Synthesis and Photochemical Application of Hydrofluoroolefin (HFO) Based Fluoroalkyl Building Block

Article abstract of DOI:10.1021/acs.orglett.1c01709

A novel fluoroalkyl iodide was synthesized on multigram scale from refrigerant gas HFO-1234yf as cheap industrial starting material in a simple, solvent-free, and easily scalable process. We demonstrated its applicability in a metal-free photocatalytic ATRA reaction to synthesize valuable fluoroalkylated vinyl iodides and proved the straightforward transformability of the products in cross-coupling chemistry to obtain conjugated systems.

Full text of DOI:10.1021/acs.orglett.1c01709

pubs.acs.org/OrgLett
Letter
Synthesis and Photochemical Application of Hydrofluoroolefin
(HFO) Based Fluoroalkyl Building Block
Bálint Varga, Balázs L. Tóth, Ferenc Béke, János T. Csenki, András Kotschy,* and Zoltán Novák*
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ABSTRACT: A novel fluoroalkyl iodide was synthesized on multigram scale from refrigerant gas HFO-1234yf as cheap industrial
starting material in a simple, solvent-free, and easily scalable process. We demonstrated its applicability in a metal-free photocatalytic
ATRA reaction to synthesize valuable fluoroalkylated vinyl iodides and proved the straightforward transformability of the products in
cross-coupling chemistry to obtain conjugated systems.
n recent years fluorinated functional groups became one of
iodide in the fluoroalkyl backbone, could open the way for
Ithe most important motifs in compounds used in the field further selective transformations.
of pharmaceutical, agrochemical, and material sciences.1 The
search for new methods for fluorine incorporation, and design
of novel fluorinated scaffolds are constantly at the center of
chemical and pharmaceutical research.2 The possibility to
develop new fluorine-containing building blocks is offered by
the utilization of cheap and commercially available fluorinated
organic feedstock materials. In this category, hydrofluoroole-
fins (HFOs) are potential novel candidates, as they serve as a
greener alternative to refrigerant gases to hydrofluorocarbons
or chlorofluorocarbons gaining widespread household applica-
tion.3 One of their representatives HFO-1234yf has very low
global warming potential (GWP = 4), a short atmospheric
lifespan, and practically zero ozone depletion potential.4
Moreover, its heat transfer performance is similar to the
commonly used refrigerants, which needs to be substituted,5
and it is already a common industrial coolant in car and other
air conditioners.
One of the existing and extensively studied fluoroalkylating
methods focuses on the use of fluoroalkyl iodides. The
relatively weak iodine−carbon bond can be activated by
transition metal catalysts to achieve the halofluoroalkylation of
unsaturated molecules in a radical addition,10 providing
intermediates capable of sequential functionalization to give
more complex molecular structures.11 A more robust and
benign activation method is photochemistry either using
sensitizers12 or with the formation of electron donor−acceptor
(EDA) complexes also known as charge transfer (CT)
complexes.13 It was reported by Paixao
̃
et al. that an electron
donor and an acceptor can form complexes in a way that new
absorption bands (CT band) can be observed in their
spectrum.14 Irradiating at these wavelengths produces
exciplexes which initiate electron transfer events. This can
lead to the formation of reactive radical species that open new
chemical pathways. Irradiation of these complexes with visible
light can offer selective and nondestructive excitation, which
was also used to incorporate perfluoroalkyl chains into organic
molecules.15
The synthetic usage of HFO-1234yf is somewhat explored
but remains rather limited to the polymer industry.6 However,
there are few published organic chemical transformations
which focus on reaction with transition metals,7 the
nucleophilic substitution of one of the fluorines,8 or its
transformation into different hydrofluorolefins.9
In our work, we studied the transformation of HFO-1234yf
(1) into an iodinated species through the addition of iodine
monochloride.
Considering the recently established synthetic value of HFO
gases, we aimed to expand their applicability in organic
synthesis with the design of novel building blocks originating
from easily available fluoroolefin HFO-1234yf (1). Since 1 is a
gas under standard conditions we planned to convert it into a
more reactive and a user-friendly derivative such as its halogen
adduct. The presence of a different halogen atom, especially
Received: May 21, 2021
Published: June 7, 2021
https://doi.org/10.1021/acs.orglett.1c01709
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4925−4929
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Its electrophilic addition to double bonds is a well-
established protocol to create reactive functions.16 1 is easy
to liquify, and thus, there is no pressure buildup even when it is
used on larger scale. Reaction of ICl and neat HFO-1234yf (1)
at 40 °C in an autoclave afforded the desired 3-chloro-1,1,1,2-
tetrafluoro-2-iodopropane 2 (Scheme 1) with 95% regiose-
lectivity as a liquid in 67% yield.
