Monofluorovinyl tosylate: A useful building block for the synthesis of terminal vinyl monofluorides via suzuki-Miyaura coupling

Article abstract of DOI:10.1021/ol102645g

Monofluorovinyl tosylate was developed as a practical vinyl fluoride building block to couple with a variety of arylboronic acids in the presence of a palladium catalyst. The high stereoselectivity of 2-aryl-1-fluoroethene derivatives was achieved. This a

Full text of DOI:10.1021/ol102645g

ORGANIC
LETTERS
2010
Vol. 13, No. 4
560–563
Monofluorovinyl Tosylate: A Useful
Building Block for the Synthesis of
Terminal Vinyl Monofluorides via
Suzuki-Miyaura Coupling
He Zhang, Chang-Bing Zhou, Qing-Yun Chen, Ji-Chang Xiao,* and Ran Hong*
Key Laboratory of Organofluorine Chemistry and Key Laboratory of Synthetic
Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
jchxiao@sioc.ac.cn; rhong@sioc.ac.cn
Received November 1, 2010
ABSTRACT
Monofluorovinyl tosylate was developed as a practical vinyl fluoride building block to couple with a variety of arylboronic acids in the presence of
a palladium catalyst. The high stereoselectivity of 2-aryl-1-fluoroethene derivatives was achieved. This approach is also applicable to the
synthesis of 2,2-diaryl-1-fluoroethenes in good yields.
It has been known that fluorinated compounds are
the least abundant natural organohalides.1 Due to their
unique properties such as hydrophobicity and metabolic
stability, fluorinated compounds have been widely utilized
in drugs, polymers, liquid crystals, and so on.2 Terminal vinyl
fluorides are oneof the mostimportantfluorinated organic
compounds, especially for mimicking the peptide bond,
often possessing spectacular characteristics in compari-
son with their hydrogen analogs. Robins and co-workers
reported that 50-fluoro-40,50-didehydro-Ei0-deoxyadenosine
(ZFDDA) and its derivatives exhibited effective antivirus
and enzyme inhibitory activities.3 Vinyl fluorides can also
be copolymerized with ethylene by palladium-mediated
catalysis, as reported by Jordan.4 Experimental and
theoretical investigations carried out by Haufe and
€
Wurthwein indicated a profound effect of vinyl fluorides
in the Diels-Alder reaction of R- or β-fluorostyrenes with
typical dienes.5
(3) Wnuk, S. F.; Yuan, C.-S.; Borchardt, R. T.; Balzarini, J.;
De Clercq, E.; Robins, M. J. J. Med. Chem. 1994, 37, 3579–3587.
(4) Weng, W.; Shen, Z. L.; Jordan, R. F. J. Am. Chem. Soc. 2007, 129,
15450–15451.
(1) Harper, D. B.; O’Hagan, D.; Murphy, C. D. The Handbook of
Environmental Chemistry; Springer: Berlin Heidelberg, 2003; Vol. 3, pp
141-169.
€
(5) Ernet, T.; Maulitz, A. H.; Wurthwein, E.-U.; Haufe, G. J. Chem.
€
(2) For reviews, see: (a) Muller, K.; Faeh, C.; Diederich, F. Science
Soc., Perkin Trans. 1 2001, 1929–1938.
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2007, 317, 1881–1886. (b) Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine
Chem. 2006, 127, 992–1012. (c) Roth, B. D. Progress in Medicinal
Chemistry; Elsevier: Amsterdam, 2002; Vol. 40, pp 1-22. (d) Manteau,
B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2010, 131, 140–
158. (e) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, reactivity,
applications; Wiley: Weinheim, 2004; Chapter 4, pp 205-212. (f) Kirsch, P.
Modern Fluoroorganic Chemistry: Synthesis, reactivity, applications;
Wiley: Weinheim, 2004; Chapter 4, pp215-234.
(6) (a) Swarts, F. Bull. Soc. Chim. Fr. 1919, 25, 145–174. (b) Bergmann, F.;
Kalmus, R.; Breuer, E. J. Am. Chem. Soc. 1958, 80, 4540–4543. (c) Moss,
R. A.; Maksimovic, L.; Merrer, D. C. Tetrahedron Lett. 1997, 38, 7049–
7052. (d) Ocampo, R.; Dolbier, W. R., Jr.; Zuluaga, F. Collect. Czech. Chem.
Commun. 2002, 67, 1325–1334. (e) McCarthy, J. R.; Jarvi, E. T.; Matthews,
D. P.; Edwards, M. L.; Prakash, N. J.; Bowlin, T. L.; Mehdi, S.; Sunkara, P. S.;
Bey, P. J. Am. Chem. Soc. 1989, 111, 1127–1128.
r
10.1021/ol102645g
Published on Web 12/30/2010
2011 American Chemical Society

