Stereoselective access to trisubstituted fluorinated alkenyl thioethers

Article abstract of DOI:10.1039/c7cy00076f

We report the first copper-catalyzed olefinic ethoxy carbonyl difluoromethylation of alkenyl thioethers via direct C-H bond functionalization using BrCF₂COOEt. The developed methodology allows the preparation of trisubstituted olefins with a controlled stereochemistry. A mechanistic study is reported and a radical mechanism is revealed.

Full text of DOI:10.1039/c7cy00076f

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ISSN 2044-4753
PAPER
Qingzhu Zhang et al.
Catalytic mechanism of C–F bond cleavage: insights from QM/MM
analysis of fluoroacetate dehalogenase
rsc.li/catalysis

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Journal Name
ARTICLE
Stereoselective Access to Trisubstituted Fluorinated Alkenyl
Thioethers
Received 00th January 20xx,
Indira Fabre,a b Thomas Poisson,c Xavier Pannecoucke,c Isabelle Gillaizeau,d Ilaria Ciofini,*b
Laurence Grimaud*a
We report the first copper-catalyzed olefinic ethoxy carbonyl difluoromethylation of alkenyl thioethers via direct C-H bond
functionalization using BrCF2COOEt. The developed methodology allows the preparation of trisubstituted olefins with a
controlled stereochemistry. A mechanistic study is reported and reveals a radical mechanism.
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
As part of these sulfur-containing molecules, alkenyl thioethers7
are a versatile chemical platform and represent an interesting
motif to access complex sulfur-containing molecules. It is
1. INTRODUCTION
Since the last decade, organofluorine chemistry has known a
very fast expansion since fluorinated molecules became
popular in the quest for drugs and agrochemicals. This is
reflected in the continuing increase of the number of
fluorinated drugs already approved or drug candidates entering
clinical trials.1–3 Indeed, the presence of a fluorine atom or a
fluorinated group strongly affects the physical and chemical
properties of a molecule. These features result from the
particular properties of the fluorine atom, like its
electronegativity, its small size and the strength of the carbon
fluorine bond, for instance.4 In that context the development of
new methodologies to access these strategic molecules is of
high demand toward the discovery of new bioactive molecules.
For this purpose, the direct C-H bond functionalization was
recently recognized as an outstanding and efficient method for
a straightforward access to the desired fluorine-containing
molecules.5
noteworthy, that Julia and coworkers developed the
introduction of alkyl, allyl or silyl groups on 1-tert-butylthio-3-
methoxy-1-alkenes using metallating agents (Scheme 1a).8
However, most efforts to functionalize this motif focused on the
development of palladium-catalyzed arylation of alkenyl
thioethers (Scheme 1b).9–11 Concerning the synthesis of
fluorinated alkenyl mercaptans, Marquet and coworkers
described an approach based on the anodic functionalization of
alkenyl thioethers allowing the introduction of a fluorine atom
at the α or β position (Scheme 1c).12,13 More recently, β-
trifluoromethyl-α-functionalized-vinyl
sulfides
were
synthesized under anionic conditions by Hanamoto and
coworkers.14,15 As a complementary approach, Zard and
coworkers reported the synthesis of tri- and tetra-substituted
functionalized alkenyl thioethers by radical allylation, including
examples bearing a CF3 motif.16 The fluorination of thiophenes
and benzothiophenes, which have an aromatic scaffold, have
been reported with different metal catalysts (Ag,17 Pd,18 Fe19
and Ir20 or Ru21,22 with light irradiation) and under
photochemical conditions23 (Scheme 1d). These reactions are
selective for the C2 position. To the best of our knowledge, no
example of alkenyl thioether fluorination has been reported so
far using functionalized fluorinated building blocks as the
CF2CO2R group. Stimulated by our previous works dealing with
the copper-catalyzed ethoxy carbonyl difluoromethylation of
various scaffolds through a direct C-H functionalization,24–27 we
report herein a successful application to the functionalization of
alkenyl thioethers (Scheme 1e). In addition, significant insights
regarding the mechanism of this reaction were also disclosed,
demonstrating the existence of a radical pathway.
