Simple and convenient synthesis of fluoroalkenes via direct coupling of alcohols, alkynes and fluoroboric acid under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2014.05.069

A novel and convenient method for the synthesis of fluoroalkenes from alkynes, alcohols and fluoroboric acid has been developed under mild conditions. The present protocol provides an attractive approach to access various fluoroalkenes from simple and commercially available starting materials without any metal catalyst, ligand or additive.

Full text of DOI:10.1016/j.tetlet.2014.05.069

Tetrahedron Letters 55 (2014) 3750–3752
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Tetrahedron Letters
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Simple and convenient synthesis of fluoroalkenes via direct coupling
of alcohols, alkynes and fluoroboric acid under metal-free conditions
c
a,
Xiao-wei Yan a,b, Qiang Zhang a, , Wei Wei , Jian-xin Ji
⇑
⇑
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b University of Chinese Academy of Sciences, Beijing 100049, China
c School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 February 2014
Revised 8 May 2014
Accepted 15 May 2014
Available online 21 May 2014
A novel and convenient method for the synthesis of fluoroalkenes from alkynes, alcohols and fluoroboric
acid has been developed under mild conditions. The present protocol provides an attractive approach to
access various fluoroalkenes from simple and commercially available starting materials without any
metal catalyst, ligand or additive.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Fluoroalkenes
Alkynes
Alcohols
Fluoroboric acid
Metal-free
Organofluorine compounds play a significant role in pharma-
ceutical, agrochemical and material sciences, because the intro-
duction of fluorine atom into organic compounds can
significantly change their physicochemical properties.1 Among
the various fluorinated motifs, fluoroalkenes have attracted spe-
cial attention because of their pharmacological properties such
as anti-diabetic,2 antiviral,3 antibacterial4 and anticancer5 activity.
For example, (2S,3S)-3-(3-(2-chloro-4-(ethoxysulfinyl)phenyl)-
1,2,4-oxadiazol-5-yl)-1-cyclopentylidene-1-fluorobutan-2-amin-
ium2a shows inhibitory activity of dipeptidylpeptidase IV
(DPP-4) and (2E,4E,6E)-6-fluoro-7-(5,5,8,8-tetramethyl-3-pro-
poxy-5,6,7,8-tetrahydronaphthalen-2-yl)octa-2,4,6-trienoic acid2b
can activate retinoid X receptor, both of which have potential
therapeutic application in type 2 diabetes; N-((Z)-7-fluoro-8-mer-
captooct-6-enyl)benzamide5 can be used as a potent inhibitor of
histone deacetylases.
Scheme 1. Methods for the preparation of fluoroalkenes.
In light of the importance of fluoroalkenes, many efforts have
been devoted towards the synthesis of these moieties.6–11 Gener-
ally, the strategies for the preparation of fluoroalkenes are mostly
based on Wittig reaction (Scheme 1(a))6 and Julia olefination
(Scheme 1(b)),7 in which the preformed fluorinated phosphonium
salts and fluorinated sulfones are used as fluoride sources. Recently,
the direct fluorination of alkynes with Et3Nꢀ3HF, 4-Tol-IF2, CsF or
other fluoride sources11 has become a powerful tool for the
construction of fluoroalkenes (Scheme 1(c)). Nevertheless, most of
these methods suffer from limitations such as costliness, requiring
metal catalysts or unavailability of starting materials. Therefore,
there is still a great demand for the development of more
convenient and efficient methodologies to access fluoroalkenes.
Here, we wish to report a simple and convenient method for
the synthesis of various fluoroalkenes from alkynes, alcohols and
fluoroboric acid under mild and metal-free conditions
(Scheme 1(d)).
⇑
Corresponding authors. Tel.: +86 28 82855463; fax: +86 28 82855223.
E-mail addresses: cibzhangq@outlook.com (Q. Zhang), jijx@cib.ac.cn (J.-x. Ji).
http://dx.doi.org/10.1016/j.tetlet.2014.05.069
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

