A domino approach of heck coupling for the synthesis of β-trifluoromethylstyrenes

Article abstract of DOI:10.1021/ol300076y

A domino approach of Heck coupling was used to synthesize β-trifluoromethylstyrene derivatives from iodoarenes and 1-iodo-3,3,3-trifluoropropane in moderate to good yields. This method avoids the use of low-boiling, gaseous reagents such as 3,3,3-trifluoropropene, and additives and phosphines in the catalytic system.

Full text of DOI:10.1021/ol300076y

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1146–1149
A Domino Approach of Heck Coupling
for the Synthesis of
β-Trifluoromethylstyrenes
G. K. Surya Prakash,* Hema S. Krishnan, Parag V. Jog, Anjali P. Iyer,† and
George A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry,
University of Southern California, University Park, Los Angeles, California 90089-1661,
United States
gprakash@usc.edu
Received January 12, 2012
ABSTRACT
A domino approach of Heck coupling was used to synthesize β-trifluoromethylstyrene derivatives from iodoarenes and 1-iodo-3,3,3-
trifluoropropane in moderate to good yields. This method avoids the use of low-boiling, gaseous reagents such as 3,3,3-trifluoropropene, and
additives and phosphines in the catalytic system.
The trifluoromethyl group is known for its ability to
alter the lipophilicity, metabolic activity, and bioavailabil-
ity of host compounds.1 The electron-withdrawing nature
ofthe trifluoromethyl groupisalsoanaddedadvantage for
further chemical transformations as the electron density
around the adjacent carbon center is altered. Specifically,
the 3,3,3-trifluoropropenyl (CF3CHdCH;) group has
found important implications in medicinal chemistry and
agricultural chemistry (insecticides) and has been found to
impart volatality to aliphatic compounds.2 Conjugated
aromatic systems with trifluoromethyl groups such as
β-trifluoromethylstyrene derivatives have found wide use
in Organic Light Emitting Diodes (OLEDs) and in other
material chemistry applications.3
One is by transition metal catalyzed trifluoromethylation
of β-halostyrenes using various trifluoromethylating re-
agents (Figure 1, disconnection 1).4 The second approach
involves both the traditional Horner reaction and reverse
Wittig reaction (Figure 1, disconnection 2).2,5 The former
approach requires access to β-halostyrenes and, in some
cases, synthesis of the trifluoromethylating reagent as
an added step. Latter approaches involve the synthesis
of corresponding ylides, which can be cumbersome and
require aldehydes as one of the starting components. In
1981, Fuchikami et al. reported the palladium cata-
lyzed coupling of aromatic halides and 3,3,3-trifluor-
opropene to synthesize β-trifluoromethylstyrenes in
high yields (Figure 1, disconnection 3).6 Unfortunately,
the latter method requires the use of gaseous 3,3,3-tri-
fluoropropene as a reaction component in an autoclave
and the substrate scope is limited. In 2005, Vogel et al.
reported7 another palladium catalyzed cross-coupling
reaction between styrene (5 equiv) and trifluoromethane-
sulfonyl chloride to synthesize β-trifluoromethylstyrene
The synthesis of β-trifluoromethylstyrene derivatives
has been explored mainly by two different pathways.
† 2011 Summer Intern, Diamond Bar High School, CA.
(1) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679–1681.
(2) Kobayashi, T.; Eda, T.; Tamura, O.; Ishibashi, H. J. Org. Chem.
2002, 67, 3156–3159.
(3) Shimizu, M.; Takeda, Y.; Higashi, M.; Hiyama, T. Angew. Chem.,
Int. Ed. 2009, 48, 3653–3656.
(4) (a) Kitazume, T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107,
5186–5191. (b) Chen, Q.; Wu, S. Chem. Commun. 1989, 705–706. (c)
Chen, Q.; Duan, J. Chem. Commun. 1993, 1389–1391. (d) Duan, J.; Su,
D.; Chen, Q. J. Fluorine Chem. 1993, 61, 279–284.
(5) (a) Hanamoto, T.; Morita, N.; Shindo, K. Eur. J. Org. Chem.
2003, 4279–4285. (b) Landge, S. M.; Borkin, D. A.; Torok, B. Lett. Org.
Chem. 2009, 6, 439–443.
(6) Fuchikami, T.; Yatabe, M.; Ojima, I. Synthesis 1981, 365–366.
(7) Dubbaka, S. R.; Vogel, P. Chem.;Eur. J. 2005, 11, 2633–2641.
r
10.1021/ol300076y
Published on Web 02/03/2012
2012 American Chemical Society

