Simple synthesis of β-trifluoromethylstyrenes using (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane

Article abstract of DOI:10.1021/ol300670n

(E)-Trimethyl-(3,3,3-trifluoroprop-1-enyl)silane (1) was synthesized as a reagent for use in Hiyama cross-coupling reactions for the production of β-trifluoromethylstyrene derivatives. Cross-coupling of 1 with electronically diverse aryl iodides was achieved by treatment with CsF in the presence of catalytic amounts of palladium to afford the desired products in moderate to good yields.

Full text of DOI:10.1021/ol300670n

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2286–2289
Simple Synthesis of
β-Trifluoromethylstyrenes Using
(E)-Trimethyl-(3,3,3-trifluoroprop-1-
enyl)silane
Masaaki Omote, Miyuu Tanaka, Akari Ikeda, Shiho Nomura, Atsushi Tarui,
Kazuyuki Sato, and Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho,
Hirakata 573À0101, Japan
aando@pharm.setsunan.ac.jp
Received March 21, 2012
ABSTRACT
(E)-Trimethyl-(3,3,3-trifluoroprop-1-enyl)silane (1) was synthesized as a reagent for use in Hiyama cross-coupling reactions for the production of
β-trifluoromethylstyrene derivatives. Cross-coupling of 1 with electronically diverse aryl iodides was achieved by treatment with CsF in the
presence of catalytic amounts of palladium to afford the desired products in moderate to good yields.
Trifluoromethylation of materials such as pharmaceu-
ticals, agricultural chemicals, and functional materials
significantly improves their performances in most cases.1
This is exemplified by the fact that more than 150 fluori-
nated drugs have come on the market in the past 50 years
and now account for about 20% of all pharmaceuticals.2
The trifluoromethylation of carbonyl groups and aryl
halides has been intensively investigated. Excellent prog-
ress has been made in the catalytic trifluoromethylation of
aryl halides and is now a well-established research area.3
Although much success has been achieved with regard
to trifluoromethylation, there are still few reactions for
constructing 3,3,3-trifluoropropynylorpropenylsubstruc-
tures, despite the robust methodology involving three-
carbon-elongation reactions. There have been some re-
ports of 3,3,3-trifluoropropynylation using 2-bromo-3,3,
3-trifluoropropene4,5 and 1,1,1,3,3-pentafluoropropane6 as
three-carbon building blocks. They can be converted in situ
into (3,3,3-trifluoropropynyl)lithium which can add to car-
bonyl compounds or couple with aryl halides through a zinc
intermediate. Despite the commercial availability of these
materials for three-carbon building blocks, the widespread
application of such processes, especially in industry, has
been hindered by the low boiling points of the materials,
(1) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224–228.
(2) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320–330.
(3) (a) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.;
Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901–20913. (b)
Tomashenko, O. A.; Escudero-Adan, E. C.; Martinez Belmonte, M.;
Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655–7659. (c) Samant,
B. S.; Kabalka, G. W. Chem. Commun. 2011, 47, 7236–7238. (d) Kondo,
H.; Oishi, M.; Fujikawa, K.; Amii, H. Adv. Synth. Catal. 2011, 353,
1247–1252. (e) Weng, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang, W.; Feng,
X.; Huang, K.-W. Organometallics 2011, 30, 3229–3232. (f) Morimoto,
H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 3793–3798. (g) Knauber, T.; Arikan, F.; Roeschenthaler,
G.-V.; Goossen, L. J. Chem.;Eur. J. 2011, 17, 2689–2697. (h) Cho,
E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald,
S. L. Science 2010, 328, 1679–1681. (i) Chu, L.; Qing, F.-L. Org. Lett.
2010, 12, 5060–5063. (j) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun.
2009, 1909–1911. (k) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am.
Chem. Soc. 2008, 130, 8600–8601. (l) Prakash, G. K. S.; Hu, J.; Olah,
G. A. Org. Lett. 2003, 5, 3253–3256. (m) Kobayashi, Y.; Kumadaki, I.;
Sato, S.; Hara, N.; Chikami, E. Chem. Pharm. Bull. 1970, 18, 2334–2339.
(n) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 47, 4095–4096.
(4) For addition to carbonyl group: (a) Mizutani, K.; Yamazaki, T.;
Kitazume, T. J. Chem. Soc., Chem. Commun. 1995, 51–52. (b) Yamazaki,
T.; Mizutani, K.; Kitazume, T. J. Org. Chem. 1995, 60, 6046–6056.
(5) For cross-coupling reaction with aryl halide: Konno, T.; Chae, J.;
Kanda, M.; Nagai, G.; Tamura, K.; Ishihara, T.; Yamanaka, H.
Tetrahedron 2003, 59, 7571–7580.
(6) (a) Brisdon, A. K.; Crossley, I. R.; Pritchard, R. G.; Sadiq, G.;
Warren, J. E. Organometallics 2003, 22, 5534–5542. (b) Brisdon, A. K.;
Crossley, I. R. Chem. Commun. 2002, 20, 2420–2421.
r
10.1021/ol300670n
Published on Web 04/18/2012
2012 American Chemical Society

