Copper-Catalyzed Perfluoroalkylation of Alkynyl Bromides and Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.1c00906

A copper-catalyzed one-pot perfluoroalkylation of alkynyl bromides and terminal alkynes has been disclosed, and the corresponding perfluoroalkylated alkynes could be attained in good to excellent yields. The new straightforward transformation shows high efficiency (0.01-0.5 mol % catalyst loading), broad substrate scope, and remarkable functional group tolerance and provides a facile approach for useful application in life and material sciences.

Full text of DOI:10.1021/acs.orglett.1c00906

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Letter
Copper-Catalyzed Perfluoroalkylation of Alkynyl Bromides and
Terminal Alkynes
Shilu Fan,* Chenggong Zheng, Kaiting Zheng, Junlan Li, Yaomei Liu, Fangpei Yan, Hua Xiao,
Yi-Si Feng,* and Yuan-Yuan Zhu*
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ABSTRACT: A copper-catalyzed one-pot perfluoroalkylation of alkynyl bromides and terminal alkynes has been disclosed, and the
corresponding perfluoroalkylated alkynes could be attained in good to excellent yields. The new straightforward transformation
shows high efficiency (0.01−0.5 mol % catalyst loading), broad substrate scope, and remarkable functional group tolerance and
provides a facile approach for useful application in life and material sciences.
Scheme 1. Perfluoroalkylation of Terminal Alkynes and Its
Derivatives
erfluoroalkyl compounds have been the object of
increasing attention in the fields of pharmaceutical,
P
agrochemical, and material sciences since the incorporation
of perfluoroalkyl groups (RF) into organic molecules brings
significant changes in their physical, chemical, and biological
properties owing to the unique properties of the perfluoroalkyl
group.1,2 Consequently, C−RF bond formation has attracted
considerable research interest in recent years. In the past
decades, the rapid development of new perfluoroalkylation
methods has been witnessed after arduous efforts of organic
chemists. In comparison with the advances achieved in the
formation of C(sp3)−RF bonds and C(sp2)−RF bonds, the
construction of C(sp)−RF bonds by direct perfluoroalkylation
of terminal alkynes (C−H) or alkyne derivatives (C−X) is still
suffering from many limitations, notwithstanding the poten-
tially booming demand of perfluoroalkylated acetylenes.3 In
2010, Qing and co-workers reported a copper-mediated
oxidative trifluoromethylation of terminal alkynes with
nucleophilic trifluoromethylating reagent (TMSCF3),4 which
provided a new approach for C(sp)−CF3 bond formation
(Scheme 1a).5 Soon afterward, the copper-mediated direct
conversion of C(sp)−H bonds to C(sp)−CF3 bonds has also
6
been discovered by using CuCF3, Ph3P+CF2CO2 (PDFA),7
−
8
and PhSOCF3 as CF3 sources. Alkyne derivatives such as
(Scheme 1b). Unfortunately, the reported copper-catalyzed
pathways did not show a high efficiency, and 20−30 mol %
catalysts were required. In these cases, several kind of
copper alkynes,9 potassium alkynyltrifluoroborates,10 arylpro-
piolic acids,11 and TMS-protected alkynes12 were smoothly
employed in similar copper-mediated processes. Although the
above approaches are attractive, the copper-catalyzed methods
for preparation of perfluoroalkyl alkynes remain highly
desirable in view of the requirement of a stoichiometric
metal catalyst. To attain the goal, Qing, Huang, Weng, and Fu
and Guo described the copper-catalyzed trifluoromethylation
of terminal alkynes or potassium alkynyltrifluoroborates with
nucleophilic5 or electrophilic13 trifluoromethylating reagents
Received: March 16, 2021
Published: April 1, 2021
https://doi.org/10.1021/acs.orglett.1c00906
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3190−3194
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Letter
a
perfluoroalkyl reagents have been utilized for the synthesis of
alkynyl-RF compounds, and only CF3 sources are, however,
commercially available, which limits the incorporation of other
perfluoroalkyl substituent into organic molecule.