To our delight, the reaction between 3-iodotoluene and
1-iodo-3,3,3-trifluoropropane using DMF as an aprotic,
high dielectric constant solvent with K2CO3 (3.5 equiv)
as base and Pd(OAc)2 (2 mol %) as catalyst in a micro-
wave reactor at 200 °C for 1 h yielded the desired product
in 83% conversion based on 19F NMR analysis. Different
palladium catalysts such as Pd2(dba)3 and Pd(PPh3)2Cl2
were also tested for their efficacy with no observed
improvement in yields. Analysis of the results of various
reactions yielded the optimized conditions for the title
reaction, which were applied to a variety of substituted
iodobenzenes. The results are shown in Table 1. Bromo-
benzene and chlorobenzene were also subjected to the
same reaction under identical conditions. As expected,
bromobenzene yielded the desired β-trifluoromethyl-
styrene product, albeit in 10% yield, and chlorobenzene
did not give any of the desired product as evidenced
by 19F NMR analysis.
Figure 1. Previous approaches toward the synthesis of β-
trifluoromethylstyrenes.
derivatives albeit in 50% yield, again with limited substrate
scope.
Wedecidedtosynthesizeβ-trifluoromethylstyrenes using
our recently reported8 domino Heck chemistry approach.
This approach involves a palladium catalyzed Heck reac-
tion between aryl halides and commercially accessible
1-iodo-3,3,3-trifluoropropane under highly basic conditions
(>3 equiv). Under such conditions, 1-iodo-3,3,3-trifluo-
ropropane undergoes dehydrohalogenation to produce 3,3,
3-trifluoropropene (vinyl-CF3) in situ, which would react
with aryl halides with palladium(II) acetate as a catalyst to
yield the desired β-trifluoromethylstyrenes.
Iodobenzene gave the corresponding trifluoromethyl-
styrene in 76% isolated yield. Both electron-withdrawing
and -donating substituents are well tolerated by this meth-
od; however electron-donating substituents tend to give
slightly better yields than electron-withdrawing substitu-
ents. Steric effects also do not seem to affect the overall
yield much (Table 1, entry 5 vs 6). 2-Aminoiodobenzene,
which is generally known to poison palladium catalysts,
possiblydue tothelone pairson thenitrogenatom(a Lewis
base), surprisingly gave a 52% isolated yield of the corre-
sponding trifluoromethylstyrene. However, 3-hydroxy
and 2-carboxyl iodobenzene failed to give any of the
desired product, which could be due to catalyst poisoning
under the chosen reaction conditions.
In addition, heterocyclic iodoarenes also gave the
desired trifluoromethylated styrenes in low to moderate
yields (Figure 2). Previously unknown (E)-5-(3,3,3-tri-
fluoroprop-1-en-1-yl)-1H-indole (17) could be an inter-
esting compound for biological studies. 3-Iodopyridine
gave moderate yield of the desired Heck-coupled pro-
duct, but both 2-iodopyridine and 2-iodopyrazine did
not show any reaction under the identical reaction con-
ditions. Diiodoarenes gave the corresponding bis-
(trifluoromethyl) styrene derivatives in moderate to
good isolated yields (Figure 2), with the exception of
2,3,5,6-tetrafluoro-1,4-diiodobenzene, which did not
show any reaction.
There are many advantages with this approach. First,
1-iodo-3,3,3-trifluoropropane is a liquid at room tempera-
ture and hence can be easily handled. Second, the reaction
setup does not require an autoclave or any other sophis-
ticated equipment. Another advantage is that this reaction
can be performed under microwave irradiation conditions,
which reduces the reaction time drastically compared to
other methods such as the one reported by Fuchikami et al.
(14À97 h depending on substrate vs 1 h reported here). As
will be seen later, the substrate scope of this reaction is
broad, which increases its applicability in synthesizing
various trifluoromethylated styrenes as potential monomers
in polymer and material synthesis. Based on Fuchikami’s
report,6 we began our study of the optimization of the
reaction conditions with methanol/water (1:1) as the
solvent. As the Heck reaction usually requires high
temperatures and long reaction times, we decided to
carry out the reactions using a microwave reactor to try
and reduce the reaction times. However, the reaction of
2-iodoanisole with 1-iodo-3,3,3-trifluoropropane in this
solvent system with different bases (Li2CO3, Na2CO3,
K2CO3, and Cs2CO3) under microwave reaction condi-
tions (150 °C, 1 h) yielded only up to 40% of the desired
trifluoromethylated styrene. The poor yields could be a
result of the steric bulk of the methoxy group. Accord-
ingly, 3-iodotoluene was chosen as the substrate of
choice for further optimization of reaction conditions.
In all cases, isolated yields tend to be less than the NMR
conversions due toeitherlow boiling pointsof the products
or difficulties in purification of crude products using
column chromatography.
During the purification of 20, another product 20a was
also isolated (8% yield). This product could be the result of
two simultaneous reactions, Heck coupling at one position
and arylÀaryl homocoupling (side reaction) occurring at
the other position of 1,3-diiodobenzene. During optimiza-
tion studies with iodobenzene as a substrate, we observed
the formation of an interesting product under certain
reaction conditions. Unfortunately, we were not able to
isolate this product as a pure material. However, GC-MS
analysis of the reaction mixture and crude product
(8) (a) Prakash, G. K. S.; Jog, P. V.; Krishnan, H. S.; Olah, G. A.
J. Am. Chem. Soc. 2011, 133, 2140–2143. (b) Prakash, G. K. S.;
Krishnan, H. S.; Jog, P. V.; Olah, G. A. 242nd ACS National Meeting &
Exposition, Denver, CO, United States, Aug 28- Sep 1, 2011. ORGN 144.
Org. Lett., Vol. 14, No. 4, 2012
1147

