Transition metal free decarboxylative fluorination of cinnamic acids with selectfluor

Article abstract of DOI:10.1016/j.tetlet.2016.11.003

Herein we report a transition metal free decarboxylative fluorination of cinnamic acids with selectfluor. A range of functionalized cinnamic acid derivatives reacted with 2 equiv. of selectfluor and 4 equiv. of base in hydrophobic solvent and water to afford β-fluorostyrene with good yield and Z-stereoselectivity. Kinetic study was conducted.

Full text of DOI:10.1016/j.tetlet.2016.11.003

Accepted Manuscript
Transition Metal Free Decarboxylative Fluorination of Cinnamic Acids with
Selectfluor®
Cheng-Tan Li, Xi Yuan, Zhen-Yu Tang
PII:
S0040-4039(16)31452-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.003
TETL 48289
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 September 2016
24 October 2016
1 November 2016
Please cite this article as: Li, C-T., Yuan, X., Tang, Z-Y., Transition Metal Free Decarboxylative Fluorination of
Cinnamic Acids with Selectfluor®, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.003
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Graphical Abstract
Transition Metal Free Decarboxylative
Fluorination of Cinnamic Acids with
Selectfluor®
Leave this area blank for abstract info.
Cheng-Tan Li, Xi Yuan and Zhen-Yu Tang

1
Tetrahedron Letters
Transition Metal Free Decarboxylative Fluorination of Cinnamic Acids with
Selectfluor®
Cheng-Tan Li, Xi Yuan and Zhen-Yu Tang 
Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, P.R.China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report a transition metal free decarboxylative fluorination of cinnamic acids with
selectfluor®. A range of functionalized cinnamic acid derivatives reacted with 2 equivalents of
selectfluor® and 4 equivalent of base in hydrophobic solvent and water to afford -fluorostyrene
with good yield and Z-stereoselectivity. Kinetic study was conducted.
Available online
Keywords:
2016 Elsevier Ltd. All rights reserved.
Decarboxylation
Fluorination
Cinnamic Acids
Selectfluor®
Alkene
Fluorine-containing structures have become common sense in
drug candidate development.1 The special nature of fluorine atom
equipped the medicines with a variety of properties, including
enhanced binding interactions, metabolic stability, changes in
physical properties and selective relativities.2 Advances in
fluorine chemistry have provided synthetic chemists with various
carbon-fluorine bond synthesis methods.3 Among them, creation
of C(sp2)–F bonds attracted much attention.4 Elegant examples
included bromo/triflate-fluorine exchange,5 fluorination of aryl
trifluoroborates6 and deoxofluorination of phenol.7 However,
employment of the other common C(sp2) functionalities, such as
widely available carboxylic acid, are still missing. The early
fluorodecarboxylation of carboxylic acid employed toxic F2 or
XeF2 with low yields.8 Recently, several examples of aliphatic
acid decarboxylative fluorination were reported (scheme 1). Li
group reported silver-catalyzed decarboxylative fluorination of
aliphatic carboxylic acids in aqueous solution.9 Sammis group
reported both alkyl fluorination of peresters with N-
fluorobis(benzenesulfonyl)imide (NSFI) and catalytic photoredox
decarboxylative fluorination of aryloxyacetic acid.10 McMillan
group developed a general method for the photoredox catalyzed
decarboxylative fluorination of aliphatic carboxylic acids.11
Despite those progresses, the fluorination of C(sp2) carboxylic
acid remains virtually unexplored and is still challenging. Herein,
we wish to report a transition metal free decarboxylative
fluorination of -unsaturated carboxylic acids with commercial
available, stable selectfluor®.
Figure 1. Recent advances in decarboxylative fluorination
Our study started with cinnamic acid (1a), selectfluor® (2
equiv.) and potassium fluoride (4 equiv.) in aqueous solution of
acetonitrile at room temperature (Table 1). This condition
afforded about 7% NMR yield with prevailed Z-isomer
stereoselectivity of 3.7:1 (entry 1).12 Further solvent test revealed
that hydrophobic solvents, such as toluene and cyclohexane,
resulted in higher yields and selectivities than hydrophilic
solvents, such as acetonitrile and dioxane (entries 2 to 5). Neither
pure water nor pure cyclohexane afforded any fluorinated
———
 Corresponding author. Tel.: +86 731 88879616; fax: +86-000-000-0000; e-mail: zytang@csu.edu.cn