Table 1. Optimization of the Reaction Conditions
Perfluoroalkyl iodides (RFI) are commercially available,
inexpensive, low toxic, easily operated, and thereby, would be
the very appealing RF sources in the preparation of
perfluoroalkylated compounds. Whereas the formation of
alkyl−RF and alkenyl−RF bonds have been extensively studied
through radical addition reaction of alkenes14 and alkynes15
with perfluoroalkyl radicals, respectively, perfluoroalkylation
reactions for the construction of alkynyl−RF bonds by using
RFI are rather underdeveloped. Blancou described the earlier
addition−elimination process for perfluoroalkylation of termi-
nal propargyl alcohol.16 Cho and co-workers reported on the
visible-light photoredox-catalyzed perfluoroalkylation of termi-
nal alkynes17 and alkynyl bromides18 with RFI as the ultimate
RF source, in which several perfluoroalkylated arylacetylenes
were obtained in good to high yields (Scheme 1c). Very
recently, we accomplished a silver-mediated perfluoroalkyla-
tion reaction for C(sp)−RF bond formation, which showed a
good reactivity toward arylacetylenes.19 Notably, the available
studies paid more attention to reactions with aromatic alkynes
rather than those of aliphatic alkynes. Herein, we describe a
practical protocol of copper-catalyzed one-pot perfluoroalky-
lation of alkynyl bromides and terminal alkynes (Scheme 1d).
The distinct characteristics of this method are its high
efficiency, low catalyst loading (0.5 mol %), broad substrate
scope (both aromatic and aliphatic alkynes), outstanding
functional group tolerance, and applicability for large-scale
production.
b
entry
[Cu] (mol %)
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
CuI (10)
CuCN (10)
CuI (10)
CuI (10)
CuI (10)
CuI (0.5)
THF
100
100
100
100
100
100
100
100
100
100
80
60
40
80
80
80
80
(72)
88
(90)
40
47
23
(91)
(90)
(94)
72
(95)
(88)
(78)
(92)
(85)
(73)
ND
dioxane
toluene
DMSO
DMPU
DMF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
c
15
d
CuI (0.1)
CuI (0.01)
16
17
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 3 (1.0 equiv), solvent
b
(2 mL). NMR yield determined by 19F NMR using fluorobenzene as
an internal standard; the number in parentheses is the isolated yield.
With 0.1 mol % phen and 20 μL of DMF. With 0.01 mol % phen
and 20 μL of DMF. phen = 1,10-phenanthroline. ND = not detected.
c
d
Scheme 2. Alkynyl Bromide Scope in Copper-Catalyzed
a
Perfluoroalkylation Reaction
Our studies began with the perfluoroalkylation reaction for
the formation of 6a by using 1-(bromoethynyl)-4-propylben-
zene 1a and perfluoroalkylzinc reagent 320 as the model
substrates (Table 1). In our initial efforts, we found that
desired product 6a was produced in 72% isolated yield when
the reaction was conducted with 1a (0.2 mmol), 3 (1.0 equiv),
and Cu(acac)2 (10 mol %) in THF at 100 °C (Table 1, entry
1). The nature of solvents is the critical factor for the reaction
(Table 1, entries 2−6). When the polar solvents (such as
DMSO, DMPU, and DMF) were employed, the unsatisfactory
results were exhibited. Numerous copper(II) and copper(I)
salts in toluene at 100 °C were able to afford the desired
product 6a (Table 1, entries 7−10), with CuI serving as the
most effective catalyst with a yield of 94% (Table 1, entry 9).
The decrease of temperature (80 °C) was favorable to the
transformation (Table 1, entry 11). However, the yields
decreased with further decreasing temperature (Table 1,
entries 12 and 13). To our surprise, this reaction condition
showed a powerful catalytic efficiency at a low catalyst loading
of CuI (0.5 mol %) (Table 1, entry 14). Of particular interest,
no obvious impact on the reaction efficiency has been found by
decreasing the catalyst loading to 0.01 mol %, and a high yield
of 6a was still afforded (Table 1, entry 16). In addition, the
formation of desired product was not observed in the absence
of copper sources, which implies that the copper intermediate
plays a crucial role in the promotion of the reaction (Table 1,
entry 17).
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 3 (1.0 equiv), CuI
b
(0.5 mol %), toluene (2 mL), 80 °C, 12 h. This reaction was
operated under air.
by the robust catalytic system, and excellent yields were
realized under standard conditions (6a−g). The robust
reactivity was illustrated with an open air operated reaction.
