Direct heptafluoroisopropylation of arylboronic acids via hexafluoropropene (HFP)

Article abstract of DOI:10.1039/c5cc07616a

A novel and straightforward strategy for heptafluoroisopropylation of arylboronic acids at room temperature has been developed. This method, directly using commercial available hexafluoropropene (HFP) as the starting material, provides a new way to synthesize a variety of synthetically useful heptafluoroisopropylated arenes.

Full text of DOI:10.1039/c5cc07616a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Wu, Y. Li, X.
wang, Y. Guo, Z. Zhu and Y. gong, Chem. Commun., 2015, DOI: 10.1039/C5CC07616A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C5CC07616A
ChemComm
COMMUNICATION
Direct Heptafluoroisopropylation of Arylboronic Acids via
Hexafluoropropene (HFP)
Yajun Li,ab Xiaojun Wang,ac Yuwei Guo,ac Zhentong Zhu,ad Yongming Wu,*a Yuefa Gong*b
Received 00th January 2015,
Accepted 00th January 2015
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
novel
and
straightforward
strategy
for (Scheme 1). Several attempts for synthesizing of
O O
heptafluoroisopropylation of arylboronic acids at room
temperature has been developed. This method, directly using
commercial available hexafluoropropene (HFP) as the starting
material, provides a new way to a variety of synthetically useful
heptafluoroisopropylated arenes.
S
HN
N
O
N
I
NH
HN
CF3
F
O
O
CF3
F
N
CF3
CF3
O
Flubendiamide (A)
Pyrifluquinazon (B)
F
F
CF3
F3
C
CF3F3
C
Perfluoroalkylated arenes play a unique role in the field of
modern pharmaceuticals, agrochemicals and functional
materials.1 Among them, heptafluoroisopropylated arenes, in
F3C
F
CF3
F
H
N
O2S
SO2
F3C
CF3
O
NH
HN
Cl
CF3
F
CF3
spite
of
showing
better
performances
than
O
trifluoromethylated arene in some cases2, are still severely
Experimental insecticide (C)
Organocatalyst (D)
underexploited compared to their analogues. For instances,
2a
Flubendiamide (compound
A
)
and Pyrifluquinazon
2b
(compound
excellent activity against
compound C2c is
potential insecticide. Meanwhile,
B
)
are commercial available insecticides with
heptafluoroisopropylated arenes are repoeted. For instances,
Burton et al. realized the synthesis of heptafluoroisopropyl
copper(I) from heptafluoroisopropyl iodide with the assistance
of cadmium.6 But the copper species show no reactivity to
halogenated arenes. Hu’s group has described a method for
trifluoromethylation−iodinaꢀon of arynes promoted by
silver.7a However, the intermediate heptafluoroisopropyl silver
reagent decomposed when 1,10-phenanthroline was added as
a ligand, even before the difunctionalization of arynes.7b
a
broad-spectrum pests, and
a
heptafluoroisopropylated arenes can be applied to the
development of organocatalysts with better selectivity and
2d
yield (compound
D
)
and also have potential applications in
the field of liquid crystal2e.
Although many new methds for introducing triflromethyl
group onto organic molecules are reported in recent years,3
but the methods for heptafluoroisopropylation of organic
compounds are rarely reported. The traditional means for
introducing a heptafluoroisopropyl group (i-C3F7) onto an
aromatic ring rely on Sulfinatodehalogenation reaction4 and
Ullmann reaction5 using heptafluoroisopropyl iodide or
bromide, which is synthesized from hexafluoropropene (HFP)
Moreover,
described
by
Hirano
and
Uchiyama,
failed in
heptafluoroisopropyl
zinc
reagents
heptafluoroisopropylation of ortho-iodobenzoate.8 Grushin’s
group reported great successes in cupration of CF3H9 and
C2F5H10. But this method met its limitation when tried the
cupration of i-C3F7H, which might be used to synthesize
heptafluoroisopropylated arenes. There are only very few
other successful examples to heptafluoroisopropylated
arenes11-15. For examples, Ishikawa et al. described a method
to form heptafluoroisopropylated arenes under ultrasonic
irradiation condition from heptafluoroisopropylhalide.11 Chen
et al. reported a synthetic route to heptafluoroisopropylated
arenes via pre-prepared copper complexes from
heptafluoroisopropylhalide.12
This journal is © The Royal Society of Chemistry 2015
Chem. Commun., 2015, 00, 1-4 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C5CC07616A
COMMUNICATION
ChemComm
Despite
the
progress
in
the
synthesis
of based on 19F NMR spectroscopy, implying that the use of DMF
heptafluoroisopropylated arenes, the known methods suffer as a solvent is essential to this reaction (Table 1, entry 4). The
from the use of toxic heptafluoroisopropylhalide agents,
product yield could be further improved to 50% by the
removal of acetonitrile via evaporation before adding DMF
(Table 1,
Table 1 Condition Optimizationa
Entry
Condition Variation
Yieldb(%
)
Scheme 1 Synthesis of Heptafluoroisopropylated Arenes Derived from
Hexafluoropropene.