Besides, sulfur-containing molecules are prevalent in a broad
range of pharmaceuticals and natural products, and often
display interesting various biological activities.6
a.
Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris
06, CNRS, Département de Chimie, PASTEUR, Sorbonne Universités,
UPMC Univ Paris 06, ENS, CNRS, PASTEUR, 24, rue Lhomond, 75005
Paris, France. E-mail : laurence.grimaud@ens.fr
b.
PSL Research University, Institut de Recherche de Chimie Paris, CNRS
Chimie ParisTech, 11 rue P. et M. Curie, 75005 Paris, France. E-mail:
ilaria.ciofini@chimie-paristech.fr
Normandie Univ, INSA Rouen UNIROUEN, CNRS, COBRA (UMR 6014),
c.
76000 Rouen (France).
Institut de Chimie Organique et Analytique, UMR 7311 CNRS, Université
d.
d’Orléans, rue de Chartres, 45067 Orléans cedex 2, France
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1 Optimization of the reaction conditions
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DOI: 10.1039/C7CY00076F
Entry Deviation from the standard conditions
Yield
82 % a
60 %a
59 %a
70 %a
0 %
1
None
2
3
Catalyst: Cu(OTf)2
Catalyst: CuI
4
5
6
7
Catalyst: Cu(CH3CN)4PF6
Ligand: Neocuproine
Ligand: TMEDA
Ligand: TMHD
0 %
0 %
8
9
Ligand: 2,2’-bipyridine
Base: Cs2CO3
Base: Na2CO3
35 % a
28 %b
12 %b
< 5 %b
0 %
0 %
24 %b
30 %b
10
11
12
13
14
15
Base: Et3N
Scheme 1 Schematic illustration of previous and present works
Base: 2,6-lutidine
Base: nBu4NOAc
Catalyst: Cu2O 2 mol%
BrCF2CO2Et: 1.3 equiv
2. RESULTS AND DISCUSSION
2.1 Optimization of the Reaction
Default catalyst, ligand and base are Cu2O, 1,10-phenanthroline and
K2CO3. a Isolated yield. b 19F NMR yield, α,α,α-trifluorotoluene was used as
an internal standard.
The reaction conditions were optimized using n-hexyl(styryl)sulfane
1a as a model substrate. Standard screening of solvent, catalysts,
bases, ligands, temperature and reagent stoichiometry confirmed
that the best yield is obtained using the conditions previously settled
for the ethoxy carbonyl difluoromethylation of enamides,26 with
longer reaction time. A brief overview of the optimization of the
reaction is displayed in Table 1 (for a more complete study, see
Supporting Information). The desired product 2a was isolated in 82%
yield (Table 1, entry 1) when using Cu2O (10 mol%), 1,10-
phenanthroline (12 mol%) as a ligand in the presence of K2CO3 (2
equiv) and BrCF2CO2Et (2 equiv), in acetonitrile at 80 °C for 24 h.
Several copper sources were also found to be efficient (Table 1,
entries 2-4); however, the use of different ligands (Table 1, entries 5-
8) or bases (Table 1, entries 9-13) gave very low to no conversion.
Unfortunately, the catalyst loading could not be reduced since the
yield significantly dropped when using 2 mol% of copper salt (Table
1, entry 14). Similarly, we could perform the reaction with 2 equiv of
BrCF2CO2Et but lowering its amount (1.3 equiv) greatly impacted the
reaction yield (Table 1, entry 15). The reaction was carried out under
an air atmosphere, but with a lower yield (65%). Control experiments
showed no reactivity in the absence of ligand, catalyst or base, and
that no conversion occurred at room temperature. Under this
optimized set of experimental conditions, the reaction turned out to
be highly regio- and stereoselective. Indeed, the trisubstituted
alkene 2a was isolated as the major compound with a 5:95 Z/E ratioi
starting from alkenyl thioether 1a as a Z/E (10:90). A NOE between
the alkenyl proton and the alkyl chain on the sulfur atom allowed us
to unambiguously confirm the regioselectivity of the reaction as
shown in Table 2.
