Stereospecific anti SE2′ fluorination of allenylsilanes: Synthesis of enantioenriched propargylic fluorides

Article abstract of DOI:10.1039/b803888k

The electrophilic fluorodesilylation of enantioenriched allenylsilanes proceeds with efficient transfer of chirality. The silylation-fluorination of propargylic alcohols occurs with overall retention of stereochemistry, a result consistent with a stereosp

Full text of DOI:10.1039/b803888k

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Volume 6 | Number 10 | 21 May 2008 | Pages 1693–1856
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2WT\XRP[ꢀBRXT]RT
Véronique Gouverneur et al.
Stereospecific anti S 2¢ fluorination
of allenylsilanes: synEthesis of
enantioenriched propargylic fluorides
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www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereospecific anti SE2ꢀ fluorination of allenylsilanes: synthesis of
enantioenriched propargylic fluorides†
Laurence Carroll, Samantha McCullough, Tom Rees, Timothy D. W. Claridge and Ve´ronique Gouverneur*
Received 6th March 2008, Accepted 20th March 2008
First published as an Advance Article on the web 3rd April 2008
DOI: 10.1039/b803888k
The electrophilic fluorodesilylation of enantioenriched al-
lenylsilanes proceeds with efficient transfer of chirality. The
silylation–fluorination of propargylic alcohols occurs with
overall retention of stereochemistry, a result consistent with a
stereospecific anti SE2ꢀ mechanism for the fluorination step.
to the problem of erosion of ee occasionally observed upon
nucleophilic fluorination and it allows for the preparation of both
(+)- and (−)-propargylic fluorides using (+)-N-methylephedrine
as the unique chiral component. Scheme 1 illustrates how this can
be achieved and shows the connectivity between the nucleophilic
(DAST) and electrophilic (Selectfluor) approaches.
Innovative organofluorine chemistry is continuously attracting
interest, owing to the unique properties that the fluorine atom can
impose on a molecule.1 In this context, propargylic monofluorides
are important building blocks which can be manipulated in various
ways.2 Recently, Gre´e and Gre´e have successfully used these
alkynes as dipolarophiles in 1,3-dipolar cycloadditions including
Cu-catalysed azide–alkyne cycloaddition, a reaction commonly
referred to as click chemistry.3 Undoubtedly, easy access to enan-
tioenriched propargylic fluorides can only increase the synthetic
value of these underexplored compounds. The deoxyfluorination
of enantioenriched propargylic alcohols reported by Gre´e et al.
is based on the use of the nucleophilic fluorinating reagent di-
ethylaminosulfur trifluoride (DAST).4 This nucleophilic approach
delivered the corresponding propargylic fluorides with moderate
to excellent stereocontrol. For selected substrates, it is necessary
to carry out the reaction at low temperature in order to minimise
erosion of enantiomeric purity upon fluorination of enantioen-
riched propargylic alcohols.4d Recently, we reported that racemic
allenylsilanes are conveniently converted into propargylic fluorides
when reacted at room temperature in the presence of 1-chloro-
4-fluoro-1,4-diazonia-bicyclo[2.2.2]octane bis(tetrafluoro-borate)
(Selectfluor), a widely used electrophilic fluorinating reagent.5 This
chemistry raised several unanswered questions for the preparation
of enantioenriched propargylic fluorides, such as the efficiency of
transfer of chirality upon fluorodesilylation of optically enriched
allenylsilanes or the sense of stereocontrol for the fluorination step.
Our mechanistic hypothesis for the fluorination step (SE2ꢀ with anti
approach of the fluorinating reagent with respect to the silyl group)
led us to anticipate that both enantiomers of a target propargylic
fluoride may be accessed from a single enantioenriched propargylic
alcohol using either a nucleophilic or electrophilic fluorination
approach. We describe herein the feasibility of this approach
for the synthesis of enantioenriched propargylic fluorides and
compare the value of the electrophilic route with the well-
established nucleophilic variant. This chemistry offers a solution
Scheme 1 Synthesis of (+)- or (−)-propargylic fluorides.
