A general and green fluoroalkylation reaction promoted: Via noncovalent interactions between acetone and fluoroalkyl iodides

Article abstract of DOI:10.1039/c9cc09517a

The first example of visible light promoted fluoroalkylation reactions initiated via noncovalent interactions between acetone and fluoroalkyl iodides is presented. The reaction system features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance. A wide range of substrate scopes such as alkenes, alkynes and (hetero)arenes were all compatible with the reaction system.

Full text of DOI:10.1039/c9cc09517a

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DOI: 10.1039/C9CC09517A
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A General and Green Fluoroalkylation Reaction Promoted via
Noncovalent Interactions between Acetone and Fluoroalkyl
Iodides
Received 00th January 20xx,
Accepted 00th January 20xx
Ting Mao, a, † Ming-Jian Ma, a, † Liang Zhao, a,b De-Pu Xue, a Yanbo Yu, c Jiwei Gu, c and Chun-Yang He
a,b
DOI: 10.1039/x0xx00000x
*
www.rsc.org/
Abstract: The first example of visible light promoted organic molecules.3 In such transformations, the noncovalent
fluoroalkylation reactions initiated via noncovalent interactions interaction usually occurred between excess amounts of amines
between acetone and fluoroalkyl iodides is presented. The reaction or substrates and RFI. We envision that the noncovalent
system features synthetic simplicity, mild reaction conditions interaction might also occur between the solvent and RFI, and a
without any photoredox catalyst, and high functional group radical intermediate could be generated under the irradiation
tolerance. A wide range of substrate scopes such as alkenes, of visible light If the driven force is strong enough, thus leading
alkynes and (hetero)arenes were all compatible with the reaction to the discovery of unprecedented transformations.
system.
Acetone is one of the most common solvents. We assumed
that a noncovalent interaction between the carbonyl group and
C-I bond might occur, which could induce radical intermediates
under the irradiation of visible light. To test the hypothesis
above, we began our investigations by treating alkenes with RFI
in acetone to study the atom transfer radical addition (ATRA)
reaction. Usually, this protocol was realized by using radical
initiators, such as peroxide,4 Na2S2O4,5 Et3B,6 or UV light7.
Recently, transition-metal8 and photoredox catalysis9 have
emerged as more effective alternatives, and the utilization of
amines,10 phenols11 or phosphines12 as catalysts has also been
developed in the past several months (Scheme 1). Herein, we
report the first example of visible light promoted
fluoroalkylation reactions via noncovalent interactions between
solvent and RFI. A variety of substrate scopes such as alkenes,
alkynes and (hetero)arenes were all compatible with the
reaction system.
Fluorinated compounds have attracted much attention as
candidates for pharmaceuticals and functional materials
because of their superior lipophilicity, binding selectivity,
bioavailability, and metabolic stability compared to their
nonfluoroalkylated analogs.1 Consequently, to meet the
increasing demand for these materials in the life sciences and
materials science, the development of more practical,
economical and environmentally friendly methods enabling the
efficient construction of the fluorine-containing organic
compounds has been one of the most important research topics
in organofluorine chemistry.
In the past ten years, numerous methods have been
developed to synthesize fluoroalkylated compounds with high
efficiency, and major improvements were made via transition-
metal catalysts or photo-excited catalysts.2 Very recently,
noncovalent interactions (EDA complexes or halogen bond)
initiated radical fluoroalkylations have emerged as an attractive
and useful strategy to directly introduce fluorinated groups into
Previous work:
1: radical initiators (peroxide, Na2S2O4, ect.)
2:transition-metal catalysts ( Co, Fe, ect.)
I
Rf
R
+
R
I
f
3: hv (photo-excited catalysts)
4: electron donors (amines, phenols or phosphines)
R
This work:
I
Blue LEDs
acetone
R
I
Rf
R
+
f
aKey Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province,
Generic Drug Research Center of Guizhou Province. School of Pharmacy.
Zunyi Medical University, Zunyi, Guizhou, P.R. China
E-mail: hechy2002@163.com;
R
visible Light
RF
I
acetone
RF
initiated via non-covalent
interactions
bKey Laboratory of Basic Pharmacology of Ministry of Education and Joint
International Research Laboratory of Ethnomedicine of Ministry of Education.
School of Pharmacy.
Scheme 1 Methods for 1,2-Addition of Fluoroalkyl Iodides to Alkenes and Alkynes.
Zunyi Medical University, Zunyi, Guizhou, P.R. China
cSchool of Medicine，Washington University in St. Louis，St. Louis, Missouri,
United States
Accordingly, we conducted this reaction by treating tert-butyl
allylcarbamate 1a and ethyl iododifluoroacetate 2a (1.5 equiv)
as model substrates. To our delight, 74% yield of the desired
product 3a was obtained when the reaction was performed
†
T. Mao and M-J. Ma Contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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with K2CO3 (1.0 equiv.) in acetone and irradiated by blue LEDs
for 16 hours. Further optimization of the inorganic bases
demonstrated that other bases were less effective, and the
desired product 3a was isolated in 93% yield when 2.0 equiv. of
K2CO3 was used (Table 1, entries 1-4). No desired product was
observed when control experiments were carried out in the
dark, confirming the photochemical nature of the
transformation (Table 1, entry 5). To our surprise, the product
3a at 49% yield was still obtained without bases (Table 1, entry
6). Finally, various short-wavelength LEDs were used as light
sources to examine the influence of optical wavelength on the
reaction, comparable yields were still obtained when LEDs with
wavelengths between 425-475 nm were used, and the yields
decreased with longer wavelengths (Table 1, entries 7-11). For
other ketones, 82% yield was still obtained when 3-pentanone
was used, and no reaction was observed using ketones with
larger substituents (Table 1, entries 12-14). Those results
indicate that the interactions between the solvent and
fluoroalkyl iodides were decreased with the increase of the
steric hindrance. Other solvents were also examined (Table 1,
entries 15-18), no reaction occurred when the reaction
performed in dioxane or toluene, and 68% yield was obtained
when MeCN used as the solvent. The major products come from
atom transfer radical addition-elimination (ATRE) reaction
when conducted in DMA or DMSO. We reason noncovalent
interactions also occurred between those solvent and RFI (Table
1, entries 17-18, for details, see ESI).
17
18
Blue (430-490)
DMA
K2CO3 (2)
DOI: 10.1039/C9CC09517A
K2CO3 (2)
26
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Blue (430-490)
DMSO
5
O
O
O
S-3:
S-1:
S-2:
a
Reaction conditions (unless otherwise specified): 1a (0.3
mmol, 1.0 equiv.), 2a (0.45 mmol, 1.5 equiv.), acetone (2.0 mL),
room temperature, 16 h. NMR yield determined by 19F NMR
using fluorobenzene as internal standard and number in
parenthese is yield of isolated product.
b
With the optimized reaction conditions in hand, the scope of
this photochemical atom transfer radical addition was
evaluated using an abundant structurally diverse terminal
alkenes.10 As shown in Table 2, functional groups such as amine,
esters naphthyl and methoxy were well-tolerated and provided
difluoroalkylated ATRA products in good to excellent yields
(Table 2, 3a-g). This reaction system is also amenable to the use
of other commercial perfluoroalkyl iodides, such as C4F9I and
C6F13I, and the corresponding products were obtained in
moderate to good yields (Table 2, 3h-o). CF3I was less reactive,
moderate to good yields could be provided when 5.0 equiv. of
CF3I was used (Table 2, 3p-r). Remarkably, when the reaction
was performed on a gram scale (3a), an 80% yield was still
obtained, demonstrating the synthetic utility of the protocol.
Table 2. Scope of the 1,2-Addition Reaction of Fluoroalkyl
Iodides to Alkenes. a,b
R
Blue LEDs
RF
R
+
IRF
Table 1. Representative results for the optimization of the
K2CO3 (2.0 equiv.)
I
a
acetone, r.t., 16 h
visible-light-promoted difluoroalkylation of allylcarbamate 1a.
1
2
3
Base
BocHN
CF2COOEt
ICF2COOEt
+
acetone, r.t., 16 h
12 W LEDs
BocHN
O
I
1a
2a
3a
BocHN
CF2CO2Et
CF
2CO2Et
O
CF2CO2Et
4
I
I
I
Entry
LEDs (nm)
Solvent
Base (equiv.)
Yield % b
c
3a
3b
3c
, 93% (80%)
, 78%
, 85%
CF
2CO2Et
1
Blue (430-490)
Blue (430-490)
Blue (430-490)
Blue (430-490)
-----
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
S-1
K2CO3 (1)
KOAc (1)
K2CO3 (2)
Na2CO3 (2)
K2CO3 (2)
-----
74
64
99 (93)
81
0
CF
2CO2Et
CF
2CO2Et
I
I
I
2
d
3f
, 84%
3e
, 73%
3d
, 96%
3
CF2CO2Et
BocHN
RF
RF
4
I
I
I
MeO
4
3j
RF=C4F9, , 76%
3g
RF=C4F9, 3h, 72%
, 91%
d
3k
RF=C6F13
,
, 72%
3i
RF=C6F13
,
, 70%
5
C6F13
C4F9
RF
I
I
6
Blue (430-490)
Blue (450-455)
Blue (470-475)
Blue (490-495)
Green (510-515)
Green (545-550)
Blue (430-490)
Blue (430-490)
Blue (430-490)
Blue (430-490)
Blue (430-490)
49
93
91
72
67
52
82
0
MeO
I
d
3l
RF=C4F9, , 79%
3n
3o
, 68%
, 84%
7
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
3m
RF=C6F13
,
, 79%
8
CF3
BocHN
CF3
CF3
4
I
I
I
9
e
e
e
3p
3q
3r
, 41%
, 72%
, 55%
a
Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), 2 (0.45 mmol,
10
11
12
13
14
15
16
1.5 equiv.), K2CO3 (0.6 mmol, 2.0 equiv.) in acetone (2.0 mL),
room temperature, 12 W blue LEDs (430-490 nm), 16 h. b Yield
of isolated product. c 1a (10 mmol, 1.0 equiv.), 2a (15 mmol, 1.5
equiv.), K2CO3 (2.0 equiv.), acetone (40 mL), room temperature,
S-2
24 W Blue LED (430-490 nm), 48 h. 2 (2.0 equiv.) was used. e
d
S-3
0
CF3I (5.0 equiv.) was used.
Dioxane
MeCN
0
Then, we extended the substrate scope to a variety of
terminal alkynes. Many important functional groups, such as
halide, cyano, methoxy trifluoromethyl and even nitro
68
2 | J. Name., 2012, 00, 1-3
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underwent the process smoothly (Table 3). For aliphatic mixed, and those results indicate that non-covalenVtieinwtAertricalectOionlnines
DOI: 10.1039/C9CC09517A
alkynes, high yield with low stereoselectivity was provided occurred between acetone and 2a (Figure 1, for details, see ESI).
(Table 3, 5a-b). Phenylacetylenes were suitable substrates, and In addition, this conclusion was further confirmed by a Job’s
high stereoselectivity could be obtained (Table 3, 5c-g). plot. Finally, the light-dark experiment was performed using
Moreover, we found that the transformation presented good alternative intervals of light and dark, and the formation of the
reactivity when C4F9I and C6F13I were employed, and provided product was both feasible during periods of irradiation and
the desired products in good yields (Table 3, 5h-k).
dark, which is suggestive of a radical chain process (for details,
Table 3. Scope of the 1,2-Addition Reaction of Fluoroalkyl see ESI).
Iodides to Alkynes. a,b
Table 4. Direct Fluoroalkylation of Arenes and Heterocycles. a,b
Blue LEDs
Blue LEDs
I
IRf
K2CO3 (2.0 equiv.)
Ar
+
Ar
Na2CO3 (2.0 equiv.)
RF
IRF
2
+
R
Rf
acetone, r.t., 16 h
acetone+DMF, r.t., 24 h
R
6
2
7
4
5
CF
CF
2CO2Et
2CO2Et
CF
2CO2Et
OMe
CF
2COOEt
Cl
Me
Me
CF
CF
2COOEt
2COOEt
4
O
S
I
I
Cl
I
MeO
Me
OMe
, 94%
, 87% (E/Z = 4.3:1), (51%) c
, 80% (E/Z = 4.3:1)
, 81% (E/Z = 33:1)
5a
5b
5c
5g
7a
7b
7c
, 56%
, 59%
F3C
Me
R
CF
2CO2Et
O
O
CF
2CO2Et
CF
2CO2Et
N
CF
2COOEt
CF
2COOEt
S
5
O2N
CF
2COOEt
I
I
I
7d
7e
7f
, 69%
, 45%
, 67%
O
5d
R=CN, , 62% (E/Z = 21:1)
d
5f
, 81% (E/Z = 24:1)
, 70% (E/Z = 32:1)
5e
R=F,
, 85% (E/Z = 20:1)
Et2N
O
O
MeO
O
O
RF
Me
N
MeO
C6F13
RF
C6F13
RF
CF
2COOEt
O
N
Me
7h
Cl
Me
I
I
I
OMe
RF=CF2COOEt,
RF=C4F9, , 82%
, 95%
7j
RF=CF2COOEt, , 98%
RF=C4F9, , 54%
7g
, 79%
O
5k
, 60%
C F 5h
C F 5i
RF=
RF=
,
, 77%
, 75%
5j
, 74%
4
9
7i
7k
,
6
13
O
O
a Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), 2 (0.45 mmol,
1.5 equiv.), K2CO3 (0.6 mmol, 2.0 equiv.) in acetone (2.0 mL),
room temperature, 12 W blue LEDs (430-490 nm), 16 h. b Yield
of isolated product. c Without K2CO3. d 2 (2.0 equiv.) was used.