The preparation of vinyl fluorides has inspired many
innovative synthetic approaches. In particular, terminal
fluorides can be accessed by elimination,6 electrophilic
fluorination,7 Julia-Kocienski olefination,8 and Peterson
olefination.9 However, in these approaches, the poor
tolerance of functional groups, low stereoselectivity, and
moderate to low yields often hinder their applications.
Although the Horner-Wadsworth-Emmons reaction3,10
has been considered as the most successful protocol for the
preparation of vinyl fluorides, the starting material halo-
fluorocarbons for the synthesis of fluoromethyl phosphor-
ane ylides have been restricted in use by the law due to their
ozone depletion and greenhouse effects.11 Therefore, the
development of a practical and efficient method to synthe-
size terminal vinyl fluorides is still highly demanding.
Herein, we wish to present 2-fluorovinyl tosylate as a
useful synthon in the preparation of vinyl fluorides via a
Suzuki-Miyaura coupling reaction.
Scheme 1. Preparation of 2-Fluorovinyl Tosylate (2)
To obtain a variety of vinyl fluorides, 2-fluorovinyl
tosylates E-2 and Z-2 were prepared by treating 1 with
15
LiAlH4 in ether (Scheme 1). 2,2-Difluorovinyl tosylate
(1) could be conveniently synthesized from the elimination
reaction of 2,2,2-trifluoroethyl tosylate with butyllithium
as reported by Skrydstrup.13 The molar ratio of E-2 and Z-
2 in this reaction was 95/5 which was determined by 19F
NMR. Two stereoisomers were readily separated by flash
column chromatography. Their configurations were con-
firmed by 1H and 19F NMR.16
Vinyl tosylates have been found useful in cross-coupling
reactions because they can be readily prepared and possess
good stability in water.12 In 2007, Skrydstrup and co-
workers reported that 2,2-difluorovinylstyrenes could be
successfully synthesized via the Pd-catalyzed Suzuki-
Miyaura coupling reaction of 2,2-difluorovinyl tosylate
with aryl boronic acids.13 This method provides a facile
and straightforward approach to introduce a gem-
difluorovinyl substituent onto aromatic compounds. Very
recently, Jeong and co-workers reported that 2,2-diaryl-
1,1-difluoroethenes could be obtained through the
coupling of 2,2-difluoro-1-phenylethenyl tosylate with
arylstannane.14 Nevertheless, few reports could be found
in the literature about the synthesis of terminal vinyl
monofluorides through a metal-mediated cross-coupling
reaction.
Table 1. Optimization of the Suzuki-Miyaura Reaction be-
tween E-2 and 4-Methoxybenzeneboronic Acida
entry
catalyst
ligand
baseb
solventc
yield%
1d
2
Pd(PPh3)4
-
-
K3PO4 Dioxane/H2O 49
K3PO4 Dioxane/H2O trace
K3PO4 Dioxane/H2O trace
Pd2dba3 CHCl3
3
3
3
Pd2dba3 CHCl3 PBun
3
4
Pd2dba3 CHCl3 P(t-Bu)3 K3PO4 Dioxane/H2O trace
3
5
Pd2dba3 CHCl3 PPh3
K3PO4 Dioxane/H2O 71
K3PO4 Dioxane/H2O 44
K3PO4 Dioxane/H2O 70
K3PO4 Dioxane/H2O 98
Na2CO3 Dioxane/H2O 66
K2CO3 Dioxane/H2O 66
K3PO4 Dioxane/H2O 98
K3PO4 Dioxane/H2O 94
3
6
Pd2dba3 CHCl3 dppp
3
7
Pd2dba3 CHCl3 dppb
3
8
Pd2dba3 CHCl3 PCy3
3
9
Pd2dba3 CHCl3 PCy3
3
10
Pd2dba3 CHCl3 PCy3
3
11d Pd(OAc)2
PCy3
PCy3
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57, 629–635. (e) Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash,
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12d PdCl2(PPh3)2
13
14
15
Pd2dba3 CHCl3 PCy3
K3PO4 Toluene
K3PO4 Dioxane
K3PO4 Toluene
49
10
6
3
Pd2dba3 CHCl3 PCy3
3
Pd2dba3 CHCl3 PCy3
3
a E-2 (0.5 mmol) and 3a (0.55 mmol) were used; yield was determined
by 19F NMR using trifluoromethylbenzene as internal standard. b Bases
were dissolved in water before use except for entries 14 and 15. c The
volume ratio of Dioxane/H2O was 3/1, and 2 mL of organic solvent was
used. d The catalyst loading was 2 mol %.
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With E-2 in hand, the optimization of the reaction
between E-2 and 4-methoxybenzeneboronic acid was
undertaken, and the results are shown in Table 1. The ligands
played an important role in the coupling reaction. When
Pd(PPh3)4 wasused, the desired productE-(2-fluorovinyl)-
4-methoxybenzene (4a) was obtained in 49% yield (entry 1).
Only a trace of the desired product was detected by 19F
(12) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005,
70, 9364–9370.
NMR when Pd2dba3 CHCl3 was employed (entry 2).
3
Although the yield was low, onlythe E-isomer wasdetected
by 19F NMR. When phosphine ligands were added in the
coupling reaction, higher yields of the desired product were
ꢀ
(13) Gøgsig, T. M.; Søbjerg, L. S.; Lindhardt (nee Hansen), A. T.;
Jensen, K. L.; Skrydstrup, T. J. Org. Chem. 2008, 73, 3404–3410.
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1982.
(16) See Supporting Information for details.
Org. Lett., Vol. 13, No. 4, 2011
561

