Stereospecific synthesis of tri- and tetrasubstituted α-fluoroacrylates by mizoroki-heck reaction

Article abstract of DOI:10.1021/acs.orglett.5b03571

Ligand-free, efficient, palladium-catalyzed Mizoroki-Heck reaction between methyl α-fluoroacrylate and arene or hetarene iodides is reported for the first time. The reaction is stereospecific and provides fair to quantitative yields of fluoroalkenes. The Mizoroki-Heck reaction starting from more hindered and usually reluctant trisubstituted acrylate, to access tetrasubstituted fluoroalkenes, is also reported. Finally, the use of a three-step synthesis sequence, including Mizoroki-Heck reaction, allows the synthesis of fluorinated analogues of therapeutic agents with high yield.

Full text of DOI:10.1021/acs.orglett.5b03571

Letter
pubs.acs.org/OrgLett
Stereospecific Synthesis of Tri- and Tetrasubstituted
α‑Fluoroacrylates by Mizoroki−Heck Reaction
Kevin Rousee, Jean-Philippe Bouillon, Samuel Couve-Bonnaire,* and Xavier Pannecoucke
́
̀
Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesniere 76821
Mont-Saint-Aignan Cedex, France
S
* Supporting Information
ABSTRACT: Ligand-free, efficient, palladium-catalyzed Mizoroki−Heck reaction between methyl α-fluoroacrylate and arene or
hetarene iodides is reported for the first time. The reaction is stereospecific and provides fair to quantitative yields of
fluoroalkenes. The Mizoroki−Heck reaction starting from more hindered and usually reluctant trisubstituted acrylate, to access
tetrasubstituted fluoroalkenes, is also reported. Finally, the use of a three-step synthesis sequence, including Mizoroki−Heck
reaction, allows the synthesis of fluorinated analogues of therapeutic agents with high yield.
rganofluorine chemistry is an area of tremendous
expansion, and the market for organofluorine fine
new strategy to construct relevant fluoroalkene building blocks.
As a matter of fact, complete methodological studies of the
Mizoroki−Heck reaction with aryl halides have only been
reported twice to produce monofluoroalkene derivatives
(Scheme 1).15
O
chemicals still keeps growing every year.1 Fluorinated molecules
have applications in almost all areas of science and clearly have a
crucial impact on everyday life and on modern society. Among
the fluoroorganic compounds, the fluoroacrylates have been
proven to be versatile compounds that have found many
applications in material sciences2 and medicinal chemistry3 and
can also serve as relevant intermediates in the synthesis of
peptidomimetics4 and drugs.5
Patrick et al.15a reported in 2008 the synthesis of 3-
fluorobenzalacetone derivatives starting from 3-fluoro-3-buten-
Scheme 1. Mizoroki−Heck Reaction between Aryl Iodides
and Fluorinated Alkenes
Common efficient strategies to synthesize α-fluoroacrylates
rely almost exclusively on olefination reactions with carbonyl
derivatives for which many different experimental procedures
have been reported6 (Wittig-type,7 Horner−Wadworth−Em-
mons,8 Peterson,5a Julia−Kocienski,9 etc.). These reactions can
lead to high E/Z selectivity10 or very good yields of reaction7 and
more rarely to both excellent yield and selectivity.8a,11 Moreover,
numerous reactions suffer from limitations such as the need for a
multistep preparation of the fluorinated reagents,9,10b−d the use
of expensive reagents,8 and/or the use of harsh experimental
conditions (chromium salt,11a highly corrosive TiCl4,11b etc.). As
part of our ongoing project aimed at developing new catalytic
access to fluoroalkene fine chemicals,12 we turned our attention
to an efficient alternative reaction accessing to fluoroacrylates
based on the Mizoroki−Heck strategy, a powerful tool to
synthesize alkenes.13 Indeed, despite numerous reactions
described with acrylates and derivatives, the Mizoroki−Heck
reaction with α-fluoroacrylates has surprisingly been, to our
knowledge, reported in a single example, without details about
selectivity and yield of reaction, in a patent for the construction of
bioactive heterocycles,14 whereas this reaction could be a general
Received: December 17, 2015
© XXXX American Chemical Society
A
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Letter
2-one as fluorinated reagent requiring its presynthesis through
the formation of chlorofluorocarbene from the ozone depleter
Freon-21 (Scheme 1, eq 1). In 2011, Hirotaki and Hanamoto
reported the synthesis of β-aryl-(1-fluorovinyl)methyldiphenyl-
silane from expensive (1-fluorovinyl)methyldiphenylsilane
(around $34/mmol) as fluorinated reagent (Scheme 1, eq
2).15b Recently, synthesis of fluoroalkene derivatives ((Z)-β-
fluoro-β-(trifluoromethyl)styrene) was reported by Liu, Lu, and
co-workers through a palladium-catalyzed oxidative Heck
reaction.16 Herein, we report the first stereoselective, efficient
synthesis of fluoroacrylate derivatives by a ligand-free Mizoroki−
Heck reaction starting from methyl α-fluoroacrylate, a cheap
commercially available fluorinated reagent (around $1/mmol)
(Scheme 1, eq 3). We have also succeeded acceding to
tetrasubstituted fluorinated alkenes using scarce and reluctant
trisubstituted alkenes as coupling partner in the Mizoroki−Heck
reaction (Scheme 1, eq 4).
