Electrophilic fluorodesilylation of allenylmethylsilanes: A novel entry to 2-fluoro-1,3-dienes

Article abstract of DOI:10.1021/ol047319z

(Chemical Equation Presented) Various fluorodienes were prepared by treatment of the corresponding allenylmethylsilanes with Selectfluor. This is the first route to these compounds not based on the use of a fluorinated building block. The reaction allows

Full text of DOI:10.1021/ol047319z

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1267-1270
Electrophilic Fluorodesilylation of
Allenylmethylsilanes: A Novel Entry to
2-Fluoro-1,3-dienes
Ma Carmen Pacheco and Ve´ronique Gouverneur*
UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, OX1 3TA Oxford, UK
Veronique.gouVerneur@chem.ox.ac.uk
Received December 29, 2004
ABSTRACT
Various fluorodienes were prepared by treatment of the corresponding allenylmethylsilanes with Selectfluor. This is the first route to these
compounds not based on the use of a fluorinated building block. The reaction allows the preparation of 2-fluoro-1,3-dienes with several
substitution patterns, including di- and trisubstituted compounds.
Silicon-containing π-nucleophiles are extremely valuable
synthetic intermediates, reacting with electrophiles in an SE2′
fashion to give structurally diverse products.1 In these
reactions, the silyl group enhances the reactivity of the
π-nucleophile and controls the sense of regiocontrol upon
addition of the electrophile. In addition to allylsilanes2 and
allenylsilanes3 acting as allylic and propargylic transfer
reagents, respectively, the SE2′ reaction of allenylmethylsi-
lane has been used for the introduction of 1,3-dienyl-2-yl
groups onto electrophiles such as aldehydes, acetals, and
iminiums and also in [2 + 2] cycloadditions.4 These
substrates have also been converted into the corresponding
bromo- or iododienes upon addition of bromine or iodine,
followed by treatment with tetrabutylammonium fluoride.5
To the best of our knowledge, the reactivity of allenyl-
methylsilanes in the presence of electrophilic fluorinating
reagents has not been studied. As part of our research
program aimed at developing novel synthetic methodologies
for the preparation of fluorinated compounds, we have
reported that vinylsilanes and allylsilanes react with 1-chlo-
romethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2.]octane bis(tet-
rafluoroborate), a reagent called Selectfluor, to give struc-
turally diverse fluorinated compounds such as fluoroalkenes,
difluorinated amides, ethers, or alcohols, as well as allylic
fluorides.6 In this context, we became interested in the
development of a novel reaction for the preparation of
fluorinated dienes according to a protocol featuring the
introduction of the fluorine as the very last step of a synthetic
sequence. We report in this Communication an additional
application of the concept of electrophilic fluorodesilylation,
(1) (a) Buckle, M. J. C.; Fleming, I.; Gil, S.; Pang, K. L. C. Org. Biomol.
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10.1021/ol047319z CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/01/2005

