Synthesis of aryl allylic fluorides by direct electrophilic fluorination of alkenes

Article abstract of DOI:10.1016/j.tetlet.2009.01.052

Aryl allylic fluorides were synthesized in 47-83% yields by using Selectfluor as the electrophilic reagent in DMF. The outcome of this reaction may be explained by electronic effects while the reactivity was controlled by the stabilization effect of the aryl group on the benzylic cationic intermediates.

Full text of DOI:10.1016/j.tetlet.2009.01.052

Tetrahedron Letters 50 (2009) 1554–1556
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Tetrahedron Letters
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Synthesis of aryl allylic fluorides by direct electrophilic fluorination of alkenes
*
Hai-Qing Luo, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl allylic fluorides were synthesized in 47–83% yields by using Selectfluor as the electrophilic reagent in
DMF. The outcome of this reaction may be explained by electronic effects while the reactivity was con-
trolled by the stabilization effect of the aryl group on the benzylic cationic intermediates.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 October 2008
Revised 22 December 2008
Accepted 13 January 2009
Available online 19 January 2009
There has been significant interest in fluorinated organic com-
pounds especially in the fields of medicine, pharmaceuticals and
material science. Introduction of a fluorine atom into organic mol-
ecules produces profound effects on the biological activity, metab-
olism, solubility, hydrophobicity and bulk properties of
organofluorine compounds.1,2 Therefore, much effort has been di-
rected towards developing facile synthetic methods to introduce
fluorine into useful intermediates or desired substrates.
als. Previously, aryl alkenes have been shown to react with electro-
philic fluorinating reagents. In these reactions, solvent systems
were used as the nucleophiles to capture the fluorocarbocationic
intermediates.5 In our synthesis, we required a considerably more
direct and efficient entry to aryl allylic fluorides using alkenes as
starting materials.
In this Letter, we disclose our recent observations on electro-
philic fluorination using aryl alkenes as starting materials for car-
In connection with our interest in the synthesis of fluorinated
steroids (1, Scheme 1), we were interested in developing a method
to obtain aryl allylic fluoride 4 (Scheme 1). Although there are
methods for the synthesis of aryl allylic fluorides,3,4 most of these
fluorination reactions used allyltrimethylsilanes as starting materi-
O
O
O
O
Cl
2BF4
S
S
N
N
N
-
F
F
S
1: Selectfluor
S
2: N-fluorobenzene-
sulfonimide (NFSi)
O
O
Figure 1. Sources of fluorine.
O
Metathesis
Table 1
Reaction of
F
a
-methylstilbene (9a) with fluorine sourcesa
F
F
R
R
R
1
2
3
Fluorine source
Solvent, 4 h
O
O
O
F
O
9a
10a
Fluorination
F
Entry Solvent
Fluorine
Source
Reaction
temperature (°C)
Conversion
Yieldb
(%)
R
R
4
5
1
2
DCM
THF
NFSI
NFSI
NFSI
NFSI
NFSI
rt
rt
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
>98%
>98%
No reaction
>95%
O
O
OTMS
3
4
5
CH3CN
DMSO
DMF
75
75
75
75
rt
O
OTMS
6
CH3CN/H2O 10:1 NFSI
R
R
7
CH3CN/H2O 10:1 Selectfluor
8
12
R
6
8
9
10
CH3CN
DMSO
DMF
Selectfluor
Selectfluor
Selectfluor 75
rt
75
7
8
83
Scheme 1. Designed route to synthesize fluorinated steroids.
a
Conditions:
a-Methylstilbene (0.50 mmol), fluorine source (0.525 mmol),
reaction time 4 h.
* Corresponding author. Tel.: +65 6316 8899; fax: +65 6791 1961.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
b
Isolated yield.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.052

H.-Q. Luo, T.-P. Loh / Tetrahedron Letters 50 (2009) 1554–1556
1555
Table 2
Cl
Fluorination of various aryl alkenes with Selectfluor in DMFa
N
-
BF4
(Base)
Cl
R1
R1
N
Selectfluor
(1.05 equiv)
H
R2
R2
F
R
R
R
N
DMF
R3
R3
N
-
2BF4
F
F
9a-m
Reaction
10a-m
F
13
12
Scheme 2. Proposed fluorination mechanism.
11
Entry
1
Aryl alkene
Reaction
Main
Yieldb
(%)
time (h)
temperature (°C)
product
4
75
83
F
9a
9b
product decreased substantially in the presence of water, with for-
mation of a byproduct produced by capture of a fluorocarbocation-
ic intermediate by water.5
10a
2
3
4
4
75
75
65c
67c
F
10b
Using the optimized conditions, we explored the scope of this
reaction with various aryl alkenes. The results are summarized in
Table 2. In all cases, the desired aryl allylic fluorides were obtained
in moderate to good yields (Table 2, entries 1–11). Interestingly, a
substrate without a 1-methyl group also gave the desired product
10k in 47% yield at lower temperature. The tetra-substituted aryl
alkenes (Table 2, entries 6 and 8) reacted at a lower temperature
to afford aryl allylic fluorides as the main products.3 Carbocation
stabilization of the phenyl group is essential for clean reactions.
No reaction was detected with allylic alkene 9m.
The following mechanism is proposed to account for the ob-
served fluorinated products. The fluorocarbocationic intermediate
12 (Scheme 2) was generated upon electrophilic addition of Select-
fluor to the alkene 11, which underwent loss of a proton to produce
the aryl allylic fluoride 13.
F
10c
9c
F
4
5
4
4
6
4
6
5
5
6
4
75
75
45
75
45
70
70
40
75
82
80
59
81
68
78
71
47c
9d
9e
10d
10e
10f
F
F
6
9f
In summary, this Letter describes a direct entry into aryl allylic
fluorides using simple alkenes. The application of this reaction to
the synthesis of other fluorinated compounds is in progress.
F
7
O
O
9g
10g
Acknowledgements
F
8
We gratefully acknowledge Nanyang Technological University
and the Singapore Ministry of Education, Academic Research Fund
9h
10h
Bn
F
Bn
Tier
2 (No. T206B1221 and T207B1220RS), for funding this
9
research.
9i
10i
Supplementary data
Bn
Bn
F
10
11
10j
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.052.
9j
References and notes
F
9k
10k
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