simplified the process. During all experiments, the methyl 3-
phenyl-2-fluoroacrylate 1 was only produced as exclusive Z-
isomer, no trace of E-isomer being observed in 19F NMR of the
crude mixture. Typically, a 32−37 Hz coupling constant value
between the vinylic proton and the fluorine atom was obtained
indicating the corresponding Z-configuration.
We also applied our optimized procedure to other phenyl
halides (Ph-Br, Ph-Cl) and pseudohalide (Ph-OTf) without
success.17 Finally, using the catalytic system Pd(TFA)2 (10 mol
%)/PPh3 (20 mol %) overnight led to the production of
compound 1 in 35% yield from bromobenzene.17
We then applied our optimized procedure to substituted aryl
and heteroaryl iodides (Scheme 2). For para-substituted aryl
Scheme 2. Scope of the Reaction with Substituted Aryl and
Hetaryl Iodides
We started the optimization process by carrying out the
reaction between α-fluoroacrylate a and phenyl iodide (Table 1).
Table 1. Optimization of the Fluoroalkenylation Reaction
a
b
Yield based on isolated product after flash chromatography. 5 mol %
c
of Pd(TFA)2. Reaction performed at 60 °C.
a
Yield based on isolated product after flash chromatography.
Reaction performed overnight (12 h).
b
The experimental conditions described by Hirotaki and
Hanamoto proved to be unsuccessful with a poor 14% yield of
reaction (Table 1, entry 1). Among the palladium(II) or -(0)
catalysts tested,17 only the more electrophilic palladium(II)-
trifluoroacetate allowed us to prepare 1 with 50% yield (Table 1,
entry 2). After a screening of bases, only Ag2CO3 proved to be
efficient for the reaction to proceed.17 Taking into account the
volatility of the fluorinated reagent a, we reduced the size of the
reaction’s vial, decreasing the gaseous space above the reaction
liquid media, allowing us to increase the isolated yield to 73%
(Table 1, entry 3). Then, to ensure sufficient quantity of the
fluorinated reagent a in the media, we changed the number of
equivalents of Ph-I/a from 2/1 to 1/1.5 resulting in a quantitative
yield of 1 (Table 1, entry 4). As expected, the reaction did not
proceed in the absence of catalyst (Table 1, entry 5). Decreasing
the catalyst loading to 5 mol % allowed to obtain the product 1 in
very good 86% yields (Table 1, entry 6). Pleasingly, a quantitative
yield was also obtained using 2 equiv of Ag2CO3 (Table 1, entry
7), with 1 equiv leading to an interesting 92% yield of 1 (Table 1,
entry 8). Finally decreasing the reaction temperature to 60 °C
allowed us to obtain an excellent 98% yield of 1 (Table 1, entry 9).
It has to be noted that it was not necessary to use dry vials, operate
under inert atmosphere, or use molecular sieves15b which
iodides, whatever the electronic effect of the substituted moiety,
the reaction was efficient giving a range from 70% to quantitative
yields. Dihalogenated aryl derivatives revealed to be suitable
substrates giving the fluorinated acrylates 3 and 4 in high yields.
