Visible-light promoted atom transfer radical addition?elimination (ATRE) reaction for the synthesis of fluoroalkylated alkenes using DMA as electron-donor

Article abstract of DOI:10.3390/molecules25030508

Here, we describe a mild, catalyst-free and operationally-simple strategy for the direct fluoroalkylation of olefins driven by the photochemical activity of an electron donor?acceptor (EDA) complex between DMA and fluoroalkyl iodides. The significant advantages of this photochemical transformation are high efficiency, excellent functional group tolerance, and synthetic simplicity, thus providing a facile route for further application in pharmaceuticals and life sciences.

Full text of DOI:10.3390/molecules25030508

molecules
Communication
Visible-light Promoted Atom Transfer Radical
Addition−Elimination (ATRE) Reaction for the
Synthesis of Fluoroalkylated Alkenes Using DMA
as Electron-donor
Wen-Wen Xu 1 , Le Wang , Ting Mao , Jiwei Gu , Xiao-Fei Li 2,4,* and Chun-Yang He 1,4,
,†
2,†
1
3
*
1
Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Generic Drug Research Center
of Guizhou Province. School of Pharmacy, Zunyi Medical University, Zunyi 563003, China;
xuww20191213@163.com (W.-W.X.); 18585310741@163.com (T.M.)
Basic Medical School, Zunyi Medical University, Zunyi 563003, China; wangle526@sina.com
School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States;
jiweigu@wustl.edu
Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory
of Ethnomedicine of Ministry of Education, School of Pharmacy, Zunyi Medical University,
Zunyi 563003, China
2
3
4
*
†
Correspondence: lixiaofei@zmu.edu.cn (X.-F.L.); hechy2002@163.com (C.-Y.H.)
These authors contributed equally to this work.
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Davide Ravelli
Received: 12 December 2019; Accepted: 21 January 2020; Published: 24 January 2020
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Here, we describe a mild, catalyst-free and operationally-simple strategy for the direct
fluoroalkylation of olefins driven by the photochemical activity of an electron donor acceptor (EDA)
−
complex between DMA and fluoroalkyl iodides. The significant advantages of this photochemical
transformation are high efficiency, excellent functional group tolerance, and synthetic simplicity,
thus providing a facile route for further application in pharmaceuticals and life sciences.
Keywords: fluoroalkyl iodides; EDA; noncovalent interaction; fluoroalkylated alkenes; DMA
1
. Introduction
Owing to their tendency to alter the lipophilicity, metabolic stability, and electronic properties of
organic molecules, fluorinated organic compounds have been widely used in medicinal chemistry,
and material sciences [ ]. Therefore, the development of safer, less toxic and more selective methods
1–9
to introduce fluorinated functional groups into organic molecules has become an intensive topic of
synthetic organic chemistry [10–19].
Alkenes play a ubiquitous role in the realm of chemical synthesis due to their enriched
reactivity and abundance, fluoroalkylation of carbon-carbon double bonds is an attractive method
for accessing fluorine containing compounds. Since 1945, atom transfer radical addition (ATRA)
has extensively been utilized for fluoroalkylation of alkenes [20
alkenes containing fluorinated functional groups via Heck-type reaction were less studied owning
to the lack of efficient and general strategies [30 32]. In the past 10 years, some powerful strategies
have been developed to realize such transformation [20 21 33 36]. One of the major improvements
has been made via photo-excited catalyst such as Ru/Ir complexes and organic dyes [21 33]. Very
recently, non-covalent interaction initiated fluoroalkylation reaction has emerged as an attractive
strategy [37 47]. Inspired by our previous studies in this field [48 51], we envision that if the solvent
can serve as an electron donor compound, the reactions would be simpler. Here, we demonstrate a
–29]. However, the preparation of
–
,
, –
,
–
–
Molecules 2020, 25, 508; doi:10.3390/molecules25030508
www.mdpi.com/journal/molecules

