Copper-mediated trifluoroethoxylation of vinyl bromides

Article abstract of DOI:10.1016/j.tetlet.2016.03.023

Vinyl bromides were subjected to the trifluoroethoxylation reactions with copper reagent [(phen)₂Cu][OCH₂CF₃] at 80°C in DMF with the presence of NaOt-Bu to afford the trifluoroethyl vinyl ethers in good yields. A range of functional groups, such as cyano, nitro, alkoxy, trifluoromethyl, halide, and heterocyclic groups were well tolerated. This approach is also amenable to being performed out on gram scales.

Full text of DOI:10.1016/j.tetlet.2016.03.023

Accepted Manuscript
Copper-mediated trifluoroethoxylation of vinyl bromides
Jianping Ding, Yi You, Zhiqiang Weng
PII:
S0040-4039(16)30246-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.023
TETL 47411
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
21 December 2015
3 March 2016
8 March 2016
Please cite this article as: Ding, J., You, Y., Weng, Z., Copper-mediated trifluoroethoxylation of vinyl bromides,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.023
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Copper-mediated trifluoroethoxylation of
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Jianping Ding, Yi You,* and Zhiqiang Weng*

1
Tetrahedron Letters
Copper-mediated trifluoroethoxylation of vinyl bromides
Jianping Ding, Yi You,* and Zhiqiang Weng
State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, 350108, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Vinyl bromides were subjected to the trifluoroethoxylation reactions with copper reagent
[(phen)2Cu][OCH2CF3] at 80 C in DMF with the presence of NaOt-Bu to afford the
trifluoroethyl vinyl ethers in good yields. A range of functional groups, such as cyano, nitro,
alkoxy, trifluoromethyl, halide, and heterocyclic groups were well tolerated. This approach is
also amenable to being performed out on gram scales.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Trifluoroethoxylation
Alkenes
Copper
Synthetic methods
The incorporation of fluorine atoms into organic molecules
can highly affect their physical and chemical properties, such as
Recently we reported a convenient, and practical route to
synthesize
copper(I)
fluoroalkoxide
complexes,
lipophilicity,
metabolic
stability,
and
bioavailability,
[(phen)2Cu][OCH2RF].24,25 These complexes reacted with aryl
and heteroaryl bromides to furnish the corresponding
conformation, electrostatic potential, dipole moment, pKa, etc.1,2,
3,4
As a consequence, intensive efforts have been directed in
trifluoroethyl,
pentafluoropropyl
and
tetrafluoropropyl
recent years toward the development of efficient protocols for the
incorporation of fluorine-containing groups into functional
(hetero)aryl ethers in good to excellent yields (Scheme 1).
organic molecules.5,6-10,11,12,13 In particular, introducing
a
trifluoroethoxy (CF3CH2O-) moiety has attracted the attention of
chemists in the pharmaceutical and agrochemical industries,
because of its great stability, high electronegativity, and
improved lipophilicity.14,15
Conventionally, the trifluoroethyl aryl ethers were synthesized
through the nucleophilic substitution of a phenol or phenoxide
with suitable 2,2,2-trifluoroethyl iodide or methanesulphonate.16
However, this procedure is limited by the low SN2 reactivity of
the -carbon atom due to the presence of fluorine substituents17
and the competing -fluorine eliminations.18 Alternative
procedures include the cross-coupling of aryl halides with
trifluoroethanol in the presence of an excess of copper salts under
harsh reaction conditions.19,20 The catalytic version of the
reaction was developed by Legros and Crousse and co-workers
using neat fluoro alcohols as both reactant and solvent at reflux
conditions.21 Another example in this area was recently disclosed
by Singh and co-workers, who reported the use of Pd/BrettPhos
catalyst system for the cross-coupling of primary fluoroalkyl
alcohols with activated aryl halides.22,23
Scheme 1. Trifluoroethoxylation with [(phen)2Cu][OCH2CF3]
1.
With a desire to increase the scope of the trifluoroethoxylation
further, we decided to explore a general procedure with which to
synthesize trifluoroethyl vinyl ethers. Herein, we report an
efficient synthesis of trifluoroethyl vinyl ethers via copper-
mediated trifluoroethoxylation of vinyl bromides.
When -bromostyrene 2a was subjected to the reaction
conditions that we found effective for aryl bromides,24 that is,
DMF, 80 °C, in the presence of NaOt-Bu (1.0 equiv.), we
witnessed the complete consumption of the starting material in
———
 Corresponding author. Tel.: + 86 59122866121; fax: + 86 59122866121; e-mail: zweng@fzu.edu.cn

