Access to Trisubstituted Fluoroalkenes by Ruthenium-Catalyzed Cross-Metathesis

Article abstract of DOI:10.1002/adsc.202001612

Although the olefin metathesis reaction is a well-known and powerful strategy to get alkenes, this reaction remained highly challenging with fluororalkenes, especially the Cross-Metathesis (CM) process. Our thought was to find an easy accessible, convenient, reactive and post-functionalizable source of fluoroalkene, that we found as the methyl 2-fluoroacrylate. We reported herein the efficient ruthenium-catalyzed CM reaction of various terminal and internal alkenes with methyl 2-fluoroacrylate giving access, for the first time, to trisubstituted fluoroalkenes stereoselectively. Unprecedent TON for CM involving fluoroalkene, up to 175, have been obtained and the reaction proved to be tolerant and effective with a large range of olefin partners giving fair to high yields in metathesis products. (Figure presented.).

Full text of DOI:10.1002/adsc.202001612

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DOI: 10.1002/adsc.202001612
Very Important Publication
Access to Trisubstituted Fluoroalkenes by Ruthenium-Catalyzed
Cross-Metathesis
Augustin Nouaille,a Xavier Pannecoucke,a Thomas Poisson,a, b and
Samuel Couve-Bonnairea,*
a
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
Phone: (+33) 2 35 52 24 15
E-mail: samuel.couve-bonnaire@insa-rouen.fr
Institut Universitaire de France, 1 rue Descartes, 75231, Paris, France
b
Manuscript received: December 30, 2020; Revised manuscript received: February 8, 2021;
Version of record online: March 1, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001612
Abstract: Although the olefin metathesis reaction is a well-known and powerful strategy to get alkenes, this
reaction remained highly challenging with fluororalkenes, especially the Cross-Metathesis (CM) process. Our
thought was to find an easy accessible, convenient, reactive and post-functionalizable source of fluoroalkene,
that we found as the methyl 2-fluoroacrylate. We reported herein the efficient ruthenium-catalyzed CM
reaction of various terminal and internal alkenes with methyl 2-fluoroacrylate giving access, for the first time,
to trisubstituted fluoroalkenes stereoselectively. Unprecedent TON for CM involving fluoroalkene, up to 175,
have been obtained and the reaction proved to be tolerant and effective with a large range of olefin partners
giving fair to high yields in metathesis products.
Keywords: Fluoroalkene; Metathesis; Ruthenium; Catalysis
Introduction
appears as an ideal solution to produce fluoroalkenes.
Unfortunately, despite the tremendous studies reported
Organofluorine chemistry has blossomed over the past over the past two decades toward the development of
decade to become one of the most active research areas efficient metathesis processes to synthesize alkenes,
in organic synthesis. One of the main reasons of this the relevant combination of metathesis and fluoroal-
impressive rise lies in the strong implications of kene has been scarcely studied. Several reasons could
fluorinated molecules in several areas such as medici- explain this poorly documented reaction: i) the vinyl
nal chemistry, medical imaging, agrochemistry, fluoride and more generally vinyl halides are known to
materials…[1] Among the organofluorinated com- be reluctant substrate for metathesis;[7] ii) the main
pounds, fluorinated alkenes have emerged as an issue with ruthenium catalyst is the formation of stable
important class of molecules, which was notably used metal-fluorovinylidene – a Fischer type carbene –
to build up unavoidable materials[1c,2] (Teflon® for hampering its catalytic activities.[7c,8] Indeed, early
instance), as well as interesting bioactive compounds.[3] reports from Grubbs et al.[8a] and later from the
Another feature of the fluoroalkene moiety is its Johnson’s group[8b] showed that the reaction between
isosteric and isoelectronic mimicry with the amide di- or monofluoroethylene with the Grubbs II precata-
bond, explaining its use as a bioisostere in structure- lyst formed a stable complex with a low propensity to
activity relationship studies in the agrochemical or act as a catalytically active species (Scheme 1.a).