Interestingly, in the presence of 4-bromophenyl iodide, the
reaction was chemoselective furnishing 3 in 89% yields with a
reactive C−Br bound for further catalytic reactions. Compounds
6 and 7 bearing a ketone and a nitrile moeties, respectively, which
could be easily postfunctionnalized, have also been synthesized in
high yields.
Then, meta-substituted aryl iodides were studied furnishing
good to excellent yields in methyl 3-aryl-2-fluoroacrylates
whatever the substitution: methoxy (8), cyano (9), or nitro
(10). Finally, ortho-substituted aryl iodides were engaged in the
reaction with success. For example, valuable methyl 2-carboxylate
phenyl iodide reacted to furnish 3-aryl-2-fluoroacrylate 14 in
quantitative yield. The reaction proved to be highly efficient and
tolerant toward various functional groups. Nevertheless, it has to
be noted than the presence of labile hydrogen, i.e., iodophenol,
iodoaniline, or iodobenzoic acid, was prohibited. No reaction
occurred with those starting materials. Polysubstituted aryl
B
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iodides were also suitable substrates, and results were
independent of the position as well as of the nature of the
substituents borne by the aromatic ring (compounds 15−17). It
is noteworthy that the reaction was successfully applied to various
heterocyclic iodides. Indeed, 3-iodothiophene gave the corre-
sponding acrylate 18 in a good 60% yield. Valuables 5-
carboxaldehyde-2-iodofuran and N-protected 3-iodoindole re-
quired longer reaction time (12 h) in order to obtain relevant 3-
heteroaryl-2-fluoroacrylates 19 and 20 in fair 56% yields.
Unfortunately, the reaction failed with 2- and 4-iodopyridines
or iodopyrazine. All of the reactions were stereospecific toward
the formation of the Z-isomer.
cycle13a,b or Pd(II)/Pd(IV) system as proposed by different
authors.18 As far as the stereospecificity is concerned, we can, as
assumed in previous reports,15 postulate that the intermediate I is
highly favored compared to intermediate II because of steric
hindrance (Scheme 4). Indeed, the crucial β-hydride elimination
Scheme 4. Geometry Required for the β-H Elimination
Next, we examined the Mizoroki−Heck reaction starting with
trisubstituted 2-fluoroacrylates as substrates. Nevertheless, we
have to take into account the well-known poor reactivity of
disubstituted alkenes for which few examples have been reported
so far.19 In this case, we used trisubstituted olefins for which, to
our knowledge, no example of Mizoroki−Heck reaction has been
published so far regarding the synthesis of tetrasubstituted
olefins. Indeed, only a few works in oxidative Heck reaction
leading to tetrasubstituted alkenes have been recently reported in
nonfluorinated series.20 The reaction carried out with (Z)- or
(E)-trisubstituted 3-aryl-2-fluoroacrylates bearing an electron-
donating (b) or electron-withdrawing group (c) in Mizoroki−
Heck reaction did not furnish tetrasubstituted fluoroacrylate
probably due to steric hindrance (Scheme 3).
requires the Pd−Cα and Cβ−H bonds to be aligned in a syn
coplanar arrangement13a,b and the exclusive formation of
trisubstituted alkene Z-isomer showed that the sterically
demanding ester group, compared to fluorine atom, is pushed
away in trans relationship with the aryl moiety. Nevertheless, this
model did not allow explaining why the trisubstituted
fluoroalkene (E)-d is reactive and not the isomer (Z)-d. So, a
complete survey of the mechanism needs to be undertaken and
will be reported in due course.
Finally, the 2-fluoroacrylate derivatives are very relevant
compounds which can be used, for example, as therapeutic
agents as depicted in Scheme 5.3a,e Moreover, taking into account
Scheme 3. Mizoroki−Heck Reaction with Trisubstituted α-
Fluoroacrylates
Scheme 5. Fluoroacrylate-Containing Biomolecules and
Synthesis of Fluorinated Analogue of Therapeutic Agents
a
Yield based on isolated product after flash chromatography.