2.2 Scope of the Reaction
Having established the optimal reaction conditions, the scope of the
reaction was further examined with a wide array of alkenyl thioether
derivatives (see Table 2). Different styryl thioethers were successfully
functionalized under these conditions. The reaction turned out to be
of similar efficiency when performed with S-secondary (2b) or S-
tertiary (2c) alkyl substituents as well as with a benzyl group (2d). Aryl
styryl thioethers gave slightly lower yields of isolated adducts (2e to
2h) whatever the nature of the substituent on the aromatic ring.
When replacing the styryl moiety with an alkyl-substituted olefin, the
reaction behaved similarly affording excellent yields of the
trisubstituted alkenes 2i-2k. However, the electron-deficient sulfanyl
acrylate 1l was poorly reactive giving 2l in a modest yield (20%).
When the gem-disubstituted alkenyl thioether 1m was used, traces
of the expected product were obtained (yield about 8%) along with
the product 2m (55% yield) resulting from
isomerization.
a subsequent
The reaction turned out to be highly regio- and stereoselective.
Indeed, when starting with a nearly equimolar Z/E mixture of alkenyl
thioether (eg. 1b or 1c), the trisubstituted alkenes 2b and 2c were
isolated in a diastereomeric ratio > 90:10 in favor of the E isomer.
Except for 2l, no isomerization was observed when starting with pure
E substrates as observed for 1i and 1k. NMR experiments were
performed to determine the configuration of the trifunctionalized
thioethers. Heteronuclear NOESY experiments clearly demonstrated
a correlation between fluorine and the olefinic proton on 2j and 2k,
enabling us to establish the E selectivity of the reaction.ii
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2
Scope of the copper-catalyzed ethoxy carbonyl excess of benzylamine (Scheme 3). This transformation enlarges
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DOI: 10.1039/C7CY00076F
even more the molecular diversity accessible with this protocol.
difluoromethylation of various alkenyl thioethers 1
Scheme 3 Transformation of fluorinated alkenyl thioether 2h
2.3 Mechanistic Studies
To get more insights into the mechanism, selected reactions were
performed in the presence of radical scavengers.
When 1a was reacted under standard reaction conditions in the
presence of Galvinoxyl (1 equiv), no product was formed, while in the
presence of TEMPO (1 equiv, Table 3, entry 1), traces of product were
obtained along with 53 % of the TEMPO-adduct 4, characterized both
by 19F NMR and Mass Spectroscopy. These observations along with
the formation of diphenyldisulfide previously reported suggest that
a radical mechanism is involved in the process. These conclusions are
consistent with the recent studies of fluorination of hydrazones with
analogous copper systems28,29 and with similar radical reactions
mediated by copper.30-32 To identify the key players in the radical
formation, the trapping by TEMPO was further examined under
various conditions (Table 3). The yield of 4 is only slightly lower (44
%, Table 1, entry 2) when the reaction is performed in the absence
of the alkenyl thioether 1a, suggesting that 1a is not essential for the
formation of the difluoroacetate radical. Note that in the absence of
copper, no radical was generated (Table 3, entry 6). As already
The major isomer is represented. NOE stands for Nuclear Overhauser
Effect (between 1H and 1H) HOE stands for Heteronuclear Overhauser
Effect (between 19F and 1H).