making them difficult to handle, in addition to their cost and
the need to use excess alkyllithium in preparing 3,3,3-
trifluoropropynyllithium. On the other hand, there have
been very few reports on 3,3,3-trifluoropropenylation of
aryl halides leading to β-trifluoromethylstyrenes, which
have been used for organic light-emitting diodes and other
materials chemistry applications. In 1981, Fuchikami et al.
reported the synthesis of β-trifluoromethylstyrenes using
palladium-catalyzed cross-coupling reactions of 3,3,3-tri-
fluoropropene with aromatic halides.7 However, the use of
gaseous 3,3,3-trifluoropropene requires the use of an auto-
clave for the reaction, and the substrate scope is limited.
Very recently, Prakash et al. reported the synthesis of
β-trifluoromethylstyrenes through a Heck coupling reaction
of aryl iodides with 1-iodo-3,3,3-trifluoropropane.8 The
reaction has advantages that include 1-iodo-3,3,3-trifluoro-
propane is a liquid at room temperature and the substrate
scope is not limited. Unfortunately, the reaction requires a
microwave reactor capable of maintaining a temperature of
200 °C under microwave irradiation. We therefore focused
on the development of a simple protocol for the introduc-
tion of a 3,3,3-trifluoropropenyl unit into an aryl halide.
steps and applicability to gram-scale syntheses. In terms of
physical propensities, 1 is volatile to some extent but is a
manageable liquid at atmospheric pressure and suitable for
long-term storage in a sealed flask under refrigeration.
Scheme 1. Synthesis of 1
Table 1. Investigation of Reaction Conditions Suitable for
Hiyama Cross-Coupling Reaction of 1 with p-Iodoanisole
catalyst
(mol %)
F anion
(equiv)
time 6a yield
entry
solvent (h)
(%)a,b
1
Cu (120)c
CsF (2)
DMF
DMF
DMF
THF
DMF
DMF
DMA
DMF
4
À
31
À
Figure 1. Structure of key molecule (1) for 3,3,3-trifluoroprope-
nylation in Hiyama cross-coupling reaction.
2
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(dppe)2 (5)
Pd(dppe)2 (5)
Pd(dppe)2 (3)
CsF (2)
CsF (2)
CsF (2)
CsF (4)
CsF (2)
CsF (2)
CsF (2)
2
3d
4e
5f
6
2
4
À
We chose trimethyl-(3,3,3-trifluoroprop-1-enyl)silane
(1) as the building block for 3,3,3-trifluoropropenylation
ofarylhalides(Figure1). Ithas the advantageof being easy
to handle, and it is applicable to Hiyama cross-coupling
reactions. To our knowledge, there have been no reports of
practical large-scale preparations of 1, although there have
been a few reports of inefficient syntheses or its formation
as a side product.9 The aim of our study was to establish a
synthetic strategy for the production of 1. In the strategy,
which is shown in Scheme 1, a trifluoromethyl unit was
supplied with trifluoroacetaldehyde generated from tri-
fluoroacetaldehyde ethyl hemiacetal and sulfuric acid.
The key intermediate 3, which contains the backbone of
1, was constructed in the first reaction. The subsequent
reactions, mesylation of 3 followed by elimination, afforded
1, but isolation of 1 from the reaction mixture was difficult
because of the somewhat high volatility of 1. This problem
was circumvented by conducting the reaction without any
solvent, and consecutive distillations of the crude mixture
gave 1 as a pure liquid. This protocol has advantages that
include a high chemical yield of 1 (74%) achieved over three
3
40
92
26
92
(85)
98
(86)
50
3.5
3.5
5
7
8
9
Pd2(dba)3 (1.5)/ CsF (2)
P(mesityl)3 (15)
DMF
DMF
DMF
DMF
DMF
DMF
THF
THF
3.5
2
10
11
12
13
14
Pd2(dba)3 (1.5)/ CsF (2)
Xantphos (9)
Pd2(dba)3 (1.5)/ KF(2)
P(mesityl)3 (15)
2
23
21
21
41
À
Pd2(dba)3 (1.5)/ KF (2)/
P(mesityl)3 (15) BnBu3NCI (1)
Pd2(dba)3 (1.5)/ TBAF (2)
P(mesityl)3 (15)
14
24
2
Pd2(dba)3 (1.5)/ TASF (2)
P(mesityl)3 (15)
15g Pd2(dba)3 (1.5)/ TASF (2)
P(mesityl)3 (15)
16e
2
Pd2(dba)3 (1.5)/ TASF (2)
P(mesityl)3 (15)
2
7
a NMR yields, which were calculated by 19F NMR integration of
products 6 relative to the internal standard of ethyl 2,2,2-trifluoroacetate.
b The values in parentheses indicate the isolated yields of 6. c 1,10-Phenan-
throline was added for a ligand of Cu. d The reaction was conducted at 40 °C.
e ThereactionwasconductedinrefluxingTHF.f 4equivof1were used. g The
reaction was conducted at rt.
(7) Fuchikami, T.; Yatabe, M.; Ojima, I. Synthesis 1981, 365–366.
(8) Prakash, G. K. S.; Krishnan, H. S.; Jog, P. V.; Iyer, A. P.; Olah,
G. A. Org. Lett. 2012, 14, 1146–1149.
(9) (a) Chae, J.; Konno, T.; Kanda, M.; Ishihara, T.; Yamanaka, H.
J. Fluorine Chem. 2003, 120, 185–193. (b) Ojima, I.; Fuchikami, T.;
Yatabe, M. J. Organomet. Chem. 1984, 260, 335–346. (c) Haszeldine,
R. N.; Pool, C. R.; Tipping, A. E. J. Chem. Soc., Perkin Trans. 1 1974, 20,
2293–2296.
The chemical reactivity of 1 was investigated using a
transition-metal-catalyzed Hiyama cross-coupling with
Org. Lett., Vol. 14, No. 9, 2012
2287