pharmaceutical domains[4] or to overcome problems
Very few examples of CM with fluoroalkenes have
been described. Among them, the Johnson’s group
associated to the instability of peptides.[5]
A straightforward access to new fluoroalkenes is reported few examples of successful ring opening/
the use of the metathesis reaction. Indeed, the meta- cross-metathesis reactions using the gaseous fluoro-
°
thesis, which possesses enormous industrial potential ethylene (boiling point: À 72 C) as the fluorinated
and stands at the top of the class of olefin production,[6] olefin reaction partner. Low stereoselectivities and low
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fluorinated ones (Scheme 1.d). Several molybdenum
based monoaryloxide pyrrolide (MAP) complexes
were designed and used in combination with either
°
(E)-1-chloro-2-fluoroethene (boiling point: À 4 C;
5.23 $/mmolj11]) or the liquid (Z)-1-bromo-2-fluoroe-
thene (boiling point: +36 C; 5.62 $/mmol[11]) to
°
produce efficiently and selectively the (E)- or (Z)-
fluoroalkenes, respectively.[10] However, these reactions
are restricted to the production of terminal fluoroal-
kene, hardly post-functionalizable and require glove-
box manipulation with the air-sensitive Mo catalysts,
which constitutes a practical constraint.
To our knowledge, i) no efficient general CM
reaction with Ru-catalyst has been reported yet and ii)
the CM reaction producing trisubstituted fluoroalkenes
remains elusive and still remains a major challenge in
the metathesis area. Our first idea was to identify a
reactive fluorinated substrate, convenient to use (at
least a liquid), inexpensive and commercially avail-
able, which could ideally be classified as a type III[12]
olefin for CM reaction. The ideal candidate showed up
as one of the common fluorinated reagents used in our
lab, the methyl 2-fluoroacrylate 1a. Although it
belongs to the acrylate derivatives family, which has
been extensively used in CM reactions,[13] this reagent
has, to our knowledge, never been used in such
reaction. Moreover, it showcases several advantages: i)
it is an inexpensive commercially available liquid
(boiling point: +95 C, 0.52 $/mmol[11]) convenient to
°
use, ii) the ester group can be easily further manipu-
lated, iii) whereas acrylate belongs to type II olefin,
the 1,1-disubstituted olefin 1a should fall into the type
III olefin for CM with catalyst of type II,[12] and finally
iv) the steric hindrance resulting from gem-disubstitu-
tion along with the electronic deactivation of the
alkene by both the fluorine atom and the ester moiety
would disfavor the first coordination of the olefin with
Scheme 1. Cross-Metathesis with fluoroalkenes: state of the art
& this work.
yields were reported, except for the constrained cyclo- the precatalyst, preventing the formation of an inactive
octene and resulting release of ring strain by metathesis metal-fluorovinylidene species.
(Scheme 1.b).[7c]
Herein, we reported the unprecedented efficient
More recently, Morizawa and Takahira succeeded CM reaction of methyl-2-fluoroacrylate 1a with Ru-
in the CM of tetrafluoroolefins and derivatives via an precatalyst, leading to the stereoselective production of
elegant strategy based on
a
Fischer carbenes trisubstituted fluoroalkenes (Scheme 1.e).
interconversion.[9] Nevertheless, only few examples
have been described including one leading to a
fluoroalkene product with good NMR yield (72%),
Results and Discussion
albeit without isolated yield and with low stereo- Our first attempts were made with three different
selectivity (Scheme 1.c). Moreover the enol ether alkenes, giving high yields in standard CM with
partner, not so convenient for further post-functionali- methyl acrylate, para-bromostyrene A,[14] a type I
zation, was the sole possible reaction partner, while the olefin and two allylic alcohols B and C,[15] type II
fluorinated substrates used for this reaction were olefins. None of them led to the formation of the
hazardous gases.
desired compound (Scheme 2).