The optimal amount of TMEDA was also studied, and we
found that the decrease of TMEDA equivalents caused lower
conversion (entries 3, 5, and 6). The optimization studies
demonstrated that by using TMEDA we could either opt for a
smaller load and longer reaction time (1 equiv, 6 h) or double
the amount of added TMEDA and have a complete reaction in
5 min (entry 7, 100% with 2 and 42% with 1 equiv TMEDA).
In our further experiments we followed the conditions
employing 2 equiv of TMEDA.
With these optimization results in hand, we performed the
reaction of phenylacetylene 3 and 2 on different scales (up to 4
mmol) and isolated the addition product 4 with similar
efficiency (92% yield, Scheme 2). Increasing further the scale
Scheme 1. Synthesis of 3-Chloro-1,1,1,2-tetrafluoro-2-
iodopropane (2) from HFO-1234yf
Scheme 2. Scope of the ATRA Reaction
With the novel fluoroalkyl iodide reagent (2) in hand we
aimed to explore its reactivity in photochemical radical
addition to a C−C triple bond to synthesize new vinyl iodide
structures that are amenable for further transformations. For
this purpose, we reacted phenylacetylene (3) with the
fluoroalkyl iodide reagent 2 using the known transition-
metal-based photoredox catalysis protocol,17 with the goal to
initiate an atom-transfer radical addition (ATRA) in the
presence of Ru- or Ir-based photocatalysts and tetramethyl-
ethylenediamine (TMEDA). However, after some optimiza-
tion steps18 it became evident that the transition-metal-
catalyzed photoredox protocol can be simplified to a metal-free
method based on EDA complex formation and excitation. In
the presence of TMEDA, the radical addition reaction reached
100% conversion in MeOH after 6 h at rt (Table 1, entry 1).
a
Table 1. Optimization of the Photocatalytic Addition
b
Entry
1
2
Equiv of TMEDA
Equiv of Iodide
Conv
2
2
2
2
1
0.1
2
4
4
3
2
3
3
3
3
100%
0%
a
Method A: acetylene (0.4 mmol), 2 (1.2 mmol, 3.0 equiv), TMEDA
c
(0.8 mmol, 3.0 equiv), and MeOH (2 mL), 10 W LED (445 nm).
3
4
5
6
100%
71%
98%
35%
100%
42%
b
Method B: TMS-acetylene (0.4 mmol), MeOH (2 mL), KF (0.4
mmol), then added 2 (1.2 mmol, 3.0 equiv), TMEDA (0.8 mmol, 3.0
equiv), 10W LED (445 nm). Z/E ratio is >20:1 unless indicated
otherwise.
d
7
d
8
1
of the reaction (12−72 mmol) caused a slight reduction of the
efficiency, and 4 was isolated in 78−80% yield. The reaction
proved to be Z selective according to NOE measurements of
the product, containing less than 5% of the E stereoisomer.
The expansion of the scope required versatile arylacetylenes.
These terminal alkynes could be generated from the
corresponding 1-trimethylsilyl (TMS) derivates through
desilylation.19 In order to simplify the reaction, we aimed to
utilize TMS protected arylacetylenes as starting materials,
which are readily available from the Sonogashira coupling of
aryl halides and ethynyltrimethylsilane. MeOH is a perfect
solvent for the desilylation step facilitated by KF, and we were
able to couple this deprotection step with the key photo-
catalytic transformation. First, para-tolylacetylene (A5) gen-
erated in situ from its TMS derivative (SM5) was reacted
sequentially with 2, and the appropriate vinyl iodide (5) was
a
Reaction conditions: phenylacetylene (0.2 mmol, 1.0 eqiuv),
tetrafluoro iodide (2) (2.0−4.0 equiv), TMEDA (0.1−2.0 equiv),
MeOH (1 mL) 10 W LED (445 nm). By GC-MS. In dark. 5 min.
b
c
d
Next, we reacted the alkyne 3 and 2 in the presence of
different amine additives, under blue LED irradiation. As the
physical properties of the EDA complexes can be fine-tuned
through the choice of complexing partners, we studied the
influence of amines on the reaction, but we found TMEDA as
the best amine for the reaction.18 In the absence of light (entry
2) the reaction did not take place (0% conversion after 6 h)
meaning that the reaction pathway is photochemical in nature.