Table 1. Synthesis of β-Trifluoromethylstyrenes
Figure 2. Heterocylic and bis(β-trifluoromethyl)styrenes. aIsolated
yield. bPure product was not obtained
sequence (Scheme 1).9 Crude 19F NMR analysis of the
reaction mixture suggested that the probable “double”
Heck product could be exclusively the Z-isomer. This
product was observed only as a minor product, and fur-
ther studies to obtain this product as a major product
under appropriate reaction conditions are underway.
In order to increase the efficacy of the reported method
to synthesize β-trifluoromethylstyrenes, a better “contact”
time between the gaseous 3,3,3-trifluoromethyl propene
generated in situ and the palladium catalyst was thought to
benecessary. This can be achieved by using animmobilized
palladium catalyst, and further efforts are underway for
the development of such a catalyst to increase the efficacy
of the reported procedure for a scale-up synthesis of
β-trifluoromethylstyrenes.
Scheme 1. EliminationÀHeckÀHeck Domino Reaction Path-
way
a Isolated yield. b The product was formed in a 1:1 ratio along with PhCF3.
In conclusion, herein, we report a very easy to perform,
efficient, and simple method of synthesizing β-trifluoro-
methylstyrene derivatives using an elimination/Heck dom-
ino reaction sequence. Additionally, the reported method
gives us access to some simple, interesting, and previously
unknown β-trifluoromethylstyrenes. The method avoids
the use of a gaseous 1,1,1-trifluoropropene reagent as one
indicated it to be a “double” Heck product, probably
resulting via an eliminationÀHeckÀHeck domino reaction
(9) Kaneko, S.; Nakajima, N.; Katoh, T.; Terashima, S. Chem. Pharm.
Bull. 1997, 45, 43–47.
1148
Org. Lett., Vol. 14, No. 4, 2012

of the reactants and shows a broader substrate scope than
previously reported methods which involve Heck coupling
as one of the steps.
Supporting Information Available. General experimen-
tal procedure along with all the spectroscopic charac-
terization of new compounds is included. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. The authors are grateful for the finan-
cial support from Loker Hydrocarbon Research Institute
and University of Southern California.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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