Molecules 2020, 25, 508
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mild, catalyst-free and operationally-simple strategy for the direct fluoroalkylation of olefins driven by
the photochemical activity of electron donor acceptor (EDA) complex between DMA and fluoroalkyl
−
iodides. The significant advantages of this photochemical transformation are high efficiency, excellent
functional group tolerance, and synthetic simplicity [52].
2
. Results
We initially probed this catalyst-free fluoroalkylation reaction by using readily available tert-butyl
allylcarbamate 1a and ethyl iododifluoroacetate 2a (1.5 equiv) as model substrates. 29% yield of atom
transfer radical addition (ATRA) product 4a was obtained when the reaction was performed with
K PO (2.0 equiv) in MeCN and irradiated by blue LEDs for 16 h. After a series of reaction media were
3
4
screened (Table 1, entries 2–8), THF, Toluene and dioxane were not suitable for this transformation,
and 10% yield of desired product was obtained when DMSO was used as solvent. Both 3a and 4a
were obtained when DMA and DMF were used. To improve the selectivity of this transformation,
a variety of different bases were examined utilizing DMA as solvent for this reaction (Table 1, entries
8–11). Among them, KOAc was the best choice and afforded 3a in 64% yield (Table 1, entry 11).
Finally, different light sources were tested, the yield increased to 95% when the reaction mixtures
were irradiated under purple LEDs (Table 1, entry 13), no desired product was observed when control
experiments were carried out in the absence of light or base, demonstrating the photochemical nature
of this transformation (Table 1, entries 14, 15).
Table 1. Representative results for optimization of visible light-mediated reaction of 1a and 2a
.
Base
Solvent, r.t., 16 h
2 W LED
BocHN
CF COOEt
2
+
ICF2COOEt
+
CF2COOEt
BocHN
BocHN
I
1
a,b
1a
2a
3a
4a
Entry
Light Source
Base (equiv)
K PO (2)
Sovent
3a, yield (%)
4a, yield (%)
1
2
3
4
5
6
7
8
9
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Green LEDs
Purple LEDs
Purple LEDs
none
MeCN
DCE
THF
—-
—-
—-
—-
—-
10
21
45
43
59
64
50
95(84)
—-
—-
29
55
—-
7
trace
—-
51
36
26
5
—-
—-
—-
—-
—-
3
4
K PO (2)
3
4
K PO (2)
3
4
K PO (2)
Toluene
Dioxane
DMSO
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
3
4
K PO (2)
3
4
K PO (2)
3
4
K PO (2)
3
4
K PO (2)
3
4
K CO (2)
2
3
1
1
1
1
1
0
1
2
3
4
Cs CO (2)
2
3
KOAc (2)
KOAc (2)
KOAc (2)
None
c
1
5
KOAc (2)
a
Reaction conditions: (unless otherwise specified): 1a (0.3 mmol, 1.0 equiv), 2a (0.45 mmol, 1.5 equiv), anhydrous
b
19
solvent (2 mL), r.t. under Ar, irritated under visible light for 16 h. Determined by F NMR spectroscopy using
fluorobenzene as an internal standard, and the number within parentheses represents the yield of the isolated
product. c The reaction was performed without light.
With the optimum reaction conditions established, various alkenes were explored. As shown
in Scheme 1, The reaction exhibited good functional group tolerance. A range of functional groups,
such as esters (3c), methoxyl (3d), and even unprotected hydroxyl group (3e) generally were compatible
with the reaction and moderate to good yields were obtained. Then, styrenes were also evaluated,
and we were pleased to find that styrenes all performed well under the optimized reaction conditions,
providing the corresponding products in good to excellent yields (3f
–n). Importantly, substrate with
steric hindrance could also undergo this transformation smoothly (3o). This reaction system is also