1
2
3
4
5
6
None
Addition of CuIc
0
Trace
Trace
25
Addition of CuIc and Phenc
Addition of DMFd and CuIc
narrow substrate scope, poor regioselectivity, and harsh
conditions. Therefore, it is urgent to develop new methods to
address these problems. Herein, we report the facile synthesis
of heptafluoroisopropylated arenes directly from inexpensive
Evaporation; Addition of DMFd and CuIc 50
Evaporation; Addition of DMFd and
[Cu(OTf)]2·PhHe
18
15
14
86
7
Evaporation; Addition of DMFd and
CuClc
and readily available hexafluoropropene,
agent.16
a fire fighting
8
Evaporation; Addition of DMFd and
Hexafluoropropene and other fluorinated olefins can react
with fluoride to form heptafluoroisopropyl carbanion
directly.1b,f-g This is the most convenient and economical way
to obtain heptafluoroisopropyl carbanion. Based on this
c
Cu(CH3CN)4BF4
Evaporation; Addition of DMFd and
CuOAcc
9
10
11
12
13
14
15
Evaporation; Addition of DMFd, CuOAcc 92
and 4Å MSf
unique reactivity, we consider developing
synthesize heptafluoroisopropylated arenes directly from
hexafluoropropene. However, the stability of
a method to
Evaporation; Addition of DMFd, CuOAcc 84g
and 4Å MSf
heptafluoroisopropyl carbanion reagent needs to be
considered, because most heptafluoroisopropyl–metal species
are very unstable, even at very low temperature.17 To the best
of our knowledge, only heptafluoroisopropyl silver17e and
heptafluoroisopropyl mercury17b have been reported with
Evaporation; Addition of DMFd, CuOAcc 74h
and 4Å MSf
Evaporation; Addition of DMFd, CuOAcc 77i
and 4Å MSf
Evaporation; Addition of DMFd, CuOAcj, Trace
TBAOAcc and 4Å MSf
relative
stability
from
the
reaction
between
hexafluoropropene and fluoride. A viable methodology will not
use highly toxic mercury reagent. Thus, we envisioned that the
heptafluoroisopropyl silver reagent would be a good choice for
the synthesis of heptafluoroisopropylated arenes.
Evaporation; Addition of DMFd, CuOAcc 0k
and 4Å MSf
The reaction was initiated with phenylboronic acid18, HFP
and silver fluoride (Table 1, for details please see Supporting
Information). Heptafluoroisopropyl silver reagent could be
easily obtained by nucleophilic addition of silver fluoride to
hexafluoropropene in acetonitrile and this reagent was
relatively stable at room temperature.17e Thus, after the
heptafluoroisopropyl silver reagent was generated in situ,
phenylboronic acid was added to the reaction mixture at room
temperature. But no heptafluoroisopropylbenzene was
observed (Table 1, entry 1). It should be noted that no
additional oxidant was used in this reaction because the silver
species formed in situ may play as oxidants.19 Trace amount of
expected product was observed when CuI was added (Table 1,
entry 2). This result indicated that the copper species might be
the crucial to the success of the reaction. The addition of 1,10-
Phen ligand however, didn’t improve the yield (Table 1, entry
3).7b To our delight, when DMF (2 mL) was added, the desired
heptafluoroisopropylated product was obtained in 25% yield
a
Reaction condition: at room temperature, 0.2 mmol of phenylboronic
b
acid was added to 2.0 equiv. of silver reagent in 4 ml of CH3CN. Yields
were based on 19F NMR with PhCF3 as an internal standard. c 1.0 equiv.
DMF (4 ml). 0.5 equiv. 50 mg. g The reaction was carried out at 0 oC.
