Redox-Neutral Tetrafluoroethylation of Aryl Alkynes with 1,1,2,2-Tetrafluoroethane Sulfonic Acid Leading to α-Tetrafluoroethylated Acetophenones

Article abstract of DOI:10.1002/chem.202100137

The redox-neutral tetrafluoroethylation of alkynes with 1,1,2,2-tetrafluroroethanesulfonic acid (TFESA) and azobis(isobutyronitrile) (AIBN) proceeds via the formation of vinyl tetrafluoroethanesulfonates followed by a radical tetrafluoroethylation. Experimental and theoretical results support an intermolecular reaction.

Full text of DOI:10.1002/chem.202100137

Accepted Article
Accepted Article
Title: Redox-Neutral Tetrafluoroethylation of Aryl Alkynes with
1,1,2,2-Tetrafluoroethane Sulfonic Acid Leading to α-
Tetrafluoroethylated Acetophenones
Authors: Takuji Kawamoto, Kohki Noguchi, Ryotaro Takata, Rio
Sasaki, Hiroshi Matsubara, and Akio Kamimura
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To be cited as: Chem. Eur. J. 10.1002/chem.202100137
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Redox-Neutral Tetrafluoroethylation of Aryl Alkynes with 1,1,2,2-
Tetrafluoroethane Sulfonic Acid Leading to α-
Tetrafluoroethylated Acetophenones
Takuji Kawamoto, * Kohki Noguchi, Ryotaro Takata, [a] Rio Sasaki, [a] Hiroshi Matsubara, [b] and Akio
[
a]
[a]
Kamimura [a]
Dedicated to Professor Ilhyong Ryu in celebration of his 70th birthday.
[
a]
Dr. Takuji Kawamoto, Kohki Noguchi, Ryotaro Takata, Rio Sasaki, and Prof. Dr. Akio Kamimura
Department of Applied Chemistry
Yamaguchi University
Ube, Yamaguchi, 755-8611 (Japan)
E-mail: tak102@yamaguchi-u.ac.jp
[
b]
Prof. Dr. Hiroshi Matsubara
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
Sakai, Osaka, 599-8531 (Japan)
Supporting information for this article is given via a link at the end of the document.
Abstract: The redox-neutral tetrafluoroethylation of alkynes with
,1,2,2-tetrafluroroethanesulfonic acid (TFESA) and
azobis(isobutyronitrile) (AIBN) proceeds via the formation of vinyl
tetrafluoroethanesulfonates followed by radical
1
a
tetrafluoroethylation. Experimental and theoretical results support
an intermolecular reaction.
Introduction
Tetrafluoroethylated
compounds
are
common
among
pharmaceuticals, agrochemicals, and many organic materials
including liquid crystal displays, light-emitting diodes, and
conducting polymers.[ 1 ] 1,1,2,2-Tetrafluoroethanesulfonic acid
(
TFESA) is an attractive reagent to introduce tetrafluoroethyl
moieties due to the ease of preparation from tetrafluoroethylene
TFE), its ease of handling, and its low volatility.[2]
Scheme 1. Previous work on radical trifluoromethylation of vinyl triflates
(
We have recently reported the trifluoromethylation of vinyl
Even though syntheses of aryl-substituted vinyl triflates and their
triflates to give α-trifluoromethylated ketones in the presence of
analogues from alkynes with sulfonic acids[
7
]
are highly
B as a radical initiator (Scheme 1a).[
3,4]
Et
3
In this reaction, vinyl
promising and atom-economical methods, only few examples of
such approaches have been reported. For examples, Rioux has
triflates act both as source of trifluoromethyl radicals and as
radical acceptors.[
5 ]
As some vinyl triflates readily undergo
reported a Rh-catalyzed reaction of alkynes with sulfonic acids
hydrolysis to afford carbonyl compounds during column
chromatography on silica gel, we have also developed a simple
and efficient one-pot synthesis for the formation of α-
to afford vinyl sulfonate (Scheme 2a),[
8 ]
while Leporeꢀ has
reported a Zn(OTf)
2
-catalyzed synthesis of vinyl triflates from
alkynes and silyl triflates.[
9 ]
Very recently, Tummatorn has
trifluoromethylated
ketones
from
ketones
(Scheme 1b) via
with
O)[
6 ]
reported the chemoselective triflation of alkynes with TfOH in the
trifluoromethanesulfonic anhydride (Tf
2
presence of TMSN .[
10 ]
Here, we report the synthesis of α-
vinyl triflates.[
3a]
As triflate salts are formed during the formation
3
tetrafluoroethylated ketones from aryl alkynes[
11]
and TFESA
of vinyl triflates from ketones, only one CF
installed in the final products.