Molecules 2020, 25, 508
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amenable to the use of other commercial perfluoroalkyl iodides, such as C F I, C F I and C F I
4
9
6
13
8 17
(Scheme 1, 3p–s).
Scheme 1. Atom Transfer Radical Addition
−
Elimination (ATRE) reaction for the synthesis of
Reaction conditions (unless otherwise specified): (0.3 mmol, 1.0 equiv),
(0.45 mmol, 1.5 equiv), KOAc (0.6 mmol, 2.0 equiv) in anhydrous DMA (2.0 mL), r.t. under Ar, purple
LEDs, for 16 h. b Yield of isolated product.
a,b
a
fluoroalkylated alkenes
.
1
2
To gain insight into the mechanism of this reaction, several experiments were performed.
The reaction was completely suppressed when a radical scavenger TEMPO (1.0 equiv) was added
as an additive under the standard reaction conditions (Scheme 2a). Furthermore, a radical clock
experiment was conducted. The ring-expanded product
7 was formed when 2a was treated with
α
-cyclopropylstyrene ( ) in the absence of 1a (Scheme 2b). Optical absorption spectra of the reactants
6
found that the absorption was obvious strengthened when DMA and R I were mixed (Scheme 2c,
F
for details, see Supplementary Materials), which indicated a non-covalent interaction occurred between
them. Moreover, this conclusion was further confirmed by a Job’s plot (Scheme 2d, for details,
see Supplementary Materials). Finally, compound 4a was totally converted to 3a under optimized
condition in the dark (Scheme 2e, for details, see Supplementary Materials). This result indicated that
the reaction was performed via atom transfer radical addition elimination pathway.

Molecules 2020, 25, 508
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a
b
c
4
.5
3
A1: 2a + KOAc + DMA
A2: 2a + DMA
3
2
1
0
A3: KOAc + DMA
A4: 2a + Cyclohexane
.5
2
.5
1
.5
0
330
380
430
480
530
580
630
Wavelength(nm)
A1
A2
A3
A4
d
0.06
0.05
0.04
0.03
0.02
0.01
0
0
20
40
60
80
100
Molar fraction of 2a
e
Scheme 2. Mechanistic investigation. (
a) Addition of radical and SET inhibitors. (b) Trapping of
intermediates. (c) Optical absorption spectra study. (d) Job’s plot. (e) Control experiment.
Based on these preliminary results and previous reports [53,54], a plausible mechanism was
depicted in Scheme 3. Initially, non-covalent interactions occurred between DMA and C–I bond. Then
fluoroalkyl radical was generated under the irradition of purple LEDs. Subsequently, fluoroalkyl
radical reacted with alkenes (1) and generated a carbon radical A, which abstracted an iodine atom

Molecules 2020, 25, 508
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from R I to afford ATRA product 4 along with R radical that sustains the chain. Finally, elimination of
F
F
4
with base could afford the corresponding fluoroalkylated-ATRE products (3).
Scheme 3. Proposed Reaction Mechanism.
3
. Discussion
In the past 10 years, fluoroalkylation involving visible light promoted reactions has emerged as an
attractive and useful strategy to directly introduce fluorinated groups into organic molecules Among
those methods, fluoroalkyl iodides were commonly used substrates. Based on the investigations in our
group, we believe the noncovalent interaction between solvents (DMF, DMA, MeCN, acetone ect) and
fluoroalkyl iodides might play a crucial role in this kind of transformation.
4
. Materials and Methods
1H NMR spectra and 13C NMR spectra were recorded on an Agilent AM400 spectrometer. 19
F
NMR was recorded on an Agilent 400 MHz NMR spectrometer (CFCl as outside standard and low
3
field is positive). Chemical shifts (
δ) are reported in ppm, and coupling constants (J) are in Hertz (Hz).
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet,
19
q = quartet, m = multiplet, br = broad. NMR yield was determined by F NMR using fluorobenzene
as an internal standard before working up the reaction.
All reagents were used as received from commercial sources, unless specified otherwise,
or prepared as described in the literature. All reagents were weighed and handled in air at room
temperature. Blue LEDs (430–490 nm, peak wavelength: 455.0 nm) and purple LEDs (380–425 nm,
peak wavelength: 395.0 nm) were bought online.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: C.-Y.H. and X.-F.L. conceived and designed the experiments. W.-W.X., L.W. and T.M.
performed the experiments and mechanism studies. C.-Y.H. and X.-F.L. co-wrote the manuscript. J.G. contributed
for the edition of manuscript at revision stage. All authors discussed the results and commented on the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: We are grateful for the financial support from the National Natural Science Foundation of China
(
No. 21702241, 81760624, 21762053), Programs of Guizhou Province (No. 2017-1225, 2018-1427), Guizhou Provincial
Science & Technology “125-Plan” Major Project (No. 2015-039).
Conflicts of Interest: The authors declare no conflict of interest.
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