A convergent, unified approach to functionalized fluoro- and trifluoromethyl alkenes

Article abstract of DOI:10.1021/ol3023903

A modular, convergent, and operationally simple route to trifluoromethyl alkenes and vinyl fluorides involving a unique carbon-oxygen bond homolysis is reported. Highly functionalized trifluoromethyl alkenes and vinyl fluorides were obtained in good yield

Full text of DOI:10.1021/ol3023903

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Convergent, Unified Approach
to Functionalized Fluoro- and
Trifluoromethyl Alkenes
ꢀ
Laurent Debien, Beatrice Quiclet-Sire, and Samir S. Zard*
ꢁ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128
Palaiseau Cedex, France
Zard@poly.polytechnique.fr
Received August 28, 2012
ABSTRACT
A modular, convergent, and operationally simple route to trifluoromethyl alkenes and vinyl fluorides involving a unique carbonÀoxygen bond
homolysis is reported. Highly functionalized trifluoromethyl alkenes and vinyl fluorides were obtained in good yields and good selectivity.
It is well established that the inclusion of fluorine atoms
into a given molecule modifies profoundly and uniquely its
chemical stability, bioavailability, and lipophilicity.1 Not
surprisingly, organofluorine derivatives are in increasing
demand in the pharmaceutical, agrochemical, and material
sciences areas.2 Fluorinated molecules now account for a
quarter to a third of all medicines and agrochemicals on the
market.3 Since fluorine-containing natural products are very
rare, organofluorine compounds must be man-made, which
nicely underlines the fundamental role of organic chemists in
drug discovery and process development.4 In this context,
the introduction of the electron-withdrawing trifluoromethyl
group has recently gained some importance. While a number
of methods for the construction of sp2 carbonÀCF3 bonds
have been reported, processes allowing for the assembly of
trifluoromethyl alkenes are still relatively scarce.5,6 We now
report a convergent and general method for the preparation
of trifluoromethyl alkenes and vinyl fluorides.
As proposed by Baran et al.,4 approaches to trifluo-
romethyl arenes and heteroarenes may be divided into
two categories: those using a prefunctionalized substrate
(5) For pioneering work on programmed trifluoromethylation, see:
(a) Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. Synthesis
1980, 93. (b) Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.;
Kumadaki, I. J. Chem. Soc., Perkin Trans. 1 1980, 275. (c) Chen, Q.-Y.;
Wu, S.-W. J. Chem. Soc., Perkin Trans. 1 1989, 2385. For a review, see:
(d) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475. For
recent reports on programmed trifluoromethylation of arenes, see:
(e) Cottet, F.; Castagnetti, E.; Schlosser, M. Synthesis 2005, 798. (d) Ball,
N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878.
(f) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. (g) Wang, X.; Truesdale, L.;
Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 364. For recent reports on innate
trifluoromethylation of arene, see: (h) Reference 4. (i) Ye, Y.; Lee, S. H.;
Sanford, M. S. Org. Lett. 2011, 13, 5464. (j) Nagib, D. A.; MacMillan,
D. W. C. Nature 2011, 480, 224.
(1) (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson,
D. A.; Buchwald, S. L. Science 2010, 328, 1679. (b) Hiyama, T. Fluorine
Compounds: Chemistry and Applications; Springer: Berlin, 2000.
(c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Hagman,
W. K. J. Med. Chem. 2008, 51, 4359.
(2) (a) Smart, B. E. Introduction: Fluorine Chemistry. Chem. Rev.
1996, 96, 1555. (b) Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.
Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993. (c) Welch, J. T. Tetrahedron
1987, 43, 3123. (d) Ma, J. A.; Cahard, D. J. Fluorine Chem. 2007, 128,
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Soc. Rev. 2008, 37, 320. (b) Thayer, A. M. Chem. Eng. News 2006, 84
(23), 15.
(6) For recent approaches to trifluoromethyl alkenes, see: (a) Parsons,
A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012,
51, 1. (b) Cho, E. J.; Buchwald, S. L. Org. Lett. 2011, 13, 6552.
(c) Surya Prakash, G. K.; Krishman, H. S.; Jog, P. V.; Iyer, A. P.; Olah,
G. A. Org. Lett. 2012, 14, 1146. (d) Omote, M.; Tanaka, M.; Ikeda, A.;
Nomura, S.; Tarui, A.; Sato, K.; Ando, A. Org. Lett. 2012, 14, 2286.
(e) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060. (f) Liu, T.; Shen, Q.
Org. Lett. 2011, 13, 2342. (g) Janson, P. G.; Ghoneim, I.; Ilchenko,
(4) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc Nat. Acad. Sci. U.S.A. 2011, 108,
14411.
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N. O.; Szabo, K. J. Org. Lett. 2012, 14, 2882.
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10.1021/ol3023903
XXXX American Chemical Society