Enantioenriched allenylsilanes are directly accessible from the
corresponding propargylic alcohols. Out of the various routes
available for the synthesis of enantioenriched propargylic alcohols,
we selected the method developed by Carreira et al. featuring
the addition of an in situ generated alkynylzinc reagent onto an
aldehyde in the presence of (+)-N-methylephedrine.6 This route
was attractive as it allows access to both enantiomeric propargylic
fluorides from a common aldehyde and (+)-N-methylephedrine.
This can be achieved by inverting the order of introduction of the
silyl group and the R2 substituent when preparing the allenylsilane
(Scheme 1, Routes A and B).
In our previous study, we validated the electrophilic fluorina-
tion of racemic allenyltrimethylsilanes.5 These allenylsilanes were
prepared from trimethylsilyl-substituted propargylic alcohols by
conjugated addition of an organocopper reagent.7,8 For our study
in asymmetric series, it is necessary to prepare allenylsilanes by
silylation of alkyl-substituted propargylic alcohols (Route A). This
chemistry is known to be best performed with dimethylphenylsilyl
lithium, a reagent easier to handle than trimethylsilyl lithium.9
As we did not validate the fluorination of these presumably less
reactive dimethylphenylsilyl-substituted allenes, we investigated
first the feasibility of the silylation–fluorination of non-silylated
propargylic alcohols in racemic series prior to undertaking studies
with enantioenriched derivatives.
University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road,
Oxford, UK OX1 3TA. E-mail: veronique.gouverneur@chem.ox.ac.uk;
Fax: +44 (0)1865 275 644
† Electronic supplementary information (ESI) available: Procedures for
the preparation of all racemic and enantioenriched compounds are
provided as well as full characterisation of all new compounds. See DOI:
10.1039/b803888k
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1731–1733 | 1731
©

Using chemistry reported by Fleming et al.,8 the alkynols
( )-1a–c were converted in good yields into the allenylsilanes
( )-2a–c upon mesylation followed by conjugate addition of
dimethylphenylsilyl lithium in the presence of copper cyanide and
lithium chloride in tetrahydrofuran (Scheme 2). The fluorination
of ( )-2a–c was successfully performed at room temperature with
Selectfluor in acetonitrile. The isolated yields for ( )-3a and ( )-
3b do not reflect the efficiency of the fluorination process but
the complications arising upon purification of the propargylic
fluorides that were contaminated by dimethylphenylsilyl fluoride,
a non volatile side product of the reaction. In comparison with the
fluorodesilylation of trimethylsilyl allenes, longer reaction times
(up to 24 hours) were necessary to fully convert ( )-2a and
( )-2b into ( )-3a and ( )-3b respectively. As anticipated, the
electron withdrawing phenyl group of SiMe2Ph reduces the
reactivity of the allenylsilane towards the electrophilic fluorinating
reagent.10 The fluorination of ( )-2c is of particular interest as
it showed unambiguously that the electrophilic fluorination is
accompanied by the loss of the trimethylsilyl group rather than the
dimethylphenylsilyl group when these two substituents compete
(Scheme 2).
Scheme 3 Synthesis of allenylsilanes (R)-2b and (S)-2d
dehydroxyfluorination of the propargylic alcohol (R)-1b using
DAST in THF at −78◦C. This reaction delivered (S)-3b in
70% yield (Scheme 4, eq. 3). The signs of optical rotation
unambiguously confirmed that opposite enantiomers are formed
for the fluorination of (R)-2b and (S)-2d. In addition, the [a]D value
of the propargylic fluoride prepared by nucleophilic fluorination
of (R)-1d had a sign matching with the product resulting from
the electrophilic fluorination of the allenylsilane (S)-2d. These
data allowed us to assign the absolute configurations of all
propargylic fluorides as it has been reported that the DAST-
mediated fluorination of propargylic fluorides occurred with
inversion of configuration (SN2).4d
Scheme 2 Synthesis and fluorodesilylation of ( )-2a–c.