3 2
group of Tf O is
based on the simple addition of AIBN via vinyl tetrafluoroethane
sulfonate. We also report the one-pot synthesis of β-
tetrafluoroethyl alcohols from alkynes and TFESA (Scheme 2b).
1
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ethynylbenzene (1j), 4-ethynyltoluene (1k), 3-ethynyltoluene (1l),
and 4-ethynyl-1,1'-biphenyl (1m) afforded the corresponding
products in 72%, 78%, 90%, 83%, and 84% yield, respectively
(
2
entries 9, 10, and 12–14). Importantly, the use of 1.5 equiv of
a with 1-(tert-butyl)-4-ethynylbenzene (1j) furnished only trace
amounts of 4ja (entry 11).
Table 2 Substrate Scope [a]
entry
1
R =
3
Yield (%) [b]
90%
80%
64%
89%
96%
83%
89%
87%
72%
78%
0%
Scheme 2. Previous work and this work
1
2
3
1a
1b
1c
1d
1e
1f
4-CO
2
Me
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ja
Results and Discussion
4-COMe
4-CN
4-CF3
4-F
We chose methyl 4-ethynylbenzoate (1a) as a model substrate
for our initial investigation (Table 1). When a 1,2-dichloroethane
[c]
4
5
6
7
8
9
1
1
1
1
1
solution of 1a, HCF
AIBN) (0.2 equiv) was stirred at 80 °C for 4 h, the desired α-
tetrafluoroethylated ketone 4aa was obtained in 90% yield (entry
). Using trifluoromethanesulfonic acid (CF SO H) and
nonafluorobutanesulfonic acid (C SO H) furnished 4ab and
ac in 87% and quantitative yield (entries 2 and 3). The reaction
2 2 3
CF SO H (2a), and azobis(isobutyronitrile)
(
4-Cl
1
3
3
4
F
9
3
1g
1h
1i
4-Br
4
3-Cl
of 1a with methyl 2,2-difluoro-2-sulfoacetate (1d), which was
prepared from methyl 2,2-difluoro-2-(fluorosulfonyl)acetate and
formic acid,[12] gave the corresponding product 3ad in 31% yield
H
0
1j
4-t-Bu
4-t-Bu
4-Me
3-Me
4-Ph
3ja
(
entry 4).
1
2
3
4
1j
3ja
Table 1. Initial study[a]
1k
1l
3ka
3la
90%
83%
84%
1m
3ma
[
a] 1 (1–1.3 equiv), 2a (0.5 mmol), AIBN (0.2 equiv), CH
2 2
ClCH Cl (2 mL), 80
°C, 4 h. [b] Determined by 1H NMR spectroscopy using dibromomethane as
an internal standard. [c] 1 (0.52 mmol) and 2a (0.59 mmol, 1.14 equiv) were
used.
entry
2
3
Yield (%) [b]
90%
1
2
3
4
HCF
2
CF
H (2b)
CF CF
SO
2
SO
3
H (2a)
3aa
3ab
3ac
3ad
During purification via column chromatography on silica gel,
hydrolysis
acetophenones was observed. Thus, we examined the reduction
of the α-tetrafluoroethylated ketones with NaBH in one pot to
afford β-tetrafluoroethyl alcohols. The reduction proceeds
smoothly to give the corresponding products in moderate to
good yield (Table 3). Double-tetrafluoroethylation using 1,4-
diethynylbenzene (1n) was carried out successfully to afford 5na
in 51% yield (Scheme 3).
of
the
α-tetrafluoroethylated
ketones
to
3
CF SO
3
87%
3
CF CF
2
2
2
SO
H (2d) [c]
3
H (2c)
quant.
31%
4
MeOCOCF
2
3
[
a] 1 (1–1.3 equiv), 2a (0.5 mmol), AIBN (0.2 equiv), CH
2
ClCH
2
Cl (2 mL), 80
°C, 4 h. [b] Determined by 1H NMR spectroscopy using dibromomethane as
an internal standard. [c] Methyl 2,2-difluoro-2-sulfoacetate (1d) containing 2,2-
difluoro-2-sulfoacetatic acid and methanol (61:4:36) was used as the
substrate, see details in the supporting information.