the synthesis of 2-fluoro-1,3-dienes from the corresponding
allenylmethylsilanes (Scheme 1). This is the first route to
superior if these reactions are carried out in THF at -78 °C
instead of in ether. The starting propargylic alcohols were
prepared according to standard procedures from the literature
(Table 1).12
Scheme 1. Allenylmethylsilanes as Precursors of Fluorodienes
Table 1. Preparation of Allenylmethylsilanes 1a-i
yield
yield
entry
R
R′
product (%) product (%)
1
2
3
4
5
6
7
8
9
PhCH2CH2 Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
94
95
74
91
85
99
87
64
71
1a
1b
1c
1d
1e
1f
1g
1h
1i
81
79
49
83
69
80
75
77
54
BnOCH2
nC5H11
nC5H11
Me
Ph
Me
these valuable compounds that is not based on the use of a
fluorinated building block. Indeed, fluorinated cyclopropanes7
and fluorinated unsaturated aldehydes8 are two of the most
commonly used precursors of monofluorinated dienes, which
are obtained upon ring opening and Wittig alkenylation,
respectively. Other elegant routes toward fluorinated dienes
have also been developed such as various elimination
processes9 and palladium-mediated couplings of fluorinated
precursors.10
PhCH2CH2 SiMe3
PhCH2CH2
H
H
H
H
AcOCH2
BnOCH2
Ph
Our initial studies began with allenylsilane 1a as the dienyl
transfer reagent (Table 2). Reaction of 1a with 1 equiv of
To prepare the starting allenylmethylsilanes 1a-i, we
adapted a procedure described in the literature.4b,11 Several
substituted trimethylsilylmethylbutadienes were obtained in
good overall yields by the reaction of the propargylic
mesylates 2a-i freshly prepared from the corresponding
alcohols 3a-i, with Me3SiCH2MgCl in the presence of an
excess of CuCN and LiCl. The use of these two salts is
essential for effecting γ-attack of the Grignard reagent
leading to the exclusive formation of the desired allenyl-
methylsilanes. We found that the yields are consistently
Table 2. Electrophilic Fluorination of Silane 1a
fluorinating
reagent
time
(h)
yield
4a (%)
entry
solvent
additive
1
2
3
4
5
6
7
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
acetonitrile
acetone
THF
MeOH
acetonitrile NaHCO3
120
120
120
21
27
27
51a
49
5
43b
60
64
39
(7) (a) Patrick, T. B.; Rogers, J.; Gorrell, K. Org. Lett. 2002, 4, 3155-
3156. (b) Bessard, Y.; Kuhlmann, L.; Schlosser, M. Tetrahedron 1990, 46,
5230-5236. (c) Schlosser, M.; Dahan, R.; Cottens, S. HelV. Chim. Acta
1984, 67, 284-288. (d) Spahi, B.; Schlosser, M. HelV. Chim. Acta 1980,
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Weyerstahl, P.; Klamann, D.; Finger, C.; Fligge, M.; Nerdel, F.; Buddrus,
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1993, 49, 1445-1456. (i) Shi, G.-Q.; Cottens, S.; Shiba, S. A.; Schlosser,
M. Tetrahedron 1992, 48, 10569-10574.
acetone
acetone
NaHCO3
NaHCO3
48
a 4a was contaminated with 5% of 5a. b Ratio of 4a:5a ) 2:1.
(8) (a) Ni, J.; Liu, J.; Colmenares, L. U.; Liu, R. S. H. Tetrahedron Lett.
2001, 42, 1643-1644. (b) Liu, J.; Colmenares, L. U.; Liu, R. S. H.
Tetrahedron Lett. 1997, 38, 8495-8498. (c) Francesca, A.; Alvarez, R.;
Lo´pez, S.; de Lera, A. R. J. Org. Chem. 1997, 62, 310-319. (d) Matsuo,
N.; Kende, A. S. J. Org. Chem. 1988, 53, 2304-2308.
Selectfluor in acetonitrile afforded 51% of the desired
fluorinated diene 4a after 120 h. This compound was
contaminated with 5% of the nonfluorinated diene 5a
resulting from a protodesilylation process (entry 1). The use
of acetone as the reaction solvent did not result in any
substantial changes, whereas THF was found not to be
suitable for this transformation (entries 2 and 3). Methanol
was also tested as a solvent for this transformation, allowing
the formation of the desired diene 4a along with the
undesired nonfluorinated diene 5a in 43% combined yield
(9) Patel, S. T.; Percy, J. M.; Wilkes, R. D. Tetrahedron 1995, 51,
11327-11336. (b) Hedhli, A.; Bakloutti, A. Tetrahedron Lett. 1995, 36,
4433-4436.
(10) (a) Gernert, D. L.; Ajamie, R.; Ardecky, R. A.; Bell, M. G.;
Leibowitz, M. D.; Mais, D. A.; Mapes, C. M.; Michellys, P. Y.; Rungta,
D.; Reifel-Miller, A.; Tyhonas, J. S.; Yumibe, N.; Grese, T. A. Bioorg.
Med. Chem. Lett. 2003, 13, 3191-3195. (b) Peng, S.; Qing, F.-L.; Li, Y.-
Q.; Hu, C.-M. J. Org. Chem. 2000, 65, 694-700.
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Matsuda, F.; Kawatsura, M.; Hosaka, K.-I.; Shirahama, H. Chem. Eur. J.
1999, 5, 3252-3259. (c) Osa, Y.; Kobayashi, S.; Sato, Y.; Suzuki, Y.;
Takino, K.; Takeuchi, T.; Miyata, Y.; Sakaguchi, M.; Takayanagi, H. J.
Med. Chem. 2003, 46, 1948-1956. (d) Wipf, P.; Rahman, L. T.; Rector, S.
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41, 1084-1091.
1
in a ratio of ca. 2:1 as judged by H NMR analysis of the
purified material after 21 h. As expected, this polar protic
solvent favors the protodesilylation process but also sub-
(12) Experimental details can be found in Supporting Information.
1268
Org. Lett., Vol. 7, No. 7, 2005