The regioselectivity of the reaction was further confirmed using the
β-disubstituted styryl thioether 1n. In this case, the compound 2’n
was isolated in a modest 30% yield along with diphenyldisulfide. The
latter could result from an α-addition-desulfination sequence due to
the steric hindrance at the β-position (see Scheme 2). It is worth
noting that this byproduct has been observed in 0 to 15 % yield also
with 1a to 1l.
observed
tetrakis(acetonitrile)copper(I)
during
the
optimization
hexafluorophosphate
process,
behaved
similarly (Table 3, entry 4). This copper source allowed us to test the
effect of the ligand toward the formation of 4, indeed the use of Cu2O
without ligand was not conclusive due to solubility issues. In the
absence of phenanthroline, no traces of 4 were detected (Table 3,
entry 3), revealing its crucial role for the generation of the radical
species, and explaining the failure of the reaction in the absence of
ligand. Without a base the formation of 4 dropped significantly
(Table 3, entry 5), unveiling its contribution in the generation of the
reactive species. These experimental observations suggested that
the combination of copper, 1,10-phenanthroline and K2CO3 might be
responsible for the formation of a radical species in our reaction
conditions.
Scheme 2 Copper-catalyzed difluoroacetylation of 1n
Surprisingly, the replacement of BrCF2CO2Et with the
bromodifluoroacetamide or bromodifluorophosphonate failed to
give the corresponding fluorinated alkenyl thioethers. However, the
post-functionalization of product 2h turned out to be very efficient
as shown in Scheme 3. The ester residue can be readily converted
into the corresponding amide by treating compound 2e with an
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Table 3 Mechanistic experiments performed in the presence of
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TEMPO
Entry
1a
2
3b
4
[Cu]
Cu2O
Cu2O
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu2O
-
Base
K2CO3
K2CO3
K2CO3
K2CO3
-
Ligand
1,10-Phen 53 %
1,10-Phen 44 %
Yield of 4
-
0 %
1,10-Phen 61 %
1,10-Phen 15 %
1,10-Phen 0 %
5
6
K2CO3
Yields were evaluated by 19F NMR using α,α,α-trifluorotoluene as an internal
standard a In the presence of 1 equiv of 1a. 2 % of 2a was formed. b The
copper source was changed for solubility issues in the absence of ligand.
Scheme 4 Relative stability of possible starting complexes
computed (in kcal.mol-1)
For a better understanding of the elementary steps involved in this
transformation, further investigations on the copper(I) complex
involved in the reduction of BrCF2CO2Et were performed at the
theoretical level using density functional theory (DFT). Bulk solvent
effects were included by means of a polarizable continuum model
(PCM) (see the Supporting Information for details). Two different
mechanisms of activation of BrCF2CO2Et were compared: a single
electron transfer (SET) and a halogen atom transfer (HAT).iii Though
the approach used here cannot provide a good description of the
entropic effects that can play a role in the present case, the energetic
–ie enthalpies- associated to these reaction can be trustfully
estimated and it is here discussed. An estimate of the associated
reaction free energies is reported in SI.
Table 4 Reaction energies for the different complexes (Enthalpy in
kcal.mol-1)
A
B
C
D
E
SET
ΔE SET
HAT
55.2
-
39.9
28.4
11.7
4.7
39.1
25.8
16.7
4.1
ΔE HAT
Both SET and HAT were computed to be endothermic processes (ΔH
> 0). In the absence of the ligand (A), the energy required for the SET
is very high (ΔH = 55.2 kcal.mol-1). This energy is lowered by
complexation with 1,10-phenanthroline (B: ΔH = 39.9 kcal.mol-1 and
D: ΔH = 39.1 kcal.mol-1), and even more favorable when copper is
bound to a hydroxide anion (C: ΔH = 11.7 kcal.mol-1 and E: ΔH = 16.7
kcal.mol-1). The presence of alkenyl thioether 1b has only a tiny
effect, as one can see by comparing the energies computed for B to
the ones for D and the energies computed for C to the ones for E. In
all cases, the reaction energies for HAT reactions were lower than
those calculated for SET. A similar behavior was observed whatever
the presence of the alkenyl thioether; in the absence of
phenanthroline, no radical was formed; and the absence of base
significantly impacted the radical formation. These findings are
consistent with experimental data from Table 3.