Reaction performed overnight (12 h) with a ratio of 2/1 equiv of
b
the electronic and steric similarities of the fluoroalkene moiety
with the amide function,1b,21 our reaction should be used in
structure−activity relationship studies and/or to produce
fluorinated analogues of biomolecules. In this context, we
demonstrated the usefulness of the Mizoroki−Heck reaction by
synthesizing a fluorinated analogue of the potent biomolecule A
against inflammation22 or various types of cancer.23 This product
could be obtained through a three-step sequence synthesis: (a) a
quantitative Mizoroki−Heck reaction, (b) a saponification, and
(c) an efficient Pd/Cu-catalyzed decarboxylative/C−H fluo-
roalkenylation with phenyloxadiazole as partner.12b The
fluoroanalogue 27 of potent therapeutic agent A was thus
obtained in 65% overall yield (Scheme 5).
Ar−I/(E)-d.
Therefore, we postulated that introducing a less constrained
substituent such as an alkyl group should resolve this problem,
and so we synthesized and tested the ethyl (Z)- and (E)-2-fluoro-
5-phenylpent-2-enoate d. The compound (Z)-d was unreactive,
whereas pleasingly, compound (E)-d reacted to furnish fair to
good yields in the corresponding tetrasubstituted alkenes as (E)-
isomers. Five tetrasubstituted α-fluoroacrylates 21−25 have been
synthesized (Scheme 3). To obtain moderate 52% yield of 22 and
good 71% yield of 25, it was necessary to use 2 equiv of aryl
iodides with a reaction carried out overnight. These interesting
results proved that the Mizoroki−Heck reaction can be used
toward the synthesis of tetrasubstituted fluoroalkenes.
To resume, we have developed an efficient alternative for the
production of α-fluoroacrylates commonly synthesized by
olefination reactions. Herein we have developed the first
ligand-free palladium catalyzed Mizoroki−Heck reaction with
At this stage, it is still rather unclear if the mechanism of the
reaction is going through a common Pd(II)/Pd(0) catalytic
C
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methyl α-fluoroacrylate as fluorine and alkene sources. The
reaction proved to be highly tolerant in regard to numerous
organic functionalities, was stereospecific, and importantly, gave
good to quantitative yields in fluoroalkenes. Whereas the
trisubstituted alkenes did not usually participate in the
carbopalladation reaction (reluctant substrates), this reaction
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alkyl-2-fluoroacrylate as substrate allowing the formation infair to
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03571.
Experimental procedures, optimization tables, character-
ization data, and NMR spectra of new compounds (PDF)
Hoarau, C. Angew. Chem., Int. Ed. 2013, 52, 3246. (b) Rousee
Schneider, C.; Couve-Bonnaire, S.; Pannecoucke, X.; Levacher, V.;
Hoarau, C. Chem. - Eur. J. 2014, 20, 15000. (c) Rousee, K.; Schneider, C.;
́
, K.;
́
AUTHOR INFORMATION
Corresponding Author
■
Bouillon, J.-P.; Levacher, V.; Hoarau, C.; Couve-Bonnaire, S.;
Pannecoucke, X. Org. Biomol. Chem. 2016, 14, 353.
*E-mail: samuel.couve-bonnaire@insa-rouen.fr.
Notes
(13) (a) Brase, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
̈
Reactions and More, 1st ed.; de Meijere, A., Brase, S., Oestreich, M., Eds.;
̈
Wiley-VCH: Weinheim, 2014; Vol. 2, pp 533−663. (b) The Mizoroki−
Heck Reaction; Oestreich, M., Ed.; John Wiley & Sons, Ltd: Chichester,
UK, 2009. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work has been partially supported by INSA Rouen, Rouen
University, CNRS EFRD, Labex SynOrg (ANR-11-LABX-0029).
■
(14) Taracido, I. C.; Harrington, E. M.; Hersperger, R.; Lattmann, R.;
Miltz, W.; Weigand, K. (Novartis Institutes for Biomedical Research)
US20090291942(A1), 2009.
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(16) Li, Y.; Tu, D.-H.; Gu, Y.-J.; Wang, B.; Wang, Y.-Y.; Liu, Z.-T.; Liu,
Z.-W.; Lu, J. Eur. J. Org. Chem. 2015, 2015, 4340.
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