(programmed trifluoromethylations) and those exploiting
the substrate’s inherent reactivity (innate trifluoromethy-
lations, Figure 1, eq 1). These two strategies have proven to
be complementary and efficient for most purposes. Recent
methods for the synthesis of trifluoromethyl alkenes are
directly inspired from the programmed trifluoromethylation
(Figure 1, eq 2). Despite recent progress, this particular
strategy still faces a lack of generality with respect to the
olefin substitution pattern and functional group tolerance.6
Moreover, the preparation of trifluoromethyl alkenes from
aldehydes and ketones developed by Hiyama’s group
enables the stereocontrolled assembly of elaborated struc-
tures but requires several synthetic steps and is rather
incompatible with polar functions.7
Scheme 1. Strategies for the Preparation of Trifluoromethyl
Olefins
Scheme 2. Evaluation of Strategy Aa
Recent work from our laboratory has demonstrated that
2-fluoropyridyl derivatives of allylic alcohols are versatile
intermediates for the synthesis of highly functionalized
olefins.8 We envisioned installing a CF3 substituent di-
rectly on the double bond or alternatively on the carbon
adjacent to the oxygen of the 2-fluoropyridyl moiety in
order to generate the desired trifluoromethyl alkenes
(Scheme 1). This dual approach would impart tremendous
flexibility to this strategy. We were, however, concerned
that the presence of the strong electron-withdrawing CF3
group could dramatically affect both the first addition of
the radical derived from the xanthate and, even more
critically, the key β-fragmentation step because of a polar-
ity mismatch between the adduct radical and the departing
fluoropyridyloxyl radical, both of which are electrophilic
in character. With these concerns in mind we evaluated the
feasibility of both of these strategies.
a Reaction conditions: (a) s-BuLi, Et2O, À105 °C, 10 min then
dihydrocinnamaldehyde, À105 °C to À50 °C; (b) 2,6-difluoropyridine,
NaH, DMSO, 60 °C.
alkene 3a in good yield and good selectivity in favor of
the most thermodynamically stable geometrical isomer
(E/Z = 85:15, Scheme 2).
The formation of trifluoromethyl alkenes was extended
to more elaborate derivatives (Figure 2). Both the xanthate
and the olefin can be complex structures, as shown by
adducts 3b, stemming from a deoxyglucose derived olefin,
or 3c, arising from a steroid xanthate. Noteworthy, the
xanthate technology allows electron-rich, electron-neutral,
and even, gratifyingly, electron-deficient radicals to react
with the electrophilic trifluoromethyl alkene.
Using dihydrocinnamaldehyde as a test starting alde-
hyde we could readily prepare the corresponding fluoro-
pyridyl ether 1a by the addition of the vinyl anion derived
from commerciallyavailable 2-bromo-3,3,3-trifluoroprop-
1-ene,9 followed by aromatic nucleophilic substitution on
2,6-difluoropyridine.
Figure 1. Synthetic approaches for the construction of C(sp2)ÀCF3
bonds.
To our delight, exposure of olefin 1a and xanthate 5 to a
stoichiometric amount of lauroyl peroxide in refluxing
ethyl acetate furnished the corresponding trifluoromethyl
Figure 2. Synthesis of trifluoromethyl olefins via strategy A.
Org. Lett., Vol. XX, No. XX, XXXX
B