obtained (entries 3-8), indicating that extra ligands may
improve the efficiency of the catalysis. Among P(n-Bu)3,
P(t-Bu)3, PPh3, dppp, dppb, and PCy3 ligands used with
Scheme 2. Preparation of the 2-Fluoro-1-phenylvinyl Tosylate (7)
Pd2dba3 CHCl3, PCy3 was proved to be the most efficient
3
candidate in this reaction (entry 8). The screening of
precatalysts such as Pd(OAc)2 and PdCl2(PPh3)2 afforded
similar results (entries 11 and 12 vs entry 8). In addition,
base was also influential (entries 8-10). Potassium phos-
phate was found to be the optimal base. Therefore, the
optimal reaction conditions were identified as follows: 1
equiv of E-2, 1.1 equiv of arylboronic acids in the pre-
sence of 1 mol % Pd2dba3 CHCl3, 4 mol % PCy3, and
3
1.7 equiv potassium phosphate in dioxane and H2O at
100 °C for 14 h.
Table 2. Substrate Scope of the Suzuki-Miyaura Reaction
between E-2 and Arylboronic Acidsa
in 80% yield, and subsequent treatment with LiAlH4 at
-40 °C afforded Z-7 and E-7 in moderate yields, which
could be separated by flash column chromatography
(Scheme 2). The configuration of the major isomer Z-7
was confirmed by single crystal X-ray diffraction analysis.18
Scheme 3. Coupling Reaction between Z-7 and Boronic Acidsa
a Isolated yield; 5a (0.5 mmol) and boronic acid (0.55 mmol) were
used. b Determined by 19F NMR using PhCF3 as internal standard.
This procedure was then extended to other arylboronic
acids, and the results are shown in Table 2. The functional
group tolerance was quite broad. Substrates bearing elec-
tron-withdrawing groups, electron-donating groups, and
highly steric substituents can be successfully coupled with
vinylfluoride tosylateinexcellentyields. All oftheproducts
are the E isomer, indicating that the configuration was
completely retained in the reaction.
When our work was in progress, Paquin and co-workers
reported the first synthesis of 1,1-diaryl-2-fluoroethenes
using Suzuki-Miyaura cross-coupling via boronic acids
and vinylbromides.17 Enlightened by his work to expand
the scope and applicability of our method, 2-fluoro-
1-phenylvinyl tosylate (7) was synthesized and then con-
verted to 1,1-diaryl vinylfluorides (8) under the optimized
reaction conditions. Since 6 and 7 are more susceptible to
nucleophilic attack, LiHMDS was chosen for deprotona-
tion and elimination of 2,2,2-trifluoro-1-phenylethyl tosy-
late (5) at -78 °C, giving 2,2-difluoro-1-phenylvinyl tosylate (6)
a Isolated yield and the E/Z selectivity were determined by 19F NMR
of the reaction mixture. Isolated as a E/Z mixture. The E/Z isomers
were separated by flash column chromatography.
b
c
As shown in Scheme 3, Z-7 showed good reactivity for the
coupling reaction to afford the corresponding 1,1-diaryl
fluorides. 2-Fluoro-1,1-diphenylethene (8a) was success-
fully obtained in 92% isolated yield. While the unsymme-
trically substituted diaryl vinylfluorides 8b-e were synthe-
sized in moderate stereoselectivity. Two stereoisomers of
8c could be readily separated by column chromatography,
and the configuration was assigned by H,H-NOESY.19
With the treatment of E-7 with naphthalen-2-ylboronic
acid under optimal conditions (Scheme 4), compound 8b
was obtained in 95% yield with a 15/85 Z/E selectivity.
(18) CCDC 797215 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(17) Landelle, G.; Turcotte-Savard, M.-O.; Marterer, J.; Champagne,
P. A.; Paquin, J.-F. Org. Lett. 2009, 11, 5406–5409.
(19) See Supporting Information for details.
562
Org. Lett., Vol. 13, No. 4, 2011