2
Tetrahedron
product. Upon heating to 50oC, the yield of this transformation
Changing base to NaOAc, increasing selectfluor® to 4
was successfully improved to 79% albeit the selectivity
decreased to 3.7:1 (entry 5). Various bases were screened (see
supporting information table S2). Fluoride-containing bases such
as sodium fluoride (NaF) and cesium fluoride (CsF) produced the
similar or slightly higher yield than potassium fluoride (KF). We
chose KF as our choice of base due to its cost and wide
availability. Other weak base such sodium acetate (NaOAc)
afforded comparable yield (76%, entry 8). This result excluded
fluoride anion’s participation in this reaction. The ratio of base to
selectfluor® was optimized to be 2:1 (see supporting information
table S1). Various transition metal catalyzed conditions for
decarboxylative trifluoromethylations, such as silver nitrate and
copper sulphate, were also tested and lower yields were
observed.13 The other electrophilic fluorination reagents, such as
NSFI and N-fluoropyridium salts (NFPY), were also tested and
afforded no yields.14 This further proved selectfluor® as the only
specialty for this transformation. Finally, simple mixture of
potassium salt of cinnamic acid and selectfluor® afforded 23%
yield with a little higher selectivity (entry 12).
equivalents and the temperature to 70oC effectively increased the
yield to 79%. 4-Chloro- and bromo- substrates were also tested
and did not afford more than 10% yield, likely due to their poor
solubility in hydrophobic solvents. Different methoxy-substituted
derivatives resulted in good yield in dichloromethane (2g-2i). On
the other hand, the poor solubility of substrate 1j and 1n resulted
in low yields under current condition. Cinnamic acids with
electron withdrawing group on aromatic ring and heteroaromatic
acrylic acids were also tested and no reaction was observed. At
last, alkyl substituted cinnamic acids (1k-1m) proved to be
effective substrates for this transformation with good yields and
selectivities.
Table 2. Decarboxylative fluorination of unsaturated carboxylic
acids a,b
Table 1. Optimization of reaction conditionsa
Entrya
Solvent
Base
Additive
Yield(%)b
(2a:3a)
1
MeCN
KF
none
7 (3.7:1)
9 (3.5:1)
36 (5.6:1)
53 (5.3:1)
42 (5.0:1)
79 (3.7:1)
52 (4.2:1)
76 (3.2:1)
48 (3.6:1)
15 (3.6:1)
0
2
dioxnae
KF
none
3
toluene
KF
none
4
cyclohexane
DCM
KF
none
5
KF
none
6c
7d
8c
9c
10c
11c
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
KF
none
a Reaction conditions: selectfluor® (2 equiv.), base (4 equiv.), 1 (1 equiv.) at
KF
none
0.1 M in solvent, 50oC, 24 hrs.
b
isolated yield, all yields are run on a 0.5 mmol scale at least twice, the
number in parentheses refers to 19F NMR yields on 0.1 mmol scale, E/Z
selectivity measured by 1H NMR
NaOAc
KF
none
c 70oC, 2 more equivalent of selectfluor®
CuSO4 (10%)
AgNO3 (10%)
NSFI
KF
Kinetic study of cinnamic acid 1a was conducted (Figure 2).
The initial reaction was fast with 44% yield in 1 hour and 5:1
selectivity. The yield reached 65% after 4 hours. The slow-down
and selectivity erosion have then been observed, trans- product
formed faster than cis- product at this stage. Up to 48 hours, the
reaction almost stopped and about 20% of the starting material
left. The kinetic behaviour of 1a revealed this transformation as
high-ordered reaction with dependence on reactant concentration.
KF
12c,e
none
none
23 (4.0:1)
a
Reaction condition: 1a 0.2 mmol, selectfluor® 0.4 mmol, base 0.8 mmol,
H2O:solvent= 1 mL: 2 mL, room temperature, 24 hrs.
b 19F NMR yield based on 4-fluorotoluene as internal standard
c 50oC
d 70oC
e Potassium salt of cinnamic acid instead of 1a
Figure 2. Kinetic study of 1a
Having the optimized conditions in hand, we investigated
scope of decarboxylative fluorination of cinnamic acid
derivatives with different combination of solvent and base (Table
2). A range of commercial available and functionalized -
unsaturated carboxylic acids 1a-n underwent decarboxylative
fluorination with selectfluor®. -methyl cinnamic acid 1b was
converted to fluorinated product 2b in 39% isolated yield with
the rest of starting material recovered. Due to the volatility of the
product and loss in the separation procedure, the isolated yield is
lower than the NMR yield (47%). Moderate yields (36%-58%)
were observed for the methyl-substituted aromatic ring
derivatives 2c-e. The reaction of 4-fluorocinnamic acid with KF
at 50oC initially gave the expected product 2f in 46% yield.