Having validated in racemic series the feasibility of the fluori-
nation of both trimethylsilyl- and dimethylphenylsilyl-substituted
allenes, we investigated next the fluorination of enantioenriched
precursors. We selected the propargylic fluoride (S)-3b and its
enantiomer (R)-3b as our targets. The propargylic alcohols (R)-1b
and (R)-1d were prepared with high enantiomeric excesses (>94%
ee) according to the methodology developed by Carreira et al.
and revised by Rein et al (Scheme 3).6,11 The conversion of the
enantioenriched alkynols into the corresponding allenylsilanes
(R)-2b and (S)-2d was carried out using the reaction conditions
applied for the preparation of racemic samples and proved to
be uneventful. Difficulty arose when attempting to determine the
enantiomeric purity of the allenylsilanes. All of our attempts to
measure their ee prior to fluorination failed using either chiral
GC or HPLC. We assumed that, in analogy with literature
data,8 the conjugated addition of the organolithium proceeded
stereospecifically anti to the mesylate (Scheme 3).
Scheme 4 Fluorination of (R)-2b, (S)-2d and (R)-1b.
Measurement of the enantiomeric excesses of propargylic
fluorides is notoriously difficult. Standard methods such as use
of chiral HPLC and chiral GC lead to elimination of HF or no
separation of the enantiomers. The only method currently known
for measuring the enantiomeric excess of a propargylic fluoride has
been developed by Courtieu et al., which involves the use of chiral
liquid crystalline solvents such as poly(c-benzyl L-glutamate)
(PBLG) with chloroform.12 We employed this approach using
13C NMR spectroscopy to assess the enantiomeric purity of each
fluoride via the resulting peak resolution of the two sp carbon
centres (Fig 1; see Supporting Information for details†). Pleasingly,
the propargylic fluorides resulting from electrophilic fluorination
gave high enantiomeric excesses, suggesting minimal loss of
enantiomeric purity for the synthesis of the allenylsilanes from
the corresponding propargylic alcohol and for the fluorination
step. The direct dehydroxyfluorination using DAST was less
satisfactory and led to significant erosion of enantiomeric excess
(ee ≈ 30%). For the propargylic fluoride (−)-3b prepared by
fluorodesilylation of the trimethylsilylallene (S)-2d, we estimate
any second minor enantiomer to be present at less than 2% of
The electrophilic fluorodesilylation of the enantioenriched al-
lenylsilanes (R)-2b and (S)-2d was performed using Selectfluor in
acetonitrile and afforded the corresponding propargylic fluorides
(R)-3b and (S)-3b in 47% and 70% yield respectively (Scheme 4,
eq. 1 and 2). For comparative studies, we also performed the
1732 | Org. Biomol. Chem., 2008, 6, 1731–1733
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©

Scheme 5 Mechanistic pathways for both nucleophilic and electrophilic
fluorinations.
process. The propargylic alcohol (R)-1b could be converted to both
enantiomeric propargylic fluorides 3b using either the nucleophilic
(inversion) or electrophilic (overall retention) approach. The
ee measured for the propargylic fluoride (S)-3b prepared by
nucleophilic fluorination was determined to be ∼30%, suggesting
significant loss of enantiomeric purity upon fluorination. This
limitation was corrected by validating route B that led to (S)-
3b with an enantiomeric excess estimated to be superior to
95%. Notably, the electrophilic route allowed access to both
enantiomers using (+)-N-methylephedrine as the unique chiral
non racemic component.
Fig. 1 Regions from 13C NMR spectra recorded in chiral liquid crystalline
media showing the carbon sp centres; A: racemic sample; B: sample
prepared reacting (S)-2d with Selectfluor ee >96%; C: sample prepared
reacting (R)-2b with Selectfluor ee > 90%; D: sample prepared treating
(R)-1b with DAST ee ≈ 30%.