Scheme 4. Synthesis of 8b from Z-11 and E-7a
Scheme 5. Proposed Mechanism for the Stereoselectivity of
Monofluoroalkenes
a 95% yield of 8b was obtained from E-7 and 91% yield was obtained
from Z-11.
A similar result was also found in the reaction of Z-11 with
phenylboronicacid.20 Itseems thattheconfigurationof the
CdC bond was almost maintained in this reaction.
It is interesting to note that the reduction of difluoroalk-
enes 1 and 6 with LiAlH4 preferentially resulted in E-2 and
Z-7 isomers, respectively. This reaction may proceed
through an addition-elimination pathway (Scheme 5).
In this process, the coordination of atomic Li with fluoride
would make the fluoride more prone to leave than tosylate.
Moreover, the steric repulsion between the OTs group and
F makes TS2 more favorable and E-2 was thus isolatedas a
major isomer. For compound 6, the introduction of a
phenyl ring would make the carbanion tend to adopt sp2
hybridization21 in 60 due to the better electron conjugated
effect between the phenyl ring and the negative charge.
Therefore, the steric repulsion between Ph and F may
destabilize TS4 and the corresponding product E-7 was
less abundant. The ratio of Z/E is thus inversed from 5/95
in 2 to 80/20 in 7.
In conclusion, 2-fluorovinyl tosylate and 2-fluoro-1-
phenylvinyl tosylate were synthesized and employed to
prepare 1-arylvinyl fluoridesand 1,1-diarylvinylfluorides.
High yields and good stereoselectivity were achieved in the
reaction of E-2 with aryl boronic acids. Further studies on
the synthesis of 1,2-diaryl-fluorovinyls are underway in
our laboratory.
In the presence of Pd2dba3 CHCl3/PCy3/K3PO4 at 100 °C
3
for 14 h, Z-8c could isomerize to E-8c, giving a mixture
of Z/E (62/38). While the starting material Z-7 was
employed, no isomerization happened.22 This indicates
that the stereoselectivity observed in the coupling reaction
was probably attributed to the product isomerization
undertheoptimized Suzuki-Miyaurareactionconditions.
Acknowledgment. We thank the “Hundred of Talents
Program of CAS”, the Shanghai Rising Star Program
(08QA14079 to R.H.), and NSFC (20972179 and 2103-
2006) for financial support. We thank Jie Sun (SIOC) for
X-ray analysis and Dr. Shao-Ji Xiang (Zhejiang Chemical
Industry Research Institute) for helpful discussions.
(20) See Supporting Information for details.
(21) (a) Konishi, K.; Onari, Y.; Goto, S.; Takahashi, K. Chem. Lett.
Supporting Information Available. Experimental de-
tails and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
1975, 717–720. (b) Schmidbaur, H.; Schler, A.; Lauteschlager, S.; Riede, J.;
Mul, G. Organometallics 1984, 3, 1906–1909. (c) Harder, S. Chem.;Eur.
J. 2002, 8, 3229–3232.
(22) See Supporting Information for details.
Org. Lett., Vol. 13, No. 4, 2011
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