X. Yan et al. / Tetrahedron Letters 55 (2014) 3750–3752
3751
Table 1
Table 2
Screening of the reaction conditionsa
Results for the reaction of alkynes with various alcoholsa,b
Entry Catalyst
Fluoride donator
Solvent
DBE
Yieldb
(%)
1
FeF3
TBAF, NFSI, selectfluor, KF, CsF,
0
LiF, TEA.3HF
HF
2
3
4
FeF3
FeF3
InF3
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DBE
DCE
DME
THF
CH3CN
35
58
60
56
56
51
51
63
44c
66d
59e
66f
18g
8h
HBF4
HBF4
5
6
7
Cu(OTf)2 HBF4
Sc(OTf)3 HBF4
Pd(OAc)2 HBF4
8
9
AgNO3
None
None
None
None
None
None
None
None
None
None
None
None
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
10
11
12
13
14
15
16
17
18
19
20
59
0
0
0
Cyclohexane 18
TBAF = tetra-n-butyl ammonium fluoride, NFSI = N-fluorobisbenzenesulfonimide,
selectfluor = N-fluoro-N0-(chloromethyl)-triethylenediamine bis(tetrafluoroborate),
TEAꢀ3HF = triethylamine trihydrofluoride.
a
Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst (5 mol %), fluoride
donator (0.75 mmol), solvent (2 mL), 10 h, 55 °C.
b
Isolated yields of the E:Z mixtures.
HBF4 (0.5 mmol).
HBF4 (1.0 mmol).
Activated molecular sieves (4 Å) (500 mg).
Anhydrous MgSO4 (5.0 mmol).
2,6-Lutidine (0.5 mmol).
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.5 mmol).
c
d
e
f
g
h
a
Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), HBF4 (0.75 mmol), DBE (2 mL),
55 °C, air, 8–10 h.
b
Isolated yields of the E:Z mixtures; the E:Z ratio was determined by 1H NMR.
Initially, the activities of various fluoride sources were exam-
ined by using a model reaction of 1-phenyl-1-dutyne 1a and
diphenylmethanol 2a with catalytic amount of FeF3 in 1,2-dibro-
moethane (DBE) at 55 °C (Table 1, entries 1–3). Among these fluo-
ride sources screened, only HBF4 and HF were able to afford the
desired product 3a in 58% and 35% yields, respectively. Further
investigation showed that the employment of other metal catalysts
such as InF3, Cu(OTf)2, Pd(OAc)2, Sc(OTf)3 and AgNO3 failed to
improve the reaction efficiency (Table 1, entries 4–8). A 63% yield
of 3a was obtained when HBF4 (1.5 equiv) was solely used and
an increase of the amount of HBF4 (2 equiv) or addition of desiccat-
ing agents did not obviously improve the reaction (Table 1, entries
9–13). However, the yield was sharply decreased in the presence of
bulky bases, indicated that proton acid might be critical to this
transformation (Table 1, entries 14–15). The screening of a range
of solvents showed the reactions performed in halogenated sol-
vents such as DBE and 1,2-dichloroethane (DCE) were significantly
better than those in non-halogenated solvents THF, DME, CH3CN
and cyclohexane, and DBE was found to be the optimal reaction
medium (Table 1, entry 9 and entries 16–20).
Scheme 2. Control experiments.
With the optimal reaction conditions in hand, the scope and
limitations of the reaction were investigated and the results are
shown in Table 2. In general, benzhydrol and its derivatives with
electron-donating or electron-withdrawing groups on the aryl
rings were all suitable for this transformation, and the correspond-
ing products were obtained in good yields (3a–3h). With respect to
alkynes, both aliphatic and aromatic alkynes were tolerable as the
Scheme 3. Postulated reaction pathway.

3752
X. Yan et al. / Tetrahedron Letters 55 (2014) 3750–3752
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3i) were more reactive than terminal alkynes (3j–3o) in the pres-
ent reaction system when benzhydrol was used. The configuration
of E-3j was confirmed by X-ray crystallographic analysis.12
In order to obtain clear mechanistic insights into this reaction,
several control experiments were performed. When 1-phenyl-1-
dutyne 1a and diphenylmethanol 2a were subjected to the stan-
dard conditions for 2 h, a trace amount of 3a and 90% yield of
dimeric ether 4a were obtained (Scheme 2(a)). Furthermore, a
47% yield of the desired product 3a could be obtained when the
reaction of 4a and 1a was conducted under the standard conditions
for 10 h (Scheme 2(b)). The above results suggested that dimeric
ether 4 might be an intermediate in this reaction system.
Based on the above results and previous studies,13 a postulated
reaction pathway of this reaction is illustrated in Scheme 3. Firstly,
alcohol 2 was activated by proton acid and attacked by another
alcohol to form the dimeric ether 4. Subsequently, the ether might
combine with hydrogen ion to generate alcohol 2 and carbocation
intermediate 5, the latter then attacked alkyne 1 to form a vinyl
cation 6. Finally, the vinyl cation 6 was fluorinated by BFꢁ4 to deli-
ver the desired product 3.
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In summary, we have developed a simple and convenient
method for the synthesis of monofluoroalkenes from alkynes, alco-
hols and fluoroboric acid. The present protocol, which utilizes
simple and commercially available starting materials and metal-
catalyst-free conditions, provides an attractive approach to various
fluoroalkenes. Further studies on the scope and application of this
reaction are underway.
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12. The structure of E-3j was confirmed by X-ray crystallography. Deposit
number of this compound from Crystallographic Data Centre is 921081.
Copies of the data can be obtained free of charge on application to CCDC, 12,
Union Road, Cambridge CB21EZ, UK; fax: +44 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk.
Acknowledgment
We thank the National Natural Science Foundation of China
(21172213) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2014.05.069.
References and notes
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