The amount of the reagent 2 can be reduced to 3 equiv
without the loss of efficiency (entry 3), but the use of 2 equiv
resulted only 71% conversions of the starting alkyne (entry 4).
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obtained in 90% yield. The other tolyl isomers 6 and 7 were
isolated in similar yield in the two-step sequential process, but
in the case of the ortho derivative the Z/E ratio decreased to
8:1, showing some ortho substituent effect in the addition
reaction.
Scheme 3. Scope of Palladium Catalyzed Couplings
The presence of the strongly electron-donating methoxy
group on the aromatic ring had no negative effect on the
efficiency, affording 8 in 83% yield, while substrate SM9 having
the electron-withdrawing acetyl group in the para position gave
the vinyl species 9 in lower 64% yield. Halogenated substrates
underwent smooth reaction in the photochemical trans-
formation, and the products were isolated in good yields
(61−79%, 10−13). In the case of the bromo derivatives, as a
cross-check, we performed the two-step reaction starting from
SM10 and from the terminal acetylene A10 and obtained
similar yields (75% and 77%) demonstrating that the reaction
can be performed with TMS-protected acetylenes in a
sequential manner. Similarly to A7, the presence of F, Ph,
COOEt, and NH2 in the ortho position of the aryl ring also led
to the increased formation of the E-isomers (14−16).
Although in this series the presence of an electron-withdrawing
ester group led to a lower yield (52%, 15), the presence of a
free amino group was well tolerated (86%, 16). Similarly, to
the ortho substituted substrates, 1-naphthyl derivative SM18
gave an increased trans product ratio in the mixture of
regioisomers isolated in 67% yield.
As in the case of heterocyclic alkynes, we successfully
performed the photoaddition on quinoline, pyridine, thio-
phene, and benzofuran derivatives and prepared the corre-
sponding vinyl iodides in 24−65% yield (19−22). Aliphatic
acetylenes reacted readily as well; however, due to the volatility
of the products (23−26) their isolation proved difficult
resulting in lower yields (21−30%). The limitation of the
reaction is based on the sterically demanding alkyl group.
Unfortunately, we could not achieve full conversion starting
from internal alkynes or from substrates with steric bulk
around the reactive center. Propargylic ethers or amines
stopped the reactions at low conversion,18 supposedly due to
the competitive interaction with the fluoroalkyl iodide, thus
blocking the required EDA formation.
a
Reaction conditions: Vinyl iodide (0.4 mmol), alkyne (0.45 mmol,
1.12 equiv), Pd2dba3, (5 mol %) 40 mol % PPh3(40 mol %), CuI (20
b
mol %), TEA (2 mL). Vinyl iodide (0.4 mmol), alkyne (0.45 mmol,
As the products contain the reactive vinyl iodide function,
we aimed to explore their synthetic potential to obtain new
conjugated diarylalkene and enyne systems bearing a
fluoroalkyl group.
1.12 equiv), PdCl2(PPh3)2 (2 mol %), CuI (2 mol %), TEA (2 mL).
c
Vinyl iodide (0.4 mmol), boronic acid (0.6 mmol, 1.5 equiv),
Pd2dba3, (1 mol %), PPh3 (8 mol %) and K2CO3 (0.8 mmol, 2.0
equiv), THF (4 mL), water (2 mL). Vinyl iodide (0.4 mmol),
d
For this purpose, we selected Sonogashira and Suzuki cross-
coupling reactions as a powerful and diverse tool for carbon−
carbon bond formation, already demonstrated on similar
motifs.20 These examples utilize a relatively high 10 mol %
loading of Pd(PPh)4 catalyst, so we started our experimenta-
tion with a similar palladium loading with the addition of 5
mol % of Pd2dba3 and 40 mol % PPh3 besides CuI for the
Sonogashira coupling of vinyl iodides with terminal acetylenes,
and the coupling partners were transformed into the desired
enyne in good yields (Scheme 3). With the application of these
catalytic conditions for the transformation of selected alkyne
coupling partners, we demonstrated that the fluoroalkylated
vinyl iodides can be coupled with different terminal alkyl, aryl,
and silyl alkynes efficiently, to obtain versatile fluorinated
enyne derivatives 27−34 in good yields (69−87%). With an
additional group of substrates, we also demonstrated that
applying a more general Sonogashira condition, such as 2
mol % PdCl2(PPh3)2 and 2 mol % CuI, is also suitable for the
boronic acid (0.6 mmol, 1.5 equiv), PdCl2(PPh3)2 (2 mol %), K2CO3
(0.8 mmol, 2.0 equiv), THF (4 mL), water (2 mL).
catalytic functionalization of the fluorinated vinyl iodides with
versatile terminal alkynes (35−38).