We next examined the second approach utilizing pre-
cursors 2 as the trifluoromethyl partner (Scheme 1). The
requisite allylic alcohol precursors were synthesized in
good yields by addition of vinyl magnesium bromide to
various trifluoromethyl ketones. The latter were prepared
from the corresponding carboxylic acids by a procedure we
developed some time ago and which has since been used by
industry to prepare trifluoromethyl ketones on the several
hundred kilogram scale.10 We were relieved to find that it
was possible to substitute the 2,6-difluoropyridine by
operating at 60 °C to overcome the poor nucleophilicity
of alcoholate 6 (Scheme 3). Our concern was that the
harsher conditions would cause elimination of a trifluoro-
methyl anion (the well-known haloform reaction which
also operates in the fluorine series).11
reaction conditions (Figure 3). Modifying steroid side
chains by installing CF3 moieties is a challenging problem
of some interest for biological studies, in particular in the
context of Vitamin D3 and sterols bearing a 24-methyl
group in their side chain.12 In this respect, the bile acid
derived adducts 4a and 4e are particulary noteworthy.
Even a xanthate derived from 9-fluorohydrocortisone
could be readily converted into highly complex trifluoro-
methyl steroid 4d. It is interesting to note that the glucose
derived trifluoromethyl alkene partner 2a used to make
adducts 4h and 4g was itself obtained from trifluoromethyl
ketone 8, prepared by a xanthate addition, as shown in
Scheme 4.13,14
With the required substrates in hand, we explored the
scope of thereaction withrespecttothe olefin and xanthate
component (Figure 3). Generally, 2 equiv of the starting
olefin were used to simplify the purification, but we found
that performing the reactions with an excess of xanthate
(2 equiv) does not impact the outcome (4g and 4h) and can
even be beneficial in some cases (4a).
Scheme 4. Exploitation of the Xanthate Radical Mediated
Addition/Reduction for the Preparation of Trifluoromethyl
Ketone 8
Scheme 3. Synthesis of Precursors 2
Finally, the direct introduction of an R-chloro-ketone
motif in 4j is remarkable and offers numerous possibilities
for further ionic or radical transformations.15,8a
Monofluoroalkenes may be accessed by a similar ap-
proach. Vinyl fluorides are known to be good bioisosteres
of amides and have been used as metabolically stable
and conformationally constrained peptide mimics in med-
icinal chemistry. Not surprisingly, this motif is found in a
number of compounds covering a range of pharmacological
activities.16
The precursor fluoroallylic alcohols were obtained ac-
cording to literature procedures starting from dodecene17a,b
and 3-aryl-1,2-allenes.17c The radical addition/elimination
process was straightforward, and we could access various
Enones (4d), R-chloro-ketones (4j), ketals (4g and 4h),
free alcohols (4d), amides (4f), ketones (4a, 4d, 4i, and 4j),
and oxazolidinones (4g) were well tolerated under the mild
(7) (a) Shimizu, M.; Fukimoto, T.; Minezaki, H.; Hata, T.; Hiyama, T.
J. Am. Chem. Soc. 2001, 123, 6947. (b) Fujita, M.; Hiyama, T. Tetra-
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synthesis of Panomifene and analogs, see: (d) Liu, X.; Shimizu, M.;
Hiyama, T. Angew. Chem., Int. Ed. 2004, 43, 879. For recent
reviews, see: (e) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem.
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2005, 44, 214.
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Chem.;Asian J. 2010, 5, 1875. For other methods for the preparation of
trifloromethylated terminal allylic alcohols, see: (b) Hong, F.; Tang, X.;
Hu, C. J. Chem. Soc., Chem. Commun. 1994, 289. (c) Hanamoto, T.;
Yamada, K. J. Org. Chem. 2009, 74, 7559.
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(b) Jiang, B.; Xu, Y. Y. J. Chem. Soc., Chem. Commun. 1996, 861.
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Chem. Commun. 1996, 2511. (b) For the tris(trimethylsilyl)silane mediated
reduction of xanthates, see: Chatgilialoglu, C. Chem. Rev. 1995, 95,
1229.
(14) For reviews on the xanthate radical transfer reaction, see: (a)
Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b) Quiclet-Sire,
B.; Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002. (c) Quiclet-Sire, B.; Zard,
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Haufe, G. Synthesis 1997, 953. (c) Tranel, F.; Haufe, G. J. Fluor. Chem.
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€
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Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 4. Scope of the radical olefination for vinyl fluorides.
Reaction conditions: olefin (2 equiv), xanthate (1 equiv), lauroyl
peroxide was added in 30 mol % portions (with respect to the
xanthate) every hour (5À7 h). For 10c, the reaction was run in
refluxing DCE.
Scheme 5. Combination of the Xanthate Addition with the
Allylation Reaction
Figure 3. Scope of the radical olefination process via strategy B.
functionalized vinyl fluorides in moderate to good yields
using identical reaction conditions (Figure 4). The (Z)-
isomer is obtained as the major product except when the
double bond is substituted by an aryl group (10b and 10d)
as determined by nOeSY experiments. The same effect was
observed for trifluoromethyl alkenes 4b, 4d, and 4i, result-
ing in these cases in the preferential formation of the
(E)-isomer. The causes underlying this difference are un-
clear at the moment.
The modularity and flexibility of the xanthate transfer
technology is further illustrated by examples 10c and 10d,
since the precursor xanthates 11 and 12 arise by a prior
addition of xanthates 13 and 5 to vinyl acetate and
N-phenyl maleimide respectively (Scheme 5).
work would be exceedingly tedious to produce by more
conventional ionic or organometallic routes.
Acknowledgment. We thank the ANR for financial
support. This manuscript is dedicated with respect and
admiration to Professor Amos B. Smith III.
Supporting Information Available. Experimental pro-
cedures and characterization spectral data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
In summary, we have developed a unified, convergent,
and practical approach to trifluoromethyl alkenes and vinyl
fluorides. Many of the products obtained in the present
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX