Synthesis of monofluoroalkenes through selective hydrodefluorination of gem-difluoroalkenes with Red-Al

Article abstract of DOI:10.1039/c5ra04221f

A novel and practical approach for the selective hydrodefluorination of gem-difluoroalkenes using Red-Al as a reductant at room temperature in CH₂Cl₂ without any additional base and metal catalyst was reported. Various monofluoroalkenes were obtained in moderate to high yields with good E-selectivity.

Full text of DOI:10.1039/c5ra04221f

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Synthesis of monofluoroalkenes through selective
hydrodefluorination of gem-difluoroalkenes with
Red-Al®†
Cite this: RSC Adv., 2015, 5, 34498
ac
b
b
bc
Received 10th March 2015
Accepted 8th April 2015
*
*
Juan Xiao, Wenpeng Dai and Song Cao
Jingjing Wu,
DOI: 10.1039/c5ra04221f
www.rsc.org/advances
A novel and practical approach for the selective hydrodefluorination of reported the preparation of 2-uorovinyl tosylate by treating
gem-difluoroalkenes using Red-Al® as a reductant at room temper- 2,2-diuorovinyl tosylate with LiAlH4 in ether.8a Shi has
ature in CH2Cl2 without any additional base and metal catalyst was described that the reductive reaction of 2-[(trimethylsilyl)
reported. Various monofluoroalkenes were obtained in moderate to methyl]-substituted 3,3-diuoropropenoate with LiAlH4 led
high yields with good E-selectivity.
exclusively to the formation of the Z-congurated mono-
uorinated allylic (only one example),8b whereas the reaction of
LiAlH4 with a simple 2-alkyl-substituted 3,3-diuoropropenoate
reported by Watanabe gave monouoroallylic alcohols with
little stereoselectivity.8c
The monouoroalkenes are an important class of uorinated
compounds and have potential applications in medicinal
chemistry and material sciences.1 Meanwhile, they can be used
as uorinated building blocks for further transformation in
organic syntheses.2 Nowadays, various methods for the prepa-
ration of monouoroalkenes have therefore been developed,3
including reductive deuorination of allylic gem-diuorides
with a Pd catalyst,4a gold-catalyzed hydrouorination of alkynes
in the presence of Et3N$3HF,4b uorination of alkenylboronic
acid4c and Julia–Kocienski uoroolenation reaction with
various ketones and aldehydes.4d
Hydrodeuorination (HDF) is the simplest transformation of
C–F bond.5 Selective hydrodeuorination of polyuorinated
compounds has become a useful approach to access partially
uorinated compounds which are difficult to obtain otherwise.6
However, most research focused on the catalytic selective
hydrodeuorination of uoroarenes, the selective hydro-
deuorination of uoroalkenes have remained rare.7 In partic-
ular, only few examples referring to the transformation of
diuoroalkene derivatives to the corresponding mono-
uoroalkenes have been observed.8 Xiao and Hong have
Recently, Paquin and coworkers developed two novel
methods for the synthesis of b-uorostyrene and 1,1-diaryl-
2-uoroethenes respectively.9 In both pathways, a common
intermediate (Z)-1-aryl-2-uoro-1-(trimethylsilyl)ethene was
generated via an addition/elimination reaction of lithium trie-
thylhydridoborate (LiEt3BH) to silylated b,b-diuorostyrene
derivative. Furthermore, Red-Al® (NaAlH2(OCH2CH2OCH3)2)
was also used as a reducing agent for the conversion of
diuoroalkenes to monouoroalkenes.10 However, these
methods suffer from several drawbacks, such as narrow
substrate scope, low stereoselectivity, lack generality, over
reduction and the use of environmentally unfriendly solvent
such as benzene and toluene. Consequently, the development
of the synthesis of monouoroalkenes via the selective reduc-
tion of common diuoroalkenes under mild reaction condi-
tions is highly desirable. Herein, we report an efficient and
practical approach for the monouoroalkenes via the hydro-
deuorination of diuoroalkenes using Red-Al® as reductant at
room temperature in CH2Cl2 without any added base and metal
catalyst (Scheme 1).
As part of our continued interest in the C–F bond of orga-
nouorine compounds,11 in this communication, we focused on
the selective reductive cleavage of sp2 C–F bonds of gem-
diuoroalkenes. Initially, we used 1-(2,2-diuorovinyl)-
4-methoxy-benzene 1a as the model substrate to examine the
reduction activities of various reducing agents (Table 1, entries
1–8). Among the reducing agents tested, LiAlH4, LiEt3BH and
Red-Al® promoted the reaction much more efficiently and gave
a mixture of monouoro product 2a and over-reduction product
aSchool of Chemical and Environmental Engineering, Shanghai Institute of Technology
(SIT), Shanghai 201418, China. E-mail: wujj@sit.edu.cn; Fax: +86-21-60877231; Tel:
+86-21-60877220
bShanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology (ECUST), Shanghai 200237, China. E-mail:
scao@ecust.edu.cn
cKey Laboratory of Organouorine Chemistry, Shanghai Institute of Organic Chemistry
(SIOC), Chinese Academy of Sciences, Shanghai 200032, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra04221f
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were also suitable for this transformation (entries 12–15).
However, when THF, Et2O, toluene and benzene were used as
solvents, the yield of byproduct 3a would increase aer a pro-
longed reaction time, whereas CH2Cl2 still afforded the mono-
uoro product 2a in excellent yield with high E-selectivity (entry
15). Considering the generality, toxicity and volatility of solvent,
CH2Cl2 was the most suitable solvent for this reaction.
In addition, the reaction proceeded less efficiently when the
amount of Red-Al® was decreased to 2.0 or 1.4 equiv. (entries 16
and 17).
Scheme 1 Selective hydrodefluorination of gem-difluoroalkenes with
Red-Al®.
Having established the optimized method (Table 1, entry 15),
we next probe the generality and scope of this hydro-
deuorination reaction of different gem-diuoroalkenes with
Red-Al® (Table 2). All the gem-diuoroalkenes (1a–n) were
prepared according to the reported procedure.13 It was found
that diuoroethenes with strong electron-donating substituents
on the aromatic ring afforded the corresponding E-monouoro
products 2a–j in good to high yields (more than 96%, GC/MS)
and good stereoselectivity. 1-(2,2-Diuorovinyl) naphthalene
(1m) and 4-(2,2-diuorovinyl)-1,10-biphenyl (1n) were also good
substrates for this reduction reaction. When diuoroethenes
with weak electron-withdrawing substituent on the aromatic
ring such as 1-chloro-4-(2,2-diuorovinyl)benzene (1k) and 1-
bromo-3-(2,2-diuorovinyl)benzene (1l) were used as substrates,
the reaction also proceeded smoothly. Unfortunately,
(E)-isomers could not be separated from the corresponding
(Z)-isomers due to their similarity in affinity to chromato-
graphic silica gel.
3a in high yields but with poor selectivity (entries 6–8). It is
reported that Red-Al® is a safer substitute for LiAlH4 and
LiEt3BH,12 therefore, we chose Red-Al® as the reductant for
further optimization of reaction conditions.
The reaction results were signicantly affected by the
amount of Red-Al®. The use of 2.8 equiv. of Red-Al® could
provide monouoroalkene 2a as major product along with
small amount of 1-methoxy-4-vinylbenzene 3a (entry 8).
However, when the amount of Red-Al® was increased to 4.0 or
8.0 equiv., the yields of 2a decreased dramatically (entries 9 and
10). Interestingly, attempts to further improve the yield of 3a by
using large amount of Red-Al® were unsuccessful.
To our delight, when the reaction was performed at room
temperature within 1 hour, the desired product 2a was obtained
in higher yield and the amount of over-reduction product 3a
decreased obviously (entry 8 vs. entry 11). Further screening of
the solvent showed that Et2O, toluene, benzene and CH2Cl2
Table 1 Selective hydrodefluorination of 2,2-difluoroalkenes under different conditionsa
Entry
Reducing agent (equiv.)
Solvent
Temp. (ꢀC)
Time (h)
Yieldb (%) (2a/3a)
1
2
3
4
5
6
7
8
NaH (4.0)
NaBH4 (4.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Toluene
Benzene
CH2Cl2
CH2Cl2
CH2Cl2
60
60
60
60
60
60
60
60
4
4
4
4
4
4
4
4
4
4
1
1
1
1
1
1
1
N.R.
N.R.
N.R.
N.R.
12/0
58/42
81/5
87/13
68/32
35/65
95/5
97/3
95/5
97/3
99/1
94/0
89/0
Bu3SnH (4.0)
LiAl(O-t-C4H9)3 (4.0)
DIBAL-H (4.0)
LiEt3BH (4.0)
LiAlH4 (2.0)
Red Al® (2.8)
Red Al® (4.0)
Red Al® (8.0)
Red Al® (2.8)
Red Al® (2.8)
Red Al® (2.8)
Red Al® (2.8)
Red Al® (2.8)
Red Al® (2.0)
Red Al® (1.4)
9
60
60
10
11
12
13
14
15
16
17
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
a
Reaction condition: 1a (1.0 mmol), solvent (8 mL). b Yields determined by GC analysis.
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Table
2
Selective
hydrodefluorination
of
various
gem- Table
3
Selective hydrodefluorination of symmetrical gem-
difluoroalkenesa,b,c
difluoroalkenesa,b
a
Reaction condition: symmetrical gem-diuoroalkenes (1.0 mmol),
b
c
Red-Al® (2.8 mmol), CH2Cl2 (8 mL), 25 ꢀC. Isolated yield. The
reaction was completed within 5 minutes.
Scheme 2 A plausible mechanism.
In summary, we have developed a novel and highly efficient
method for the selective reduction of diuoroalkenes with Red-
Al® in CH2Cl2 under mild conditions. The monouoro products
were obtained in moderate to high yields with high E-selectivity.
Compared with the previously reported methods,10 the protocol
developed in this communication has some obvious synthetic
advantages such as the use of relative green solvent (CH2Cl2 vs.
benzene), performing the reaction under mild condition (room
temperature vs. reux), the high stereoselectivity (9 : 1 vs. 3 : 1)
and the broad substrate scope. Furthermore, no over-reduction
products were observed even aer a prolonged reaction time.
The protocol reported herein provided a practical access to a
variety of different monouoroalkenes.
a
Reaction condition: gem-diuoroalkenes (1.0 mmol), Red-Al®
b
c
(2.8 mmol), CH2Cl2 (8 mL), 25 ꢀC. Isolated yield. The E/Z selectivity
were determined by 19F NMR. The reaction was completed within
d
15–20 minutes.
Finally, symmetrical gem-diuoroalkenes 1o–q were also
compatible with the reaction conditions and gave the mono-
uoro products 2o–q in good yields (Table 3). The symmetrical
gem-diuoroalkenes (1o–q) were prepared according to the
reported procedure.14
On the basis of the above results and literatures,15 we
tentatively suggest a plausible mechanism (Scheme 2). In the
rst step, addition of negative hydrogen ion (Hꢁ) originated
from Red-Al® to gem-diuoroalkene would result in the
formation of the key carbanion intermediate I. Subsequently,
rotation of the intermediate I by ꢂ60 degrees would generate
two conformations, II and III. The conformation III is unstable
due to electronic repulsion between the aryl group and uorine
atom. Finally, the elimination of a uoride ion from the
preferred conformation II affords (E)-isomer as the major
product.
Acknowledgements
We are grateful for nancial supports from the National Natural
Science Foundation of China (Grant no. 21302128, 21272070).
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