C4F9
CF
2COOEt
RF
HN
Me
Me
O
N
O
O
N
H
Me
O
7m
RF=CF2COOEt,
7n
, trace
7o
, 54%
7l, 42%
RF=C4F9, , 10%
a Reaction conditions: 6 (0.3 mmol, 1.0 equiv.), 2 (0.9 mmol, 3.0
equiv.), Na2CO3 (0.6 mmol, 2.0 equiv.), acetone (1.0 mL) + DMF
(1.0 mL), room temperature, 12 W blue LEDs (430-490 nm), 24
h. b Yield of isolated product.
Encouraged by the results of the 1,2-addition of RFI to alkenes
and alkynes, we proceeded to investigate direct fluoroalkylation
of arenes.13 Pleasingly, by using DMF as a co-solvent, a wide
range of arenes and heteroarenes underwent the catalyst-free
fluoroalkylation smoothly. 94% yield was obtained when 1,3,5-
trimethoxybenzene was treated (Table 4, 7a). Five membered
heteroarenes such as furan, thiophene and pyrrole were
relatively inert reaction partners, and only moderate yields
were given (Table 4, 7b-e). Coumarins and 1,3-dimethyluracil
were also suitable substrates for this transformation, delivering
the desired products in good to excellent yields (Table 4, 7f-h,
7j). In addition, the C-H perfluoroalkylation of heteroarenes
with C4F9I was also investigated, and moderate to good yields
were still obtained (Table 4, 7i, 7k-l). Unprotected uracil failed
to give satisfactory results (Table 4, 7m-n), which indicated the
mechanism of this transformation is different from our previous
report.3f Moreover, butopyronoxyl was also a suitable substrate,
and 54% yield was obtained (Table 4, 7o).
To gain insight into the mechanism of this transformation, a
series of experiments were conducted. The reaction was
suppressed by the addition of a radical scavenger TEMPO (100
mol%) and only 15% yield of 3a was obtained, which suggests
that the involvement of radical intermediates is likely during the
reaction (for details, see ESI). A radical clock experiment
employing alpha-cyclopropylstyrene 8 as a substrate produced
the ring-opening product 9 in 82% yield (for details, see ESI).
Optical absorption spectra of the reactants found that the
absorption was clearly strengthened when 2a and acetone were
4
2a
A1:
+
+
K2CO3 + Acetone
Acetone
Acetone
+ Cyclohexane
2a
A2:
A3: K2CO3
2a
+
2
0
A4:
330
380
430
480
530
580
630
Wavelength (nm)
A1
A2 A3
A4
Figure 1 Optical absorption spectra studies.
Based on these preliminary results, a plausible mechanism for
this transformation was proposed in Scheme 2. First, the EDA
complex was generated between acetone and the fluoroalkyl
iodides in the presence of base. Then, a fluoroalkyl radical was
generated under the irradiation of blue LEDs. Subsequent
regioselective addition of •RF to alkenes or alkynes (1 or 4) lead
to the carbon-radical intermediate (B), which abstracted an
iodine atom from RFI to afford the desired product 3 or 5 and
regenerated the RF radical. For arenes, cation species were
generated via a SET process from an intermediate C, and the
fluoroalkylated products (7) were obtained by further
deprotonation.
This journal is © The Royal Society of Chemistry 20xx
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RFI
V. M. Fernández-Alvarez, M. Nappi, P. Melchiorre and F.
RF
3/5
View Article Online
R
R
Maseras, Org. Lett., 2015, 17, 2676; (c) S. R. Kandukuri, A.
Bahamonde, I. Chatterjee, I. D. JurberDg,OEI:.1C0..10E3s9c/uCd9eCrCo0-A95d1á7nA
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X.-Y. Li, F.-L. Zeng, X.-C. Liu, L.-B. Qu, Y.-F. Zhao and B. Yu, Org.
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B
1/4
RF
visible light
acetone
RF
I
RF
initiated via non-covalent
interactions
-H+
RFI
Ar
Ar
7
RF
6
RF
C
Scheme 2 Proposed a Plausible Reaction Mechanism.
In summary, we have developed a simple, mild, and efficient
protocol for photochemical fluoroalkylation reactions via
noncovalent interactions between acetone and fluoroalkyl
iodides. The significant advantages of this method are high
atom economy, excellent functional group tolerance, and
synthetic simplicity, thus providing a facile route for further
application in pharmaceuticals and life sciences. Mechanistic
studies indicate that the reaction was initiated via non-covalent
interactions between acetone and carbon-iodine bonds.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21702241,
81760624), and Programs of Guizhou Province (No. 2017-1225,
2018-1427). We thank Dr. Jiwei Gu and Dr. Yanbo Yu from
Washington University for their linguistic assistance.
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Conflicts of interest
There are no conflicts to declare.
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