The reaction was carried out at 35 oC. Phenylboronic acid was added
dropwise. j 0.2 equiv. k PhBpin was used instead of PhB(OH)2.
d
e
f
h
i
entry 5).20 Several other copper species were also screened,
such as [Cu(OTf)]2·PhH (Table 1, entry 6), CuCl (Table 1, entry
7), Cu(CH3CN)4BF4 (Table 1, entry 8), but none of them showed
better performances than CuI. Surprisingly, when CuOAc was
employed, the product yield was significantly improved to 86%
yield (Table 1, entry 9). The yield was further improved to 92%
when 4Å MS was used (Table 1, entry 10).21 It was found that
the reaction is favored at room temperature. When the
o
o
reaction temperature was switched to either 0 C or 35 C, a
slight drop of yield was observed (Table 1, entries 11 and 12).
2 | Chem. Commun., 2015, 00, 1-4
This journal is © The Royal Society of Chemistry 2015
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 5
View Article Online
DOI: 10.1039/C5CC07616A
ChemComm
COMMUNICATION
Furthermore, slow addition of phenylboronic acid resulted in a that is prone to oxidation was compatible with the reaction
descended yield (Table 1, entry 13).19d Trace amount of conditions (2g). Substrate with an ortho-methyl group could
product was detected when catalytic amount of copper was give the desired product with
used, even when DMF was used as the solvent (Table 1, entry presumably due to the steric effect
14). When phenylboronic acid pinacol ester was employed, vinylboronic acid could afford the desired product with a
instead of descended yield (2u). For heteroarylboronic acid substrates,
2v and indole 2w could give the
corresponding products in moderate
a
relatively low yield,
(
2t). Furthermore,
Scheme
2
Heptafluoroisopropylation of Various Arylboronic Acid benzothiophene
(
)
(
)
Derivatives.
yields, respectively. Substrate with a pyridine moiety only
offered a low yield of product 2x, probably due to the
coordination of the pyridine.
By our strategy, product 2y’, an important intermediate for
the synthesis of flubendiamide, could also be obtained in high
yield by heptafluoroisopropylation of arylboronic acid 1y and
successive deprotection of the Boc group (Eq 1). Furthermore,
substrate 1z derived from estrone could also be converted to
the heptafluoroisopropylated product with a moderate yield
(Eq 2).
To
demonstrate
the
practical utility of
this
heptafluoroisopropylation strategy, some enlarged reactions
for substrate 1r and 1y were conducted, the corresponding
products were obtained in satisfied yield (2r: 1.2 mmol, 232.8
mg, 74%; 6 mmol, 1.164g, 61%; 2y: 0.97 mmol, 244 mg, 69% ).
Preliminary studies have been conducted to elucidate the
reaction mechanism. The reaction promoted by copper species
might involve free radical pathways.23 Thus, a radical clock
phenylboronic acid, no heptafluoroisopropylated product was
detected (Table 1, entry 15).
substrate
(Scheme 3a).24 Only normal heptafluoroisopropylated product
was isolated and the cyclized product formed by radical
3 was employed as a probe for the mechanism
With the optimal reaction conditions in hand, the substrate
scope was then explored (Scheme 2). We were pleased to find
4
5
that
a
series of arylboronic acid derivatives were
pathway was not observed. The reaction proceeded smoothly
when TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was
added as a free radical scavenger (Scheme 3b).25 And no
heptafluoroisopropylated under this conditions. The
arylboronic acid derivatives bearing either electron-donating
or electron-withdrawing groups reacted smoothly to form the
corresponding heptafluoroisopropylated arenes in moderate
to good yields. Of note, the halides (2d and 2o) were survived
under the reaction conditions, which might be useful for
further manipulations. The carbonyl group likely reacts with
silver reagent directly to form heptafluoroisopropylated
alcohol.22 However, in this reaction the carbonyl functionalities
heptafluoroisopropylated compound
6 was detected. These
results suggest that a radical pathway may not be involved in
the reaction.
On the basis of these mechanism studies and reported
reference,26 a plausible reaction mechanism was proposed as
shown in Scheme 4. The reaction of HFP with AgF formed the
heptafluoroisopropylated silver species, which underwent
transmetalation to form the reactive heptafluoroisopropylated
could be tolerated, as indicated by the isolation of 2e and 2m
,
in good yields. Remarkably, reactions of substrates with
unprotected hydroxyl group afforded the desired products 2j
and 2k in acceptable yields, respectively. Notably, vinyl group
This journal is © The Royal Society of Chemistry 2015
Chem. Commun., 2015, 00, 1-4 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
View Article Online
DOI: 10.1039/C5CC07616A
COMMUNICATION
ChemComm
2012, 51, 8859; (e) O. Kazuo and Jpn. Kokai Tokkyo Koho, JP
2007308483, 2007.