Table 3. One-pot synthesis of β-tetrafluoroethylated alcohols [a]
Then, we investigated the tetrafluoroethylation of various aryl
2 2 3
alkynes with HCF CF SO H (2a) (Table 2). Substrates with
electron-withdrawing acetyl, cyano, or trifluoromethyl groups on
the benzene ring (1a–1d) gave the corresponding products in
good yield (entries 2–4). Para- or meta-halo-substituted ethynyl
benzene (1e–1h) afforded α-tetrafluoroethylated ketones 3ea–
3ha in 96%, 83%, 89%, and 87% yield, respectively (entries 5–
8). The reaction of ethylbenzene (1i), 1-(tert-butyl)-4-
2
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entry
1
R =
2
4
Yield (%) [b,c]
92% (74%)
92% (78%)
81% (68%)
62% (62%)
90% (69%) [e]
90% (84%) [e]
99% (70%)
79% (66%) [e]
85% (65%)
75% (57%) [e]
71% (64%)
76% (67%)
1
2
3
1a
1a
1a
1c
1d
1e
1f
4-CO
4-CO
4-CO
4-CN
2
2
2
Me
Me
Me
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
4aa
4ab
4ac
4ca
4da
4ea
4fa
4ga
4ha
4ia
4
5 [d]
4-CF
3
6
7
8
9
4-F
4-Cl
4-Br
3-Cl
H
Scheme 4. Chemoselective reactions
1g
1h
1i
To gain mechanistic insight into this transformation, we
performed the reaction in the presence of 2,2,6,6-tetramethyl-1-
piperidinyl oxyl (TEMPO) (Scheme 5). In the reaction with
TEMPO under standard conditions (Table 1, entry 1), the
formation of vinyl tetrafluoroethanesulfonate was disturbed.[
The generation of vinyl tetrafluoroethanesulfonate from 1a,
followed by treatment with AIBN and TEMPO, did not result in
the formation of tetrafluoroethylated product 3aa. This result
indicates that the transformation of the sulfonates to the
tetrafluoro products involves radical species.
10
11
12
13
14
1j
4-t-Bu
4-Me
3-Me
4-Ph
4ja
13]
1k
1l
4ka
4la
82% (72%)
88% (76%) e
1m
4ma
[
°
a] 1 (1–1.3 equiv), 2a (0.5 mmol), AIBN (0.2 equiv), CH
C, 4 h; then, NaBH
(2 equiv), MeOH (2 mL), rt, 30 min. [b] Determined by 1
NMR spectroscopy using dibromomethane as an internal standard. [c] The
yield of the product isolated after flash column chromatography on SiO is
2 2
ClCH Cl (2 mL), 80
4
H
2
given within parentheses. [d] 1 (0.50 mmol) and 2a (0.59 mmol, 1.17 equiv)
were used. [e] Calculated yields because small impurities could not be fully
removed.
Scheme 3. Double-tetrafluoroethylation using 1,4-diethynylbenzene (1n)
Subsequently,
we
examined
chemoselective
Scheme 5. Control experiments
tetrafluoroethylation reactions (Scheme 4). Subjecting
a
substrate that contains both terminal and internal alkynes to our
protocol resulted in the chemoselective reaction at terminal
alkyne. For example, the reaction of 1o and 2a in the presence
of AIBN followed by reduction furnished 4oa in 42% yield.
Furthermore, the reaction of alkyne 1p, which contains a ketone
group, with 2a and AIBN afforded tetrafluoroethylated ketone
Next, we examined
tetrafluoroethane sulfonate 3aa’ and vinyl triflate 3gb’ (Scheme
). When a 1,2-dichloroethane solution of 3aa’ and 3gb’ was
stirred for 4 h at 80 °C with AIBN, four products (4aa, 4ab, 4ga,
and 4gb) were obtained after reduction with NaBH , which
a crossover experiment using vinyl
6
4
3
2
pa. Treatment of 3pa with Tf O in the presence of a base and
indicates that ‘free tetrafluoroethyl (or trifluoromethyl) radicals’
are likely involved in the transformation. Specifically, this result
indicates that the transformation can be expected to proceed via
an intermolecular pathway.
AIBN followed by reduction gave tetrafluoroethylated-
trifluoromethylated alcohol 6 in 40% yield.
3
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-1
mol ). The intermediate then provides trifluoroacetophenone
with concomitant expulsion of a CF
3
SO
2
–
radical, which was also
1
calculated to be exothermic (~40 kJ mol ) with an energy barrier
-1
of 33.2 kJ mol . We also investigated a potential intramolecular
trifluoromethylation (Scheme 1-(b)). This pathway was also
predicted to be exothermic, albeit with a relatively large energy
–
1
barrier (~224 kJ mol ). This result indicates that the
trifluoromethylation is more likely to proceed via the
intermolecular pathway, which is supported by the results of the
crossover experiment.