Notes and references
1 B. E. Smart, J. Fluorine Chem., 2001, 109, 3.
2 J. A. L. Miles and J. M. Percy, Sci. Synth., 2006, 34, 277.
3 D. Gre´e and R. Gre´e, Tetrahedron Lett., 2007, 48, 5435.
4 (a) M. Prakesh, E. Kerouredan, D. Gre´e, R. Gre´e, J. DeChancie and
K. N. Houk, J. Fluorine Chem., 2004, 125, 537; (b) M. Prakesh, D. Gre´e
and R. Gre´e, Acc. Chem. Res., 2002, 35, 175; (c) M. Prakesh, D. Gre´e
and R. Gre´e, J. Org. Chem., 2001, 66, 3146; (d) V. Madiot, P. Lesot,
D. Gre´e, J. Courtieu and R. Gre´e, Chem. Commun., 2000, 169; (e) V.
Madiot, D. Gre´e and R. Gre´e, Tetrahedron Lett., 1999, 40, 6403; (f) D.
Gre´e, V. Madiot and R. Gre´e, Tetrahedron Lett., 1999, 40, 6399.
5 L. Carroll, M. C. Pacheco, L. Garcia and V. Gouverneur, Chem.
Commun., 2006, 39, 4113.
the major, corresponding to an ee >96%. For (+)-3b accessed
from (R)-2b, the slight resonance shoulder leads us to take a
conservative approach to estimating the ee. Whilst we believe this
shoulder arises from residual lineshape distortions rather than the
presence of a second resonance (the magnitude of the separation
DmSR would be 2.8 Hz at most which is significantly below the
>3.5 Hz enantiomeric separations seen in Fig. 1), the intensity
of this minor peak would represent 15% of the major at most, as
judged by peak summation. This leads to a conservative estimate
of the ee as being >75% for (+)-3b. However, since a similar and
significant resonance shoulder appears in the racemic sample, we
believe the ee to be >90%.
The enantiomeric excesses measured by 13C NMR and the
assignment of absolute configurations confirmed that the SE2ꢀ
fluorination of the allenylsilanes (R)-2b, (S)-2d occurred with
efficient transfer of chirality and stereospecifically anti with respect
to the silyl. These results suggest that the mechanistic pathway for
the electrophilic fluorination of allenylsilanes is consistent with
other electrophilic substitution reactions (Scheme 5).13
6 (a) N. K. Anand and E. M. Carreira, J. Am. Chem. Soc., 2001, 123,
9687; (b) D. E. Frantz, R. Fassler and E. M. Carreira, J. Am. Chem.
Soc., 2000, 122, 1806.
7 T. Nishiyama, T. Esumi, Y. Iwabuchi, H. Irie and S. Hatakeyama,
Tetrahedron Lett., 1998, 39, 43.
8 I. Fleming, R. S. Roberts and S. C. Smith, J. Chem. Soc., Perkin Trans.
1, 1998, 1209.
9 W. C. Still, J. Org. Chem., 1976, 41, 3063.
10 (a) N. Shimizu, S.-I. Watanabe, F. Hayakawa, S. Yasuhara, Y. Tsuno
and T. Inazu, Bull. Chem. Soc. Jpn., 1994, 67, 500; (b) M. A. Brook and
A. Neuy, J. Org. Chem., 1990, 55, 3609.
11 D. Strand, P.-O. Norby and T. Rein, J. Org. Chem., 2006, 71, 1879.
12 (a) A. Meddour, P. Berdague, A. Hedli, J. Courtieu and P. Lesot, J. Am.
Chem. Soc., 1997, 119, 4502; (b) M. Jakubcova, A. Meddour, J.-M.
Pechine, A. Baklouti and J. Courtieu, J. Fluorine Chem., 1997, 86,
149; (c) I. Canet, J. Courtieu, A. Loewenstein, A. Meddour and J.-M.
Pechine, J. Am. Chem. Soc., 1995, 117, 6520.
In summary, we have shown that enantioenriched propargylic
fluorides can be synthesised from enantioenriched allenylsilanes.
The mechanism of fluorination is a highly stereospecific anti SE2ꢀ
13 M. J. C. Buckle, I. Fleming, S. Gil and K. L. C. Pang, Org. Biomol.
Chem., 2004, 2, 749; M. J. C. Buckle and I. Fleming, Tetrahedron Lett.,
1993, 34, 2383.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1731–1733 | 1733
©