2
Tetrahedron
12 h and the formation of good yields of expected (2-(2,2,2-
3
83
99
trifluoroethoxy)vinyl)benzene 3a (89%; Table 1, entry 1).
To explore the scope of the trifluoroethoxylation reaction,
various substituted alkenyl bromides were examined under the
reaction conditions (Table 1). The vinyl bromides containing the
para- or meta-substituted methyl afforded the trifluoroethylated
products 3b and 3c in 84% and 83% yields, respectively (Entries
2 and 3). The vinyl bromides with methoxy substituent were well
tolerated under the present reaction conditions and furnished the
corresponding products 3d-3f in good to excellent yields (Entries
4-6). 5-(2-Bromovinyl)benzo[d][1,3]dioxole also underwent this
reaction well and provided the desired product 3g in 81% yield
(Entry 7). The vinyl bromide having the meta-substituted nitro
group was transformed into the desired product 3h in 80% yield
(Entry 8). Furthermore, the trifluoroethoxylation reaction with
vinyl bromides with the para-nitrile, or trifluoromethyl
substituents on the phenyl ring gave the corresponding products
3i and 3j with slightly compromised yields (Entries 9 and 10). It
was found that vinyl bromides with halogen substituents such as
fluoro and chloro reacted smoothly to provide the corresponding
products 3k–3n in 62–76% yields (Entries 11–14). The reaction
was compatible with the presence of a halogen atom on the
aromatic core, allowing further synthetic functionalization. When
hetero-aromatic vinyl halides such as 2-(2-bromovinyl)thiophene
were used, the desired product 3o was reached in 78% yield
(Entry 15). The reaction was also amenable to substrate
possessing a disubstitution in -position; with (2-bromoethene-
1,1-diyl)dibenzene (2p) the corresponding product 3p was
formed in 92% yields (Entry 16). Noteworthy, under the reaction
conditions, cyclic vinyl bromides, such as 2-bromo-1H-indene
(2q) participated the reaction even though the corresponding
product 3q was obtained in low yield of 8% (Entry 17). The
sterically highly demanding arylvinyl bromides, such as 2-
bromo-1,1,2-triphenylethylene (2r) also participated in the
trifluoroethoxylation reaction to give the corresponding product
3r in 56% yield (Entry 18). To assess the versatility of this
methodology, the reaction was evaluated on -bromostyrene 2s.
In this case, the expected trifluoroethoxylated styrene 3s was
obtained in 9% yield (Entry 19). Unfortunately, when 1-(2,2-
dibromovinyl)-4-methylbenzene (2t) was used as a substrate, the
product 3t was obtained in only 2% yield (19F NMR; Entry 20).
Finally, the reaction also proceeded with the use of vinyl
chlorides, albeit in lower yields: for instance under the reaction
conditions, the trifluoroethoxylation of -chlorostyrene furnished
(2-(2,2,2-trifluoroethoxy)vinyl)benzene 3a in 38% yield (19F
NMR; Entry 21). The use of -iodostyrene led to excellent yield
of the corresponding product 3a (Entry 22).
4
5
6
92
71
7
8
9
81
80
64
10
11
12
62
76
62
13
14
15
68
65
78
16
92
Table 1. Trifluoroethoxylation of alkenyl bromides by
[(phen)2Cu][OCH2CF3] 1 a
17
18
8
56
Alkenyl halide
Product
Yield b
(%)
Entry
1
(E/Z)
(E/Z)
19
20
9
89
84
2 c
2