3
Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.; Reif, D.
J. J. Org. Chem. 1993, 58, 705.
To gain some insight into the mechanism, radical scavenger
TEMPO was added to the standard reaction condition, no product
was observed. This result indicates that a free radical pathway
might be involved in this transformation. A plausible mechanism
based on single electron transfer (SET) radical pathway is
depicted (Scheme 2). After deprotonation, cinnamic acid salt
sequentially received an electron and fluorine from selectfluor®
to form a cation intermediate.16 Fast carbon dioxide elimination
lead to the Z-isomer prevailed fluorostyrene.
9.
(a) Feng, Y.; Wang, Z.; Li, Z.; Li,C. J. Am. Chem. Soc. 2012, 134,
10401. (b) Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. J. Am. Chem.
Soc. 2014, 136, 16439.
10. (a) Leung, J. C. T.; Chatalova-Sazepin, C.; West, J. G.; Rueda-
Becerril, M.; Paquin, J.-F.; Sammis, G. M. Angew. Chem. Int. Ed.
2012, 51, 10804. (b) Rueda-Becerril, M.; Chatalova-Sazepin, C.;
Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.; Paguin, J.-F.;
Sammis, G. M. J. Am. Chem. Soc. 2012, 134, 4026. (c) Rueda-
Becerril, M.; Mahe, O.; Drouin, M.; Majewski, M. B.; West, J. G.;
Wolf, M. O.; Sammis, G. M.; Paquin, J.-F. J. Am. Chem. Soc.
2014, 136, 2637.
Scheme 2. Plausible Mechanism
11. Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2015, 137, 5654.
12. For synthesis of Z- isomer of fluorostyrene, see: Landelle, G.;
Turcotte-Savard, M.-O.; Angers, L.; Paquin, J.-F. Org. Lett. 2011,
13, 1568.
13. (a) Li, Z.; Cui, Z.; Liu, Z.-Q. Org. Lett. 2013, 15, 406. (b) Hu, F.;
Shao, X.; Zhu, D.; Lu, L.; Shen, Q. Angew. Chemie. Int. Ed. 2014,
53, 6105.
14. (a) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc.
2010, 132, 2856. (b) Kiselyov, A. S. Chem. Soc. Rev. 2005, 34,
1031.(c) Differding, E.; Ofner, H. Synlett 1991, 187.
15. (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem. Int. Ed. 2005, 44, 192. (b) Singh, R.
P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
In conclusion, we have developed the C(sp2)
decarboxylative fluorination that employed selectfluor® as the
fluorine source and potassium fluoride as base. The mild
transition-metal-free experimental condition, Z-stereoselectivity,
low cost of the fluorinating source and easy reactant recovery
made it a practical method to synthesize fluorostyrene. Further
work on employing this condition on aryl carboxylic acid is
underway.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
Acknowledgement
Financial support was provided by the National Natural Science
Foundation of China 21302231, Hunan Provincial Natural
Science Foundation of China 14JJ3021, Ph.D. Programs
Foundation of Ministry of Education of China 20130162120032.
The authors acknowledge the NMR measurement by the Modern
Analysis and Testing Centre of CSU.
References and notes
1.
(a) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Solohonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432. (b) ller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (c) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d) Kirk, K. L.
Org. Process Res. Dev. 2008, 12, 305.
2.
3.
O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(a) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765. (b) Ahrens,
T.; Kohlmann, J.; Ahrens, M.; Braun, T. Chem. Rev. 2015, 115,
931. (c) Liang, T.; Neumann, C.; Ritter; T. Angew. Chem. Int. Ed.
2013, 52, 8214. (d) Wikinson, J. A. Chem. Rev. 1992, 92, 506. (e)
Shimizu, M.; Hiyama, T. Angew. Chem. Int, Ed. 2005, 44, 214. (f)
Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr. Opin. Drug Discovery
Dev. 2008, 11, 803.
4.
( a) Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612. (b)
Furuya, T.; Kamlet, A. S.; Ritter, T. Nature, 2011, 473, 470. (c)
Li, Y.; Wu, Y., Li, G.-S.; Wang, X.-S. Adv. Synth. Catal. 2014,
356, 1412.
5.
(a) Watson, D. A.; Su, M.; Teverovskiy, Teverovskiy, G.; Zhang,
Y.; Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L.; Science 2009,
325, 1661. (b) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.;
Takase, M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133,
18106.
6.
(a) Ye, Y.; Sanford, M. S.; J. Am. Chem. Soc. 2013, 135, 4648. (d)
Ye, Y.; Scimler, S. D.; Hanley, P. S.; Sanford, M. S. J. Am. Chem.
Soc. 2013, 135, 16292. (c) Mazzotti, A. R.; Campbell, M. C.;
Tang, P.; Murphy, J. M.; Ritter, T. J. Am. Chem. Soc., 2013, 135,
14012. (d) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc.
2013, 135, 2552.
7.
8.
Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133,
11482.
(a) Grakauskas, V. J. Org. Chem. 1979, 34, 2446. (b) Patrick, T.
B.; Johri, K. K.; White, D. H. J. Org. Chem. 1983, 48, 4148. (c)

4
Tetrahedron
Highlights

Transition metal catalyst free decarboxylative
fluorination of Csp2 carboxylic acids


Synthesis of -fluorostyrene with primarily Z-
selectivity
Inexpensive, commercial available and safe
fluorinating reagent selecfluor® was employed for
this transformation