary cyclo-
As an alternative to the Wittig olefination using the
2
7
3 2 3
Seyferth-Fleming phosphorane Ph PdCHCH SiMe , cross-
propyl silyl ethers with DAST provides an alternative route
(2) (a) Middleton, W. J., US Patent 3914265, 1975. (b) Blackburn, G.
(
1) For general reviews on the physical properties of fluorinated
M.; Kent, D. E. J. Chem. Soc., Chem. Commun. 1981, 511. (c) Piva, O.
Synlett 1994, 729. (d) Gr e´ e, D. M.; Kermarrec, C. J. M.; Martelli, J. T.;
Gr e´ e, R. L.; Lellouche, J.-P.; Toupet, L. J. J. Org. Chem. 1996, 61, 1918.
(e) Kermarrec, C. J. M.; Madiot, V.; Gr e´ e, D.; Meyer, A.; Gree, R
Tetrahedron Lett. 1996, 61, 1918.
compounds: (a) Smart, B. E. In Chemistry of Organic Fluorine Compounds
II: A Critical ReView; Hudlicky, M., Pavlath, A. E., Eds.; ACS Monograph
1
(
87; American Chemical Society: Washington, DC, 1995; pp 979-1010.
b) Smart, B. E. In Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum
Publishing Corp.: New York, 1994; pp 57-88. For applications of
organofluorine compounds in pharmaceutical development, see, for ex-
ample: (c) Edwards, P. N. In Organofluorine Chemistry: Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;
Plenum Publishing Corp.: New York, 1994; pp 501-541. (d) Ojima, I.,
McCarthy, J. R. ,Welch, J. T., Eds. Biomedical Frontiers of Fluorine
Chemistry; ACS Symposium Series 639; American Chemical Society:
Washington, DC, 1996. (e) Welch, J. T.; Eswarakrishnan, S. Fluorine in
Bioorganic Chemistry; John Wiley and Sons: New York, 1991.
(3) Kirihara, Masayuki; Kambayashi, Toshihiro; Momose, Takefumi
Chem. Commun. 1996, 10, 1103.
(4) Gouverneur, V.; Greedy, B. Chem. Eur. J. 2002, 8, 766.
(5) Greedy, B.; Gouverneur, V. Chem. Commun. 2001, 233.
(6) Greedy, B.; Paris, J.-M.; Vidal, T.; Gouverneur, V. Angew. Chem.,
Int. Ed. 2003, 42, 3291.
(7) Seyferth, D.; Wursthorn, K. R.; Mammarella, R. E. J. Org. Chem.
1977, 42, 3104. (b) Seyferth, D.; Wursthorn, K. R.; Lim, T. F. O.; Sepelak,
D. J. J. Organomet. Chem. 1979, 181, 293. (c) Fleming, I.; Paterson, I.
Synthesis 1979, 446.
1
0.1021/ol035991a CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2003

metathesis has recently gained increasing significance as a
novel process for the preparation of various allylsilanes due
Table 1. CM of Allyltrimethylsilane with Various Olefinsa
to the availability of catalysts with varied activities such as
8
1
and 2. We reasoned that the CM reaction should allow
direct access to various allylsilanes which, upon fluorination
using an electrophilic source of fluorine such as F-TEDA
(also called Selectfluor), might lead to the regioselective
preparation of structurally diverse allylic fluorides that are
difficult to prepare by other means. In this strategy, the
trimethylsilyl group enhances the reactivity of the alkene
toward the addition of F-TEDA and controls the regiose-
lectivity of the addition by virtue of the stabilization of the
cation â to the silicon (Scheme 1).
Scheme 1. General Strategy toward Allylic Fluorides
a
3
equiv of allyltrimethylsilane, 5 mol % of 2, DCM, reflux, 48 h.
Our study began by subjecting allyltrimethylsilane to the
CM reaction with a series of functionalized olefinic partners,
including various protected alcohols and allylic amines,
was also found to be a good olefinic partner for the CM
reaction with allyltrimethylsilane. This transformation af-
forded the desired allylsilane 4f with a chemical yield of
89% and a E/Z ratio of 3/1.
For the reactions resulting in the formation of a single
stereoisomer such as the cross-metathesis of ethylvinyl ketone
2-vinyl-1,3-dioxolane, as well as unsaturated carbonyl de-
rivatives such as esters, ketones, or imides. Typically, the
CM reactions were performed in dichloromethane at reflux
in the presence of 5 mol % of catalyst 2. Our results are
summarized in Table 1.