To date, the only efficient CM processes involving
Taking into account the difficulty of cross-meta-
fluoroalkenes are mediated by Molybdene precatalyst. thesis involving our 1,1-gem-disubstituted fluorinated
In 2016, Hoveyda and Schrock reported astonishing substrate 1a, we postulated that the introduction of
works concerning the stereoselective synthesis of higher flexibility and implicitly less steric hindrance
(E)-[10a] or (Z)-[10b] terminal halogenoalkenes, including on the olefinic partner would favor the approach of 1a
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quinone or acetic acid, have been used to circumvent
this side-process involving ruthenium hydride species,
but the reaction yield decreased without suppressing
the formation of compounds 3a and 4a.[19] Hence, to
decrease the formation of these side-products, we
decided to reduce the catalyst loading in order to
prevent or reduce the formation of ruthenium hydride.
With 1 mol% of the precatalyst, a similar yield of the
desired product 2a was obtained and the side-products
were still detected, albeit in lower amount (Table 1,
entry 4). Using 2 equiv. of methyl 2-fluoroacrylate 1a
led to our best results with 94% NMR yield, 85% of
isolated yield and a 2a:(3a+4a) ratio of 97:3
(Table 1, entry 5). Using more than 2 equiv. of 1a did
not improve the yield in 2a. Increasing the temperature
Scheme 2. Preliminary attempts.
°
to 100 C gave a lower yield probably due to the faster
on the ruthenium-alkylidene complex and allow the decomposition of the catalyst at higher temperature
cross-metathesis reaction.[16] Whereas the use of (Table 1, entry 6). The reaction was incomplete after
styrene D was inefficient, some traces (4%) of the 1 h or 7 h of reaction (Table 1, entries 7–8), showing
desired product were detected starting from 3-phenyl- that this reaction is rather slow but the catalyst is stable
prop-1-ene E as partner. To our delight, the more in our experimental conditions, as it was still active
flexible 4-phenylbut-1-ene F furnished an encouraging between 1 h and 15 h.[19] Finally, the use of an excess
22% 19F NMR yield of the desired product (Scheme 2). of non-fluorinated alkene was detrimental for the
This result served as starting point for further reaction as only the dimer of the non-fluorinated
optimization of the reaction conditions (Table 1).
alkene was produced, whereas no desired product was
°
°
Increasing the temperature from 40 C to 60 C or obtained (Table 1, entry 9).
°
80 C allowed the formation of the desired product 2a
In the Table 2 are presented selected results
in 52% and 58%, respectively (Table 1, entries 1–3). obtained with different type 2 precatalysts.[19] In our
During the course of the reaction, two major side- case the phosphine-containing ruthenium indenylidene
products 3a, with a subtracted carbon, and 4a, with an precatalyst M2[20] proved to be the most active one
additional carbon, in low percentages, were identified (Table 2, entry 1). This result differs to the cross-
as a result of the alkene isomerization during the CM metathesis with acrylate, in which chelating
process.[6,17] Conventional additives,[18] such as benzo- benzylidene-ether precatalyst gave usually better result
in CM reaction because no side-reactions triggered by
the ancillary PCy3 ligand could occur.[21] A presumable
reason is the poor reactivity of methyl 2-fluoroacrylate
Table 1. Optimization of the CM reaction.
1a as Michael acceptor, precluding the formation of
poisonous enolate for metathesis from a phospha-
Michael addition reaction.[22]
We recently showed, inspired by previous
reports,[23] the beneficial effect of an aryl substitution
entry X
Y
T
Time
Yield
(%)[a]
Ratio[b]
2a:(3a
+4a)
on the fluoroalkene partner in RCM reaction.[24] In-
deed, this modification regenerates a more stable
ruthenium-arylidene instead of ruthenium-methylidene
after a catalytic cycle. So, under the conditions from
the entry 5, trisubstituted fluoroacrylates 1b ((Z)-meth-
yl 2-fluoro-3-phenylacrylate), 1c ((Z)-methyl 2-fluoro-
3-(4-methoxyphenyl)acrylate) and 1d ((E)-methyl 2-
fluoro-3-phenylacrylate), were tested in CM reaction
but without success. The increase of the bulkiness
should preclude the approach of these substrates 1b–d,
which were categorized as reluctant fluoroalkenes in
CM process.[19]
°
(equiv.) (mol%) ( C) (h)
1
2
3
4
5
6
7
1
1
1
1
2
2
2
2
1
10
10
10
1
1
1
1
1
1
40
60
80
80
80
15
15
15
15
15
22
52
58
61
94 (85)
74 (69)
30
86 (77)
Traces
n.d.