Based on the experimental and theoretical evidence, we would
like to propose the plausible mechanism shown in Figure 1. The
thermal decomposition of AIBN generates isobutyronitrile radical
A. Subsequently, A adds to vinyl tetrafluoroethane sulfonate 3’,
which is generated in situ from the alkyne and the
Scheme 6. Crossover experiment
tetrafluoroethane sulfonic acid, to give radical B. Then, B
undergoes β-cleavage to afford 7[
15 ]
and tetrafluoroethane
sulfonyl radical C, which undergoes α-cleavage to generate
tetrafluoroethyl radical (initiation step). The generated
tetrafluoroethyl radical D adds to 3’ to furnish radical E, which
gives product 3 and C via β-cleavage, thus maintaining the
radical chain.
Subsequently, we conducted theoretical calculations in order to
examine whether the tetrafluoroethyl transfer is intermolecular or
intramolecular in nature (Scheme 7). In order to simplify the
calculations, we examined vinyl triflate as a model substrate. As
the BHandHLYP (BHLYP) functional works well for processes
involving radical species,[14] we used this method to calculate all
radical species. However, the obtained results suggested that all
species are highly spin-contaminated; therefore, we used the
restricted open-shell BHLYP method (ROBHandHLYP/aug-cc-
pVDZ//BHandHLYP/cc-pVDZ). The calculated reaction profile for
the intermolecular trifluoromethylation is summarized in Scheme
D
1-(a). The trifluoromethyl radical adds to the vinyl triflate to afford
a benzyl radical intermediate, which was calculated to be highly
–
1
exothermic (~185 kJ mol ) with a small energy barrier (11.8 kJ
4
Scheme 7. Theoretical calculations
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4
room temperature, methanol (2 mL) and NaBH (39.2 mg, 1.04
mmol) were added to the reaction mixture and stirring was
continued for 30 min at room temperature. Then, a saturated
4
aqueous NH Cl solution (10 mL) was added and the resulting
mixture was extracted with dichloromethane (3 x 5 mL). The
combined extracts were concentrated in vacuo, and the residue
was purified by flash column chromatography (silica gel,
hexane-EtOAc, 15:1, v/v) to afford 2a in 74% yield (101.9 mg,
0.36 mmol).
Acknowledgements
This work was partially supported by the Asahi Glass
Foundation, Yamaguchi University a JSPS Grant-in-Aid for
Young Scientists (B) (16K17869 and 18K14222), the Hattori
Hokokai Foundation, the Yamagin Regional Enterprise Support
Foundation, and the Tobe Maiki Scholarship Foundation.
Keywords: DFT calculations • radicals• reaction mechanisms •
synthetic methods • tetrafluoroethylation
Figure 1. Plausible reaction mechanism
[
1]
2]
J. Václavík, I. Klimánková, A. Budinská, P. Beier, Eur. J. Org. Chem.
018, 2018, 3554–3593.
2
[
a) M. A. Harmer, C. Junk, V. Rostovtsev, L. G. Carcani, J. Vickery, Z.
Schnepp, Green Chem. 2007, 9, 30–37; b) V. V. Rostovtsev, L. M.
Bryman, C. P. Junk, M. A. Harmer, L. G. Carcani, J. Org. Chem. 2008,
73, 711–714.
Conclusions
In conclusion, we have developed
a
redox-neutral
tetrafluoroethylation for aryl alkynes using tetrafluoroethane
sulfonic acid in the presence of AIBN as a radical initiator. The
reaction proceeds chemoselectively at the terminal aryl alkynes
[3]
a) T. Kawamoto, R. Sasaki, A. Kamimura, Angew. Chem. Int. Ed. 2017,
56, 1342–1345; Angew. Chem. 2017, 129, 1362–1365; b) T. Kawamoto,
R. Sasaki, A. Kamimura, H. Matsubara, J. Fluorine. Chem. 2019, 221,
6
6–69.
a) X. Su, H. Huang, Y. Yuan, Y. Li, Angew. Chem. Int. Ed. 2017, 56,
338–1341; Angew. Chem. 2017, 129, 1358–1361; b) S. Liu, J. Jie, J.
under preservation of internal aryl alkyne moieties.
A
[
4]
5]
mechanistic exploration using TEMPO, a crossover experiment,
and DFT calculations support the notion that this transformation
involves radical processes, and proceeds through an
intermolecular pathway. Further studies to investigate
multicomponent reactions based on the intermolecular trapping
of perfluoroalkyl radicals are currently in progress and will be
reported in due course.
1
Yu, X. Yang, Adv. Synth. Catal. 2018, 360, 267–271.