3
g and of the vinyl-2,3-dioxolane 3h, the Z-isomer was not
1
13
The reaction of the benzyl-protected allylic alcohol 3a with
detected in the crude mixtures by either H or C NMR,
suggesting a greater than 95:5 selectivity in favor of the
E-olefin. Finally, a cross-metathesis was attempted with the
gem-substituted olefin 3i in order to produce the trisubstituted
allylsilane 4i. Unfortunately, the chemical yield for this
transformation never exceeded 13% suggesting that this
substrate should be prepared according to one of the multistep
3
equiv of allyltrimethylsilane afforded the desired product
4a with an isolated chemical yield of 58% as an inseparable
mixture of E and Z isomers (E/Z ) 4:1). Similarly,
unsaturated esters 3b, 3c, and 3d reacted with allyltrimeth-
ylsilane to give the desired cross-metathesis products 4b-d
as inseparable mixtures of E and Z stereoisomers with
chemical yields ranging from 54% to 84%. The major
stereoisomer for all these transformations was consistently
the E-isomer. The stereoselectivity of the product 4e resulting
from a cross-metathesis with the protected allylamine 3e was
superior with an E/Z ratio of 9/1. This product was obtained
with a chemical yield of 70%. The N-allylphthalimide 3f
9
procedures reported in the literature. For all the reactions
that gave the products as the E- and Z-isomers, the mixture
of stereoisomers was engaged in the next step.
Our next goal was to validate the feasibility of the
electrophilic fluorodesilylation of the functionalized allylsi-
lanes 4a-i. These transformations were carried out in
acetonitrile at room temperature in the presence of 1 equiv
of Selectfluor (Table 2).
(8) For general reviews on cross-metathesis: (a) Chatterjee, A. K.; Choi,
T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(
(
b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. For
Allylsilane 4a possessing an ether functionality was
smoothly converted into the corresponding allylic fluoride
references on CM of allyltrimethylsilane, see, for example: (d) Crowe, W.
E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 2117. (e)
Bouzbouz, S.; De Lemos, E.; Cossy, J. AdV. Synth. Catal. 2002, 344, 627.
(9) See for example: Vidari, G.; Lanfranchi, G.; Masciaga, F.; Moriggi,
J.-D. Tetrahedron: Asymmetry 1996, 7, 3009.
(f) Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett. 2001, 3, 2209..
4892
Org. Lett., Vol. 5, No. 25, 2003

respectable yields (entries 5 and 6). To the best of our
knowledge, the methodology reported here is the most
expeditious route to these compounds. Indeed, products
similar to 5e or 5f are more often prepared by treating the
corresponding allylic amino alcohol with DAST but these
reactions suffer from poor selectivity as a result of allylic
transposition. Our technology circumvents this problem
with the trimethylsilyl group controlling the regioselectivity
of the addition of the fluorinating agent efficiently. Allyl-
silane 4g did not react with Selectfluor (entry 7). Only
starting material was recovered after prolonged reaction time.
For this substrate, the presence of the necessary cation
Table 2. Fluorodesilylation of 4a-i with Selectfluora
1
0
2 3
stabilizing group (CH SiMe ) is not sufficient to overcome
the electron withdrawing effect of the carbonyl functionality.
In contrast, allylsilane 4h possessing the acetal-protected
aldehyde could be cleanly converted into the corresponding
allylic fluoride 5h. No yield was reported for this product
due to its volatility making its purification difficult (entry
1
8
). Nevertheless, the H NMR of the crude mixture revealed
solely the presence of the desired product (entry 8). Finally,
we have also applied the methodology to the formation of
the quaternary fluorinated allylic compound 5i which was
isolated with a chemical yield of 79% (entry 9).
In conclusion, the versatility of the technology described
herein makes this chemistry a useful and highly practical
alternative to other methods for the construction of allylic
fluorides from alkenes. Most importantly, this investigation
sets the stage for the application of more elaborated targets
as numerous functional groups are compatible with this
sequential CM/electrophilic fluorodesilylation process, thus
allowing the introduction of the fluorine at a later stage of a
synthetic plan.
a
equiv of Selectfluor, acetonitrile, room temperature, 48 h. b Conver-
1
sion.
with an isolated chemical yield of 71% (entry 1). It is not
clear why the ester 4b was found to be a better substrate
than 4c for the fluorodesilylation (chemical yield of 74%
for 5b but only 33% for the formation of 5c). Indeed, no
Acknowledgment. This work was generously supported
by The Cancer Research UK (grant to S.T.) and AstraZeneca
research grant to V.G.).
(
1
other products could be detected by H NMR of the crude
Supporting Information Available: Experimental details
reaction mixture of the allylsilane 4c with Selectfluor
suggesting that 5c might be sensitive to purification. The
â-fluorinated ester 5d was easily accessible using our
methodology (entry 4, yield 69%) with no detectable side
product resulting from an elimination process, a result that
reflects the mildness of the conditions used for the fluorina-
tion step. The vicinal fluorinated protected amines 5e and
and spectroscopic data for all allylsilanes 4a-i and the allylic
fluorides 5a-i. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL035991A
(10) Van Overmeire, I.; Boldin, S. A.; Venkatamaran, K.; Zisling, R.;
De Jonghe, S.; Van Calenbergh, S.; De Keukeleire, D.; Futerman, A. H.;
5f were also obtained from the corresponding allylsilanes in
Herdewijn, P. J. Med. Chem. 2000, 43, 4189.
Org. Lett., Vol. 5, No. 25, 2003
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