As starting complexes models, A to E were considered, where solvent
molecules, alkenyl thioether 1b, 1,10-phenanthroline and hydroxide
anion (the base formed in the reaction medium) were included as
possible ligands (see Scheme 4 and Table 4, details in the Supporting
Information).iv
Overall, complexes C and E are the most likely to initiate the
formation of the difluoroacetate radical by HAT (C: ΔH = 4.7 kcal.mol-
1
and E: ΔH = 4.1 kcal.mol-1). In addition, the complexation of one
molecule of 1a to the copper/phenanthroline complex in the
1
absence of base (complex D) was evidenced by H NMR, but not in
its presence (complex E, see the Supporting Information). After HAT,
both C and E formed a copper (II) complex, bearing a phenanthroline
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ligand, a hydroxide and a bromide. Surprisingly, the alkenyl thioether
has low affinity for the copper complex and is expelled from the
coordination sphere of copper at this step for E.
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Scheme 5 Computed reaction pathways (in kcal.mol-1). Solid line: initiation with C. Dashed line: initiation with E. The last part of the
reaction path after regeneration of E by SET is omitted for clarity. This part is the same as for C. Grey: path for the formation of the main
byproduct. Blue: path for the formation of the minor stereoisomer.
The formed °CF2CO2Et radical can then add to the alkenyl thioether TS-3) and leading to the most stable (E)-2b product is computed to
1b. The addition at the α position with regards to the S atom (ΔHa = be lower in energy than the one of the corresponding Z form. Similar
7.6 kcal.mol-1, TS-1’) had a higher activation barrier than at the β conclusions can be drawn by considering the values for the Gibbs
position (ΔHa = 5.1 kcal.mol-1, TS-1), but appeared achievable under free energies. The interaction with the base leads to the two stable
the reaction conditions (Scheme 5). This small difference allowed us intermediates (E)-I-3 and (Z)-I-3 (ΔG = 2.7 kcal.mol-1). The transition
to explain the observed regioselectivity in some cases with the state for the deprotonation leading to the major product E is the
formation of the disulfide as byproduct. The addition of the lowest in energy (ΔG = 1.7 kcal.mol-1) and this major product is the
°CF2CO2Et radical on the alkenyl thioether 1b on the copper (I) most stable one (ΔG = 0.9 kcal.mol-1). The complete Gibbs free
complex D has a higher energy barrier (ΔHa = 8.2 kcal.mol-1, see the energy profile can be found in Supporting Information.
Supporting Information), and is thus less favorable. The so formed
radical I-1 can reduce the copper (II) complex to regenerate copper
(I) (ΔH = 12.9 kcal.mol-1 to regenerate C, ΔH = 13.5 kcal.mol-1 to
Based on these findings, we suggested the mechanism depicted in
Scheme 6. In the presence of 1,10-phenanthroline and a base, the
copper(I) hydroxo complex reduced BrCF2CO2Et to form a copper (II)
complex and a ethoxy carbonyl difluoromethyl radical. Then, the
addition of this radical on the alkenyl thioether 1 proceeded
according to an outsphere process and the observed
stereoselectivity is related to the relative stability of the two possible
isomers after the deprotonation step.
regenerate E). The resulting carbocation I-2 can then be
deprotonated by the base to form the final product 2b. The different
conformations of the carbocation I-2 are very close in energy (ΔH =
0.8 kcal.mol-1) and are in equilibrium. These conformers are similar
whatever the configuration of the starting alkenyl thioether (Z or E).