yield (entry 2). Notably, lowering the temperature from 80
to 40 °C hindered the reaction, and desilylation seemed to
be difficult or seriously retarded (entry 3). The solvent also
significantly influenced the reactivity, and the reaction did
not proceed in THF (entry 4). Increasing the amount of
CsF to 4 equiv with respect to 1 did not result in a large
increase in yield, increasing it from 31% to 40% (entries 2
and 5). The use of palladium with a bidentate ligand, dppe,
improved the yield dramatically, to 92%. We assumed that
the cis-oriented ligand would accelerate the reductive
elimination of the palladium(II) intermediate to generate
a newCÀC bondon6, enabling thepalladium(0) dosage to
be reduced from 5% to 3% (entries 6 and 8).
Table 2. Reaction Scope under Optimal Conditions
The optimal yield was obtained using a palladium
catalyst with a bulky ligand, trimesitylphosphine, afford-
ing 6 in 98% yield (entry 9). We expected xantphos to be an
excellent ligand becauseitisbidentateand bulky, butuseof
this ligand reduced the yield of 6 to 50% (entry 10). These
results suggest that the performance of the palladium
catalyst governed the reaction to a considerable extent
and that the bulky trimesitylphosphine ligand is the opti-
mal ligand for this reaction. A reaction temperature of
around 80 °C is also crucial for desilylation, to generate a
vinyl anion species. Other fluoride sources, KF, TBAF,
and TASF, were also assessed for the reaction. Under the
optimal conditions, the use of KF in the reaction consider-
ably decreased the yield of 6, to 23% (entry 11). In situ
generated tetraalkylammonium fluoride from KF and
corresponding ammonium chloride was not suitable for
the reaction (entry 12).11 TBAF and TASF were not good
fluoride sources either, although the production of nucleo-
philic naked fluoride ions was enabled due to distinctive
features (entries 13À16).
In terms of the Hiyama cross-coupling reactions, alke-
nyltrialkylsilanes are unreactive in the alkenylation of aryl
halides under the usual reaction conditions because they
are not inherently electrophilic to become the silicate(V or
VI) unless the more nucleophilic TASF must be used.
Alkenylsilanes susceptible to nucleophilic attack, such as
alkenylsiloxanes,12 alkenylsilacyclobutanes,13 or alkenyl-
silanols,14 are thereforeusedasthe alkenylation reagent. In
contrast, 1 participates in Hiyama cross-couplingreactions
under mild conditions, although 1 contains trimethylsi-
lane. We assumed that the inductive effect of the electron-
withdrawing trifluoromethyl group would cause 1 to be
sufficiently electrophilic for silicate formation.
Once we had obtained the optimal reaction conditions,
we explored the scope of the reaction. Various aryl iodides,
a NMR yields, which were calculated by 19F NMR integration of
products 6 relative to the internal standard of ethyl 2,2,2-trifluoroace-
tate. b The values in parentheses indicate the isolated yields of 6.
(11) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918–920.
(b) Hiyama, T. J. Organomet. Chem. 2002, 653, 58–61. (c) Hiyama, T.;
Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471–1478.
(12) Marciniec, B.; Majchrzak, M.; Prukala, W.; Kubicki, M.;
Chadyniak, D. J. Org. Chem. 2005, 70, 8550–8555. (b) Alacid, E.;
Najera, C. Adv. Synth. Catal. 2006, 348, 2085–2091. (c) Denmark,
S. E.; Butler, C. R. Org. Lett. 2006, 8, 63–66. (d) Riggleman, S.;
DeShong, P. J. Org. Chem. 2003, 68, 8106–8109.
(13) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821–
5822.
(14) (a) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123,
6439–6440. (b) Denmark, S. E.; Sweis, R. F. Org. Lett. 2002, 4, 3771–
3774.
4-iodoanisole.10 The reaction did not take place using a
stoichiometric amount of Cu powder ligated with 1,10-
Phen in the presence of CsF to dissociate the SiÀCsp2 bond
(entry 1, Table 1). A catalytic amount of palladium(0)
resulted in a reaction affording coupling product 6 in low
(10) Jeffery, T. Tetrahedron Lett. 1999, 40, 1673–1676.
2288
Org. Lett., Vol. 14, No. 9, 2012