L. L. Chu and F. L. Qing, Acc. Chem. Res., 2014, 47, 1513.
3
4
For review: W. Y. Huang and F. H. Wu, Isr. J. Chem., 1999, 39
,
167.
For selected reviews: (a) J. Hassan, M. Sevignon, C. Gozzi, E.
5
Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359; (b) F.
,
Monnier and M. Taillefer, Angew. Chem. Int. Ed., 2009, 48
6954; (c) C. Sambiagio, S. P. Marsden, A. J. Blacker and P. C.
Mcloughlin, Chem. Soc. Rev., 2014, 43, 3525; (d) V. C. R.
McLoughlin and J. Thrower, Tetrahedron, 1969, 25, 5921.
H. K. Nair and D. J. Burton, J. Fluorine Chem., 1992, 56, 341.
(a) Y. Zeng, L. Zhang, Y. Zhao, C. Ni, J. Zhao and J. Hu, J. Am.
Chem. Soc., 2013, 135, 2955; (b) Y. Zeng and J. Hu, Chem. -
Eur. J., 2014, 20, 6866.
Scheme 3 Preliminary Mechanistic Studies.
6
7
8
9
H. Kato, K. Hirano, D. Kurauchi, N. Toriumi and M. Uchiyama,
Chem. - Eur. J., 2015, 21, 3895.
A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz and
V. V. Grushin, J. Am. Chem. Soc., 2011, 133, 20901.
10 A. Lishchynskyi and V. V. Grushin, J. Am. Chem. Soc., 2013,
135, 12584.
11 T. Kitazume and N. Ishikawa, Chem. Lett., 1982, 137.
12 D. F. Jiang, C. Liu, Y. Guo, J. C. Xiao and Q. Y. Chen, Eur. J.
Org. Chem., 2014, 6303.
Scheme 4 Plausible Reaction Mechanism.
13 R. Loska and M. Mąkosza, J. Org. Chem., 2007, 72, 1354.
14 R. D. Chambers, W. K. Graya and S. R. Korn, Tetrahedron,
copper reagent (M
) and silver species.19 These silver species
1995, 51, 13167.
15 T. Umemoto and O. Mitano, Bull. Chem. Soc. Jpn., 1984, 57
might serve as oxidants in the following step. Then, oxidized by
silver species, copper reagent underwent transmetalation with
,
3361.
16 M. Robin, T. F. Rowland, J. Chien, J. Boggs, M. Cohn, V.
Hedrick and S. Brandstadter, US 6849194 B2, 2005.
arylboronic acid to form an intermediate
N. Finally, reductive
elimination released the heptafluoroisopropylated product.
17 (a) R. D. Chambers, W. K. R. Musgrave and J. Savory, J. Chem.
Soc., 1962, 1993; (b) W. T. Miller and M. B. Freedman, J. Am.
Chem. Soc., 1963, 85, 180; (c) P. E. Aldrich, E. G. Howard, W.
J. Linn, W. J. Middleton and W. H. Sharkey, J. Org. Chem.,
1963, 28, 184; (d) B. L. Dyatkin, S. R. Sterlin, B. I. Martynov, E.
I. Mysov and I. L. Knunyants, Tetrahedron, 1971, 27, 2843; (e)
In conclusion, we have developed
the first
heptafluoroisopropylation reaction of arylboronic acids
utilizing hexafluoropropene (HFP), a fire fighting and readily
available agent, directly. This reaction occurred at room
temperature and tolerated
a series of arylboronic acid
W. T. Miller and R. J. Burnard, J. Am. Chem. Soc., 1968, 90
,
derivatives bearing both electron-donating and electron-
withdrawing groups. Further investigations on the synthetic
application and the mechanism of this method are currently
ongoing in our laboratory.
7367; (f) B. L. Dyatkin, B. I. Martynov, L. G. Martynova, N. G.
Kizim, S. R. Sterlin, Z. A. Stumbrevichute and L. A. Fedorov, J.
Organomet. Chem., 1973, 57, 423; (g) H. Lange and D.
Naumann, J. Fluorine Chem., 1976, 26, 1; (h) H. K. Nair and D.
J. Burton, J. Fluorine Chem.
， 1992, 56, 341.
This work was supported by the National Basic Research
Program of China (2012CB821600) and the National Natural
Science Foundation of China (No. 21172239).