stantially reduces the reaction time (entry 4). We suppressed
fully the formation of the undesired nonfluorinated diene 5a
resulting from a protodesilylation process by adding 1.2 equiv
of NaHCO3 to the reaction mixture using acetonitrile or
acetone as the reaction solvent (entries 5 and 6). The presence
of the base not only prevents the formation of the non-
fluorinated diene 5a, therefore increasing the reaction yield,
but also reduces substantially the reaction time (27 versus
120 h). The use of acetone facilitates the workup procedure
and the purification of the product; therefore, this solvent
was selected for subsequent reactions. Finally, we probe the
reactivity of N-fluorosulfonimide13 under similar conditions,
but the use of this alternative reagent as the electrophilic
source of fluorine was not advantageous (entry 7).
best yields were obtained for substrates with a substituent
that can reinforce the â-effect14 of the trimethylsilyl group
upon addition of Selectfluor (entries 1-3, 8, and 9). As
anticipated, the lowest yield of desired fluorinated diene was
obtained for substrate 1e as this allenylsilane features an
additional trimethylsilyl group on a position where it
destabilizes the development of positive charge upon addition
of Selectfluor (entry 5). The presence of the electron-
withdrawing acetyl group of the achiral substrate 1g is
probably responsible for the lower yield of the fluorinated
diene 4g. In contrast, the two additional achiral terminal
allenes 1h,i were transformed into the corresponding 2,3-
disubstituted 1,3-dienes 4h and 4i in good yields (79 and
99%, respectively). The racemic allenylsilanes 1a-f led to
the formation of the desired di- or trisubstituted dienes as
mixtures of E/Z isomers in a 2/1 ratio with the exception of
diene 4e that was formed as a 3/1 mixture of the E/Z isomers.
The E isomer was the major product. These stereoisomers
are difficult to separate upon purification. The E/Z ratio was
determined by 1H NMR, and the configuration of the double
bond was assigned with the coupling constant of the vinyl
proton and fluorine ((E)-4 JH-F ) 22.0-28.0 Hz; (Z)-4 JH-F
) 31.6-38.0 Hz). In this series, the nature of the substituent
of the starting allenysilane does not affect significantly the
E/Z ratio of the fluorodienes.
The optimized reaction conditions were applied to various
allenylsilanes 1b-i, and the results are summarized in Table
3. The methodology allows the preparation of fluorodienes
Table 3. Fluorodesilylation of 1a-h with Selectfluora
Scheme 2. Suggested Mechanism and Preferential Formation
of the E Isomer.
From a mechanistic point of view, we propose that
Selecfluor reacts as an electrophile according to an SE2′
mechanism with the regiocontrolled addition of the fluorine
leading to the development of the positive charge â to the
trimethylsilyl group. The desilylation process restores neu-
trality and affords the desired fluorodiene. Our optimization
studies revealed that the addition of NaHCO3 prevents
protodesilylation, thereby increasing the reaction yield. The
formation of the major E isomer indicates that the electro-
phile approaches preferentially the central carbon of the
allenylmethylsilane from the side opposite to the sterically
demanding R substituent, with the organosilane adopting a
reactive conformation, allowing early stabilization of the
developing positive charge. This mechanistic pathway, well
a Conditions: 1 equiv of Selectfluor, 1.2 equiv of NaHCO3, acetone, rt,
1
up to 48 h. b Conversion assigned by H NMR.
with different degrees of substitution. The dienes recovered
after workup are sufficiently clean to be used without further
purification. The yields range from 11 to 99% depending
on the substitution pattern of the starting allenylsilane. The
(13) (a) Davis, F. A.; Han, W. Tetrahedron Lett. 1991, 32, 1631-1634.
(b) Davis, F. A.; Han, W. Tetrahedron Lett. 1992, 33, 1153-1156. (c) Davis,
F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60, 4730-4737.
(14) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,
X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183-190.
Org. Lett., Vol. 7, No. 7, 2005
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in line with what has been suggested for other electrophiles
such as iminiums or aldehydes, contrasts with the reactivity
of bridging electrophiles such as iodine and bromine. Indeed,
these reagents are believed to add on the double bond remote
from the silyl group to give a product of addition that is
then treated in the presence of TBAF to trigger the elimina-
tion process leading to the formation of the corresponding
2-iodo- or 2-bromo-1,3-diene.5
bifunctional allenylmethylsilanes that allow the sequential
addition of two electrophiles, one of them being Selectfluor.
Acknowledgment. We thank Marc Gingell and Dr. Sarah
Lee for preliminary synthetic efforts on this project. This
work was generously supported by the Spanish Ministry of
Education (EX-31/10/03) and the European Community
(MEIF-CT-2004-515589) through funding to MP.
In summary, we have shown that the concept of electro-
philic fluorodesilylation can be applied to allenylmethyl-
silanes as an entry to 2-fluorodienes with various substitution
patterns. The methodology is best applied to fluorodienes
that cannot be formed as mixtures of E/Z isomers. This is
the first route to these compounds not based on the use of
fluorinated building blocks. We are currently expanding this
chemistry to more elaborated fluorinated dienes using
Supporting Information Available: Experimental details
and spectroscopic data for all new propargylic alcohols,
mesylates, allenylmethylsilanes, and fluorodienes. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
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Org. Lett., Vol. 7, No. 7, 2005