listed in Table 2, were used in the reaction. 4-Isopropylio-
dobenzene and 1-iodonaphthalene both participated in the
reaction to afford the products in good yields (entries 1 and 2).
4-Phenyliodobenzene and 4-benzyloxyiodobenzene retarded
the reaction, producing 6d and 6e, respectively, in moder-
ate yields (entries 3 and 4). Although 4-iodothioanisole
tolerated the reaction conditions, the reaction time had to
be extended to obtain 6f in moderate yield (entry 5). The
reactivity of 3-iodo-9-phenylcarbazole 5g was almost the
same as that of 4-iodoanisole, producing a good yield of 6g
in a short reaction time (entry 6). Substrates 5h and 5i, with
ortho alkoxy substituents, could also be used in the reac-
tion, although the reaction time was longer as a result of
steric hindrance around the reaction site. In the case of
substrates with an electron-withdrawing group, the yields
were suppressed even with prolonged reaction times.
4-Ethoxycarbonyl-substituted iodobenzene 5j was con-
verted to 6j in acceptable yields. N-Boc-protected aniline
derivatives did not participate in the reaction, and strongly
electron-withdrawing nitro substituents also hindered the
reaction. To investigate the compatibility of aryl bromides
with the reaction, 4-bromoanisole was used as the substrate.
The reaction was unsuccessful and resulted in only the low
conversion of 5m to 6a (entry 12).
In summary, we synthesized 1 for use in a new strategy
for easy access to β-trifluoromethylstyrene derivatives via
Hiyama cross-coupling reactions with aryl iodides. The
synthetic protocol required commercially available materials,
gave good yields (74% over three steps), and was applicable
to gram-scale syntheses. In particular, 1 participated
in Hiyama cross-coupling reactions with aryl iodide in the
presence of CsF, without the need for any special equipment.
Palladium ligated with the bulky trimesitylphosphine ligand
catalyzed the reaction effectively, producing a variety of
β-trifluoromethylstyrenes. Further refinement of the reaction
conditions to make the reaction compatible with substrates
with electron-withdrawing substituents is now underway.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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