3
This work was supported by National Natural Science
21
22
38 c
99 c
Foundation of China (21372044), Research Fund for the Doctoral
Program of Higher Education of China (No. 20123514110003),
the SRF for ROCS, SEM, China (2012-1707), and Fuzhou
University (022494).
References and notes
a Reaction conditions: 1 (0.60 mmol), 2 (0.50 mmol), NaOt-Bu (0.50 mmol),
DMF (5.0 mL), under N2 atmosphere. The E/Z configuration ratios of
products were determined by 19F NMR.
1. Tressaud, A.; Haufe, G. Fluorine and Health: Molecular
Imaging, Biomedical Materials and Pharmaceuticals;
Elsevier: London, 2008.
2. Ojima, I.; Editor Fluorine In Medicinal Chemistry And
Chemical Biology; John Wiley & Sons Ltd., 2009.
3. Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Chem. Rev. 2013, 114, 2432.
4. Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115,
731.
5. Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed.
2013, 52, 8214.
6. Besset, T.; Schneider, C.; Cahard, D. Angew. Chem. Int. Ed.
2012, 51, 5048.
7. Jin, Z.; Hammond, G. B.; Xu, B. Aldrichim. Acta 2012, 45,
67.
8. Ye, Y.; Sanford, M. S. Synlett 2012, 23, 2005.
9. Chen, P.; Liu, G. Synthesis 2013, 45, 2919.
10. Xu, J.; Liu, X.; Fu, Y. Tetrahedron Lett. 2014, 55, 585.
11. Manteau, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R. J.
Fluorine Chem. 2010, 131, 140.
b Isolated yields.
c
The yield was determined by 19F NMR spectroscopy with PhOCF3 as
internal standard.
The stereochemistry of trifluoroethyl vinyl ethers 3 was
1
characterized by the H NMR coupling constant value of the
olefinic protons (trans configuration: J = 12.612.9 Hz; cis
configuration:
J
=
7.2 Hz).26-29 In addition, the E/Z
stereochemistry of the trifluoroethyl vinyl ethers bond
corresponds to the alkenyl bromide substrates (Entries 115).
The complete retention of the double-bond stereochemistry after
reaction indicates that the trifluoroethoxylation reaction could
proceeds via an oxidative addition−reductive elimination
pathway (Scheme 2).28
12. Chu, L.; Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513.
13. Wang, H.; Vicic, D. A. Synlett 2013, 24, 1887.
14. Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: Hoboken, 2008.
15. Irurre Jr, J.; Casas, J.; Messeguer, A. Bioorg. Med. Chem.
Lett. 1993, 3, 179.
16. Camps, F.; Coll, J.; Messeguer, A.; Pericàs, M. A. Synthesis
1980, 727.
17. Hine, J.; Ghirardelli, R. J. Org. Chem. 1958, 23, 1550.
18. Nakai, T.; Tanaka, K.; Ishikawa, N. J. Fluorine Chem. 1977,
9, 89.
Scheme 2. Plausible reaction pathway leading to the
trifluoroethyl vinyl ethers.
19. Gupton, J. T.; Idoux, J. P.; Colon, C.; Rampi, R. Synth.
Commun. 1982, 12, 695.
20. Idoux, J. P.; Gupton, J. T.; McCurry, C. K.; Crews, A. D.;
Jurss, C. D.; Colon, C.; Rampi, R. C. J. Org. Chem. 1983,
48, 3771.
To highlight the scalability and practicability of our synthesis,
the trifluoroethoxylation reaction was performed on a gram
scale. Using 1.10 g (6.0 mmol) of -bromostyrene 2a as the
substrate, the trifluoroethoxylated product 3a was obtained in
81% yield (Scheme 3).
21. Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Eur.
J. Org. Chem. 2009, 3513.
22. Rangarajan, T. M.; Singh, R.; Brahma, R.; Devi, K.; Singh,
R. P.; Singh, R. P.; Prasad, A. K. Chem.-Eur. J. 2014, 20,
14218.
23. Rangarajan, T. M.; Devi, K.; Ayushee; Prasad, A. K.; Pal
Singh, R. Tetrahedron 2015, 71, 8307.
24. Huang, R.; Huang, Y.; Lin, X.; Rong, M.; Weng, Z. Angew.
Chem. Int. Ed. 2015, 54, 5736. Corrigendum: 2015, 54,
8022.
Scheme 3. Scalability of the trifluoroethoxylation of 2a.
25. Huang, Y.; Huang, R.; Weng, Z. Synlett 2015, 26, 2327.
26. Zhang, C.-P.; Vicic, D. A. Chem. Asian J. 2012, 7, 1756.
27. Shao, X.; Wang, X.; Yang, T.; Lu, L.; Shen, Q. Angew.
Chem. Int. Ed. 2013, 52, 3457.
28. Rueping, M.; Tolstoluzhsky, N.; Nikolaienko, P. Chem.-Eur.
J. 2013, 19, 14043.
In conclusion, a convenient synthetic strategy to prepare
trifluoroethyl
trifluoroethoxylation
vinyl
ethers
reactions
was
of
explored
copper
by
reagent
the
[(phen)2Cu][OCH2CF3] with vinyl bromides. The strategy
afforded the trifluoroethyl vinyl ethers in good yields.
Additionally, the reaction tolerated a variety of substituents at the
aryl moiety of vinyl halides and is amenable to being carried out
on gram scales.
29. Huang, Y.; Ding, J.; Wu, C.; Zheng, H.; Weng, Z. J. Org.
Chem. 2015, 80, 2912.
Acknowledgments

4
Tetrahedron
Supplementary Material
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5
Highlights:
 An efficient method for synthesis of trifluoroethyl vinyl ethers has been
developed.
 The procedure tolerates a variety of substituents at the aryl moiety of vinyl
halides.
 The reaction is amenable to being carried out on gram scales.