Both can undergo a deprotonation step: after interaction with the
base (OH-) leading to two stable and closely lying intermediates (E)-
I-3 and (Z)-I-3 (ΔH = 1.4 kcal.mol-1), the E and Z products can be
formed. In agreement with the experiments, the transition state
corresponding to the deprotonation step for the E form (that is (E)-
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3. CONCLUSIONS
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We report herein a general regio- and stereoselective method for the
ethoxy carbonyl difluoromethylation of alkenyl thioethers. The
developed methodology was applied to a broad range of substrates
with good yields and an excellent selectivity in favor of the E isomer.
Mechanistic studies supported by experimental observations and
theoretical calculations gave evidences for a radical mechanism. The
generation of a difluoroacetate radical promoted by a well-defined
copper complex was established by these studies. Compared to
other strategies to introduce a fluorine atom or a fluorinated
group,19–21,23,33–39 this method allowed the generation of a radical
under mild conditions, without requirement of light irradiation,
expensive metal or radical initiator, which constitutes a real asset. It
allows an easy access to fluorinated chemical platform of interest,
since post-functionalizations of these substrates are possible thanks
to the versatility of the ester function.
Scheme 6 Proposed reaction mechanism
These findings can be generalized. Indeed, for the initiation step, we
could rationalize the absence of reactivity of BrCF2CONR2,
BrCF2PO(OEt)2 and BrCH2CO2Et with the higher barrier energies
computed for the HAT as well as with their higher reduction potential
measured by cyclic voltammetry (see the Supporting Information).
Moreover, the fact that the radical initiation did not depend on the
presence of the alkenyl thioether showed that this method is broadly
applicable to the generation of °CF2CO2Et radicals using copper
catalyst. This hypothesis was confirmed by performing a radical
trapping experiment with TEMPO in the presence of enamide (Table
5, entry 1) and benzofuranes (Table 5, entry 2 and 3) in previously
reported conditions.25,26 For example the adduct 4 was isolated in
30% yields in the case of ene-carbamates without traces of the
desired addition product, revealing a similar mechanism for these
substrates. In a previous report,26 a non-radical mechanism was
proposed based on stoichiometric reactions performed in the
absence of the base. After ruling out the direct oxidative addition of
the bromo compound with the cationic copper(I) complex (by both
NMR and electrochemistry performed at RT)26, a pre-complexation
Acknowledgements
I. F. thanks the Ministère de l'Education Nationale de
l'Enseignement Supérieur et de la Recherche (MNESR) for a
fellowship. We acknowledge the Centre National de la
Recherche Scientifique (CNRS), Chimie ParisTech, the Ecole
Normale Supérieure (ENS), as well as the Agence Nationale de
la Recherche (ANR) [program CD2I (CuFeCCBond)] for financial
support. I. G., T. P. and X. P. thank the LABEX SynOrg (ANR-11-
LABX-0029).
of the latter with enamide was established via cyclic voltammetry as Notes and references
evidenced here by 1H NMR in the case of the alkenyl thioether (in the
absence of the base). This emphasized the important role of the base
that transformed the cationic copper(I) complex to neutral copper(I)
hydroxo complex. Finally, the radical mechanism established herein
turned out to be quite general for these systems.
i
The complete elucidation of the structure of the major isomer
was established further by HOESY experiments.
All other configurations were assigned by analogy (see the
Supporting Information)
For comparison purposes, a mechanistic path involving an
oxidative addition (OA), which does not involve the
generation of radicals, was also calculated and is reported in
the Supporting Information.
ii
iii
Table 5 Experiments in the presence of TEMPO for enamide and
benzofuranes
iv
We chose Cu(CH3CN)4PF6 as a simpler starting complex whose
observed reactivity was similar to Cu2O (see the Supporting
Information and Table 3).
1
2
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Entry
Substrate
Solvent, time
CH3CN, 6 h
Yield of 4 a
1
30 %
4
5
2
3
DMF, 20 h
DMF, 20 h
10 %
10 %
6
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DOI: 10.1039/C7CY00076F