18 D. G.Hall, Boronic Acids: Preparation and Applications in
Organic Synthesis and Medicine, Wiley-VCH: Weinheim,
2005.
19 (a) K. S. L. Chan, H. Y. Fu and J. Q. Yu, J. Am. Chem. Soc.,
2015, 137, 2042; (b) B. Gao, Y. Zhao, C. Ni and J. Hu, Org.
Lett., 2014, 16, 102; (c) M. Bera, A. Modak, T. Patra, A. Maji
and D. Maiti, Org. Lett., 2014, 16, 5760; (d) Y. Ye, S. H. Lee
and M. S. Sanford, Org. Lett., 2011, 13, 5464; (e) D.
Shabashov and O. Daugulis, J. Org. Chem., 2007, 72, 7720; (f)
L. Chu and F. L. Qing, Org. Lett., 2010, 12, 5060.
20 (a) T. Liu, X. Shao, Y. Wu and Q. Shen, Angew. Chem. Int. Ed.,
2012, 51, 540; (b) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder,
J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890.
21 J. M. Stevens and D. W. C. MacMillan, J. Am. Chem. Soc.,
2013, 135, 11756.
22 (a) S. P. Kotun, J. D. O. Anderson and D. D. Des Marteau, J.
Org. Chem., 1992, 57, 1124; (b) T. Kitazume and N. Ishikawa,
Chem. Lett., 1981, 10, 1337.
23 (a) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem. Int.
Ed., 2013, 52, 8214; (b) A. N. Campbell and S. S. Stahl, Acc.
Chem. Res., 2012, 45, 851; (c) Y. Ye and M. S. Sanford, J. Am.
Chem. Soc., 2012, 134, 9034; (d) J. P. Snyder, Angew. Chem.
Int. Ed., 1995, 34, 80.
Notes and references
1
(a) R. E. Banks, Organofluorine chemicals and their industrial
applications, John Wiley & Sons: London, 1979; (b) P. Kirsch,
Modern Fluoroorganic Chemistry: Synthesis Reactivity,
Applications, Wiley-VCH, Weinheim, Germany, 2004; (c) K.
Müller, C. Faeh, F. Diederich, Science, 2007, 317, 1881; (d) V.
A. Petrov, Fluorinated Heterocyclic Compounds: Synthesis,
Chemistry and Applications, Wiley: Hoboken, NJ, 2009; (e) S.
Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem.
Soc. Rev., 2008, 37, 320; (f) Y. Macé and E. Magnier, Eur. J.
Org. Chem., 2012, 2479; (f) A. Hafner, N. Jung and S. Bräse,
Synthesis, 2014, 46, 1440; (g) A. Hafner, N. Jung and S. Bräse,
Synthesis, 2014, 46, 1448.
2
(a) M. Tohnishi, H. Nakao, T. Furuya, A. Seo, H. Kodama, K.
Tsubata, H. Fujioka, T. Hirooka and T. Nishimatsu, J. Pestic.
Sci., 2005, 30, 354; (b) M. Kimura, M. Morimoto, M. Uehara,
M. Watanabe and M. Yoshida, EP 1097932A1, 2001; (c) J.
Pierre, D. Patricia and L. William, WO 2007128410A1, 2007;
(d) J. Guin, C. Rabalakos and B. List, Angew. Chem. Int. Ed.,
24 (a) P. S. Fier and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134
10795; (b) X. Wang, Y. Xu, F. Mo, G. Ji., D. Qiu, J. Feng, Y. Ye,
,
4 | Chem. Commun., 2015, 00, 1-4
This journal is © The Royal Society of Chemistry 2015
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 5 of 5
View Article Online
DOI: 10.1039/C5CC07616A
ChemComm
COMMUNICATION
S. Zhang, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2013, 135
10330.
,
25 R. N. Loy and M. S. Sanford, Org. Lett., 2011, 13, 2548.
26 N. Nebra and V. V. Grushin, J. Am. Chem. Soc., 2014, 136
16998.
,
Graphical Abstract
ABSTRACT: A novel and straightforward strategy for heptafluoroisopropylation of arylboronic acids under mild
reaction condition has been developed, directly using hexafluoropropene (HFP), a fire fighting and readily
available agent. This method provides a new way to synthesize a variety of synthetically useful
heptafluoroisopropylated arenes. No extra oxidant was used in this reaction.
This journal is © The Royal Society of Chemistry 2015
Chem. Commun., 2015, 00, 1-4 | 5
Please do not adjust margins