82:18
83:17
92:8
97:3
95:5
n.d.
100 15
80
80
80
1
7
15
8
97:3
–
9[c]
[a] Determined by 19F NMR with fluorobenzene as internal
standard. Isolated yield into brackets.
Many other parameters (solvent, temperature, etc.)
were screened to optimize the reaction without
improvement.[19] Worthy of note that under our optimal
reaction conditions, a TON (turnover number) of 85
[b] Determined by 19F NMR and correlated by GC-FID.
[c] 4 equiv. of 4-phenylbut-1-ene.
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reaction was then extended to aliphatic alkenes,
Table 2. Screening of catalysts.
furnishing the desired trisubstituted fluoroacrylates
2u–z in good to excellent yields without the formation
of side-products (70–98%). Heterocyclic derivatives,
such as benzofuran or benzothiophene, were also
compatible with the CM process leading to the
corresponding products 2aa and 2ab in 40% and 69%
yields, respectively. The methyl 5-hexenoate displayed
a fair reactivity furnishing the diester 2ac with 51%
yield. The use of longer alkyl chain (6-phenylhex-1-
ene and 5-phenyl-pent-1-ene) was possible, leading to
the corresponding products 2ad–ae, 2ag in good
yields (64–83%), while compound 2af was surpris-
ingly obtained with a low 16% yield. The use of more
constrained 3-phenylprop-1-ene was also suitable lead-
ing to the corresponding 2ai in 60% yield. Conversely,
the bulkier allyltrimethylsilane only led to 36% yield
in the corresponding 2ah.
Unfortunately, some substrates remained reluctant
in our hand. Alkenes bearing an acidic hydrogen
(phenol or carboxylic acid), 1,1-gem-disubstituted
alkenes, conjugated alkene, allyl-bromide, alcohol or
amine (free or acetylated), vinyl-sulfone or -acetate
were unreactive probably, for most of them, because of
steric congestion (Scheme 3.b).
entry
Cat
Yield (%)[a]
Ratio[b] 2a:(3a+4a)
1
2
3
4
5
6
7
M2
G-II
HG-II
M71
M73SiPr
M832SiPr
M853SiPr
94 (85)
97:3
–
90:10
–
81:19
–
–
15
77
6
72
–
–
Importantly, the formation of the homodimer of
methyl 2-fluoroacrylate 1a has never been witnessed,
while the homodimer of 4-phenylbut-1-ene was ob-
served, as expected for type I olefin. The latter, known
to be able to enter in CM reaction, could indeed be
used directly in CM reaction furnishing the desired
[a] Determined by 19F NMR with fluorobenzene as internal
standard. Isolated yield into brackets.
[b] Determined by 19F NMR and correlated by GC-FID.
was reached, which is unprecedented for the cross- product 2a in 58% yield (see Scheme 4.a). From this
metathesis involving fluoroalkenes. Moreover, the observation, we carried out the reaction with various
reaction proved to be highly Z selective, since no trace cyclic alkenes (Scheme 4.b) as well as internal alkenes
of the E-isomer of 2a has been observed in 19F NMR (Scheme 4.c).