[
For recent work on vinyl triflates that act as radical acceptors, see: a) M.
Zheng, G. Li, H. Lu, Org. Lett. 2019, 21, 1216–1220; b) W. Dai, S. J.
Geib, D. P. Curran, J. Am. Chem. Soc. 2019, 141, 12355–12361.
[6]
For recent examples of trifluoromethylations using Tf
see: a) Y. Ouyang, X.-H. Xu, F.-L. Qing, Angew. Chem. Int. Ed. 2018,
7, 6926–6929; Angew. Chem. 2018, 130, 7042–7045; b) K. Lee, S.
Lee, N. Kim, S. Kim, S. Hong, Angew. Chem. Int. Ed. 2020, 59, 13379–
3384; Angew. Chem. 2020, 132, 13481–13486.
2
O with activators,
5
1
Experimental Section
[
7]
For synthetic examples of the formation of alkyl-substituted vinyl
triflates from alkyl substituted alkynes, see: a) P. J. Stang, R.
Summerville, J. Am. Chem. Soc. 1969, 91, 4600–4601; b) R. H.
Summerville, C. A. Senkler, P. V. R. Schleyer, T. E. Dueber, P. J.
Stang, J. Am. Chem. Soc. 1974, 96, 1100–1110; c) G. T. Crisp, A. G.
Meyer, Synthesis 1994, 667–668.
The following tetrafluoroethylation of an aryl alkyne with
tetrafluoroethane
sulfonic
acid
can
be
considered
representative: A solution of methyl 4-ethynylbenzoate (1a; 80.5
mg, 0.50 mmol) and AIBN (17.8 mg, 0.11 mmol) in 1,2-
dichloroethane (2 mL) was treated with tetrafluoroethane
sulfonic acid (87 mg, 0.48 mmol). The reaction mixture was
stirred for 4 h at 80 °C. After cooling to room temperature, the
reaction mixture was concentrated in vacuo. The yield was
[
8]
9]
a) Y. Yang, E. G. Moschetta, R. M. Rioux, ChemCatChem 2013, 5,
3
005–3013; b) Y. Yang, J. W. Chang, R. M. Rioux, J. Catal. 2018, 365,
3–54.
4
[
M. H. Al-huniti, S. D. Lepore, Org. Lett. 2014, 16, 4154–4157.
[10] J. Tummatorn, K. Punjajom, W. Rodphon, S. Ruengsangtongkul, N.
Chaisan, K. Lumyong, C. Thongsornkleeb, P. Nimnual, S. Ruchirawat,
Org. Lett. 2019, 21, 4694–4697.
1
determined by H NMR spectroscopy using dibromomethane as
an internal standard.
The following tetrafluoroethylation of an aryl alkyne with
tetrafluoroethane sulfonic acid followed by reduction using
[11] For synthetic examples of the formation of α-trifluoromethylated
ketones from aryl alkynes, see: a) A. Maji, A. Hazra, D. Maiti, Org. Lett.
2014, 16, 4524–4527; b) Y. R. Malpani, B. K. Biswas, H. S. Han, Y.-S.
NaBH
ethynylbenzoate (1a; 81.2 mg, 0.51 mmol) and AIBN (18.8 mg,
.11 mmol) in 1,2-dichloroethane (2 mL) was treated with
4
can be considered representative: A solution of methyl 4-
Jung, S. B. Han, Org. Lett. 2018, 20, 1693–1697.
[12] X.-J. Tang, C. S. Thomoson, W. R. Dolbier Jr., Org. Lett. 2014, 16,
0
4594–4597.
tetrafluoroethane sulfonic acid (89.6 mg, 0.49 mmol). The
reaction mixture was stirred for 4 h at 80 °C. After cooling to
5
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[
13] Acid disproportionation reaction of TEMPO with strong acids has been
reported, for details: V. A. Golubev, V. D. Sen, I. V. Kulyk, A. L.
Aleksandrov, Russ Chem Bull 1975, 24, 2119–2126.
[14] H. Matsubara, T. Kawamoto, T. Fukuyama, I. Ryu, Chem. Lett. 2018,
47, 1197–1199.
[15] Trace amounts of 7 were observed in the crude mixture.
6
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Insert text for Table of Contents here.
A simple and efficient radical tetrafluoroethylation was developed that generates α-tetrafluoroethylated ketones from aryl alkynes and
1,1,2,2-tetrafluoroethane sulfonic acid (TFESA) with AIBN. The reaction proceeds via the formation of vinyl
tetrafluoroethanesulfonates followed by a radical tetrafluoroethylation.
7
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