The Suzuki coupling of fluoroalkylated vinyl iodides and
arylboronic acids was performed in a THF/water solvent
mixture at 70 °C in the presence of two different catalyst
systems (Scheme 3). We successfully demonstrated that these
novel fluoroalkylated vinyl iodides are excellent coupling
partners of aryl and heteroaryl boronic acids, independently of
the applied palladium catalyst system. The desired coupling
reactions proceeded smoothly, and the appropriate products
(39−50) were isolated in moderate to excellent yields (50−
96%).
To prove the EDA complex formation of 2, we performed
19F NMR titration and a Job’s plot analysis.15d Our results
showed that 3-chloro-1,1,1,2-tetrafluoro-2-iodopropane (2)
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Letter
forms a 1:1 complex with TMEDA with the association
constant Ka of 1.65 M−1 in chloroform.18 Based upon this and
the literature precedence, we propose the following mechanism
for the addition reaction (Scheme 4a). The iodide 2 forms an
Hungary; orcid.org/0000-0001-5525-3070;
Email: novakz@elte.hu
András Kotschy − Servier Research Institute of Medicinal
Chemistry, 1031 Budapest, Hungary; orcid.org/0000-
0002-7675-3864; Email: andras.kotschy@servier.com
Scheme 4. Proposed Reaction Mechanism and Radical
Trapping Experiment
Authors
Bálint Varga − ELTE “Lendu
̈
let” Catalysis and Organic
Synthesis Research Group, Institute of Chemistry, Eötvös
́
Loránd University, Faculty of Science, H-1117 Budapest,
Hungary
Balázs L. Tóth − ELTE “Lendulet” Catalysis and Organic
̈
Synthesis Research Group, Institute of Chemistry, Eötvös
́
Loránd University, Faculty of Science, H-1117 Budapest,
Hungary
Ferenc Béke − ELTE “Lendulet” Catalysis and Organic
̈
Synthesis Research Group, Institute of Chemistry, Eötvös
́
Loránd University, Faculty of Science, H-1117 Budapest,
Hungary
János T. Csenki − ELTE “Lendulet” Catalysis and Organic
̈
Synthesis Research Group, Institute of Chemistry, Eötvös
́
Loránd University, Faculty of Science, H-1117 Budapest,
Hungary
EDA complex with TMEDA, which upon irradiation with
visible light produces the fluoroalkyl radical 51. This radical
undergoes addition to the acetylene giving the vinyl radical 52.
From this, two paths are possible. This radical (52) can either
recombine with an iodine radical formed in the previous step
to give 4 or can react with another molecule of 2 forming the
product (4) and regenerating the fluoroalkyl radical 51
propagating the chain reaction. Reaction performed in the
presence of radical scavenger TEMPO did not afford the
desired product 4, but we detected the exclusive formation of
TEMPO-adduct 53, which supports the radical path (Scheme
4b).18
In conclusion, we designed and synthesized a new
fluoroalkyl building block from cheap industrial starting
material HFO-1234yf using a simple, efficient, and scalable
method. We demonstrated its utility in a benign, metal-free,
visible light driven photoreaction proceeding through an in situ
formed EDA complex of the fluoroalkyl iodide and TMEDA.
We demonstrated that the fluorinated vinyl iodides are
valuable synthetic intermediates, as they readily participate in
palladium-catalyzed cross-coupling reactions expanding the
molecular complexity of the olefins. The exploitation of the
synthetic potential of the fluoroalkyl iodide, the vinyl iodide,
and the coupling products are the subjects of further studies in
our laboratory to produce novel fluorinated compounds.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01709
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was funded by the National Research, Develop-
ment and Innovation Office (NKFIH, K132077). This work
was completed in the ELTE Thematic Excellence Programme
2020 Supported by NKFIH - TKP2020-IKA-05 and the
́
UNKP-20-3 New National Excellence program supported by
the Hungarian Ministry of Human Capacities (B.V.). The
authors thank László Burai and Tamás Gáti at Servier Research
Institute of Medicinal Chemistry for the analytical measure-
ments.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01709.
Full optimization, LED photoreactor setup, EDA
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AUTHOR INFORMATION
Corresponding Authors
■
Zoltán Novák − ELTE “Lendu
Synthesis Research Group, Institute of Chemistry, Eötvös
Loránd University, Faculty of Science, H-1117 Budapest,
̈
let” Catalysis and Organic
́
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