of the crude mixture.[19]
The use of constrained cyclooctene allowed the ring
Having settle the optimized reaction conditions, we opening CM with 1a, the release of the ring strain led
studied the scope of the reaction (Scheme 3). With to the formation of three compounds incorporating
terminal alkenes (Scheme 3.a), although side-products respectively one (2aj) or two fluoroalkene moieties
3 and 4 were often produced during the CM process, (2ak, 2al) in 97% overall yield. Similarly, the ring-
the desired products 2 were always the major com- opening CM of the more stable cyclohexene occurred,
pound with a ratio 2:(3+4) varying from 89:11 to albeit in low yield.[25] Then, the ring-opening CM of
99:1.
cyclododecene only furnished the bis-fluoroacrylate
Importantly, whatever the metathesis partner of 1a, 2ao in a fair 32% yield.
only the Z-product 2 was obtained. Pleasingly, different
Finally, we valorized our method using fatty acid
substituents on the aromatic residue of 4-phenylbut-1- esters (Scheme 4.c). Indeed, the use of renewable
ene were suitable for the reaction, whatever its position feedstock in olefin metathesis gave birth to new
(para, meta or ortho) and its electron-donating or chemical platforms dedicated to surfactants or
-withdrawing feature. Interestingly, products bearing a polymers.[26] The combination of fluoroacrylate 1a
chlorine (2f, 2m) or bromine (2g, 2n, 2s) atom as with renewable raw materials by metathesis could give
well as an ester moiety (2i), valuable anchors for rise to original and versatile fluorinated building-
further post-functionalizations, were compatible fur- blocks. The use of 1 equiv. of 1a with methyl (Z)-
nishing fair to very good yields (36–86%). Product 2j oleate being not a selective process, we used 2 equiv.
containing a relevant carboxaldehyde moiety, was of 1a in order to maximize the yield of the both
obtained as a 1:1 mixture with the dimer of non- targeted products. Thus, 75% of α,ω-diester 2ap could
fluorinated olefin partner representing a yield of 33% be obtained along with the formation of the monofluor-
and 66% for 2j and the dimer, respectively. The oacrylate 2w in 55% yield. The geometry of the
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Scheme 3. Scope of the reaction with terminal alkenes. Reaction conditions: alkene (0.25 mmol), 1 (0.50 mmol, 2 equiv.) and M2
°
precatalyst (2.5 μmol, 1 mol%) in CH2Cl2 (0.5 mL) at 80 C for 15 h in a sealed tube. n.d., not determined; TON (turnover
[a]
[b]
number)=yield value. Isolated yield in fluorinated compounds (2+3+4). Ratio between products 2, 3 and 4 was determined
by GC/FID. [c] Inseparable mixture of 2j/dimer of non-fluorinated olefin partner in 1:1 ratio. [d] Inseparable mixture of 2ac/dimer of
non-fluorinated olefin partner in 3:1 ratio.
double bond had no influence on the reaction process formation of the active olefin complex with the less
as the methyl (E)-oleate furnished similar results. The hindered and more electron-rich non-fluorinated al-
use of bigger fatty ester like methyl erucate allowed kene, a new alkylidene complex is generated from
the formation of both α,ω-diester 2aq and monofluor- which several approaches of the fluorinated alkenes,
oalkene 2w in good 72% and 74% yields, respectively. according to the preferential bottom-bound pathway
The fluorinated α,ω-diester 2ap and 2aq could serve, for propagation,[27,28] could be envisioned. For the CM
for example, as relevant monomer for polycondensa- reaction between the 4-phenyl-but-1-ene and the meth-
tion and production of polyester and polyamide with yl 2-fluoroacrylate 1a, the complex I is the less
new properties.
hindered and therefore favored, furnishing exclusively
The use of 1,2-disubstituted alkenes bearing acid or the Z-product. Moreover, there is also an electronically
alcohol moiety, as well as more constrained internal match between the more electronegative carbon at
alkenes proved to be reluctant substrates for the CM position 3 of 1a (strong π donation from the fluorine
reaction (Scheme 4.d).
atom) and the electron deficient Ru in the 14eÀ
To explain the high selectivity of our developed alkylidene complex. Nevertheless, when the hindrance
process the following scenario was suggested is increased on the alkylidene moiety, the approach of
(Scheme 5). After the initiation of the reaction and the 1a is rather unlikely and could explain the lower yield
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Scheme 5. Proposed bottom-bound olefin complexes.
electronically mismatch. The Ru-fluoroacrylatevinyli-
dene was not observed by NMR analysis.
Interestingly, when trisubstituted 2a was submitted
to the reaction condition with n-oct-1-ene as the olefin
partner, we could obtain the CM product 2v in 26%
isolated yield (Scheme 6). Although the yield remains
low, this experiment showed that the introduction of
flexibility on the fluorinated partner allowed a fluo-
racrylate moiety exchange by CM reaction.[29] By
comparison, reaction of 4-phenylbut-1-ene or n-oct-1-
ene with more constrained 1b–d did not produce 2a or
2v, respectively.[19]
Conclusion
In summary, we reported the first formation of
trisubstituted fluoroalkenes by cross-metathesis using
methyl 2-fluoroacrylate 1a as an inexpensive and
convenient fluoroalkene source. The reaction was
successfully achieved under ruthenium catalysis prov-
ing their viability in CM involving fluoroalkene with-
out fast deactivation. The reaction was exemplified on
more than forty terminal and internal alkenes, giving
exclusively the Z-isomer in fair to excellent yields with
unprecedented turnover number with fluoroalkene (up
to 175). The used catalyst loading of 1 mol% might
appear high and consequently TON somehow low,
however it is the first time that such low catalyst
Scheme 4. Scope of the reaction with internal alkenes. Reaction
conditions: alkene (0.25 mmol), 1 (0.50 mmol, 2 equiv.) and
°
M2 precatalyst (2.5 μmol, 1 mol%) in CH2Cl2 (0.5 mL) at 80 C
for 15 h in a sealed tube. n.d., not determined; TON, turnover
number. [a] Isolated yield in fluorinated compounds 2. [b] Results
obtained with 1 eq of 1a. [c] contaminated with 5% of the dimer
of methyl oleate.
obtained with the allyltrimethylsilane and the lack of
reactivity with even more constrained alkenes. In the
complex II, the approach is hampered by the steric
hindrance between the ester and the R group. The
involvement of this complex II is unlikely as no trace
of E-isomer was detected at the end of the reaction.
The formation of complex III was also disfavored by
steric hindrance between the bigger chlorine atom and
the fluorine atom or the ester group as well as
Scheme 6. CM of n-oct-1-ene with trisubstituted fluoroacrylate.
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tion of undesired products in low proportion (ranging
from 0 to 11%). Investigations to improve the process
with more constrained alkene partner as well as the use
of other fluorinated sources are currently under
progress and will be reported in due course.
Experimental Section
General Procedure for cross-metathesis with 2-Fluoroacry-
late 1a. In a 10 mL oven dried reaction tube, the olefin
(0.25 mmol, 1.0 eq.) and the methyl 2-fluoroacrylate 1a
(0.5 mmol, 2.0 eq.) were added under argon atmosphere. Then,
0.5 mL of a prepared catalyst solution of M2 in DCM
(5.0 μmol.mLÀ 1, 1.0 mol%) was added and the tube was sealed.
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°
The reaction mixture was stirred at 80 C for 15 hours. After
coming back to room temperature, 23 μL of fluorobenzene was
added as internal standard. 19F NMR with a d1 parameter of
8 seconds was performed to determine the 19F NMR yield.
Then, the crude mixture was purified by flash column
chromatography on silica gel to afford the desired product 2.
Acknowledgements
This work was partially supported by Normandie Université
(NU), the Région Normandie, the Centre National de la
Recherche Scientifique (CNRS), Université de Rouen Norman-
die (URN), INSA Rouen Normandie, Labex SynOrg (ANR-11-
LABX-0029), and Innovation Chimie Carnot (I2 C). A.N. thanks
the MESRI for a doctoral fellowship. T.P. thanks the Institut
Universitaire de France (IUF) for support.
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