To our delight, electron-deficiency alkynyl bromides could be
smoothly perfluoroalkylated to give the desired products (6h,
6i) in 73% and 90% yields, respectively. Additionally, reactions
with heteroaryl-substituted alkynyl bromides also gave the
corresponding products 6j and 6k in good yields. While
aliphatic alkynyl bromides were not suitable coupling partners
in the reported studies,17−19 our copper-catalyzed system
enables these substrates to be useful coupling partners, which
With the optimal conditions established, a variety of alkynyl
bromides were examined and a wide range of perfluorobuthyl
acetylene derivatives 6 were furnished in good to excellent
yields (Scheme 2). Substituted ethynylphenyl rings bearing
both electron-donating and phenyl groups were well tolerated
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Letter
a
offered the aliphatic perfluoroalkylated acetylenes in high
yields (6l−r).The presence of a wide range of functional
groups, such as ether, halides, alkoxycarbonyl, heteroaryl, silyl
ether, acetate, cyano, nitryl, phosphate, and sulfonyl, was
tolerated by the process. Moreover, the steady formation of 6h,
6n, and 6r in high yields with intact chloride, acetate, and p-
methylbenzenesulfonyl groups would facilitate further trans-
formations of the target molecules without protection/
deprotection processes.
Scheme 4. One-Pot Reaction
To demonstrate whether this method could be extended to
perfluoroalkylating reagents other than 3, we examined 2 and 4
as the perfluoroalkylator (Scheme 3). Generally, good to
Scheme 3. Perfluoroalkylzinc Reagents Scope in Copper-
a
Catalyzed Perfluoroalkylation Reaction
a
Method A: RFI (3.2 equiv) and Et2Zn (1.5 equiv) in toluene (2 mL)
were stirred at −41 to −5 °C for 4 h. Then 1 (0.2 mmol, 1.0 equiv)
and CuI (0.5 mol %) were added, and the reaction was run at 80 °C
for 12 h. Method B: terminal alkynes (0.2 mmol, 1.0 equiv),
AgNO3(0.1 equiv), and NBS (1.1 equiv) in toluene (4 mL) were
stirred at rt for 3 h. Then (DMPU)2Zn(RF)2 (1.0 equiv) and CuI (0.5
mol %) were added, and the reaction was run at 80 °C for 12 h.
b
Numbers in parentheses are yields from method B. Otherwise, yields
are from method A. NBS = N-bromosuccinimide.
Scheme 5. One-Pot Gram-Scale Reaction
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2, 4 (1.0 equiv), CuI
(0.5 mol %), toluene (2 mL), 80 °C, 12 h.
To further showcase the importance and utility of this
protocol, the late-stage perfluoroalkylation of biologically
active molecules was performed (Scheme 6). The perfluor-
excellent yields of desired products 5 and 7 were furnished
under the standard conditions, respectively. To our excitement,
substrates bearing functional groups which were employed
above all showed good tolerance to the reaction conditions.
Thienyl and pyridyl groups were compatible with the coupling
reaction, providing high yields (7j and 7k). We were glad to
find that the length of perfluoroalkyl chain does not impact
reaction efficiency evidently, which implies that transmetala-
tion is not the turnover-limiting step in the overall catalytic
cycle.20
Scheme 6. Late-Stage Perfluoroalkylation in Synthesis of
Biologically Active Molecules
In view of the above encouraging results, alkynyl bromides
and terminal alkynes were employed as starting materials to
check the Cu-catalyzed perfluoroalkylation reaction under a
one-pot strategy.21 As demonstrated in Scheme 4, we were
pleased to observe that the desired products were obtained
from both of the raw materials with high yields under these
one-step methods, even at the same low catalytic loading (0.5
mol %), which indicates that the strong practicability of the
process. The reaction of substituted phenylacetylene and
substituted alkynyl bromides all proceeded well and afforded
the perfluoroalkylated acetylenes in good yields. To our
delight, the heterocyclic substrates were shown acceptable
activity, furnishing the desired products in moderate to high
yields. At the same time, the terminal aliphatic alkynes and its
derivatives were also suitable with high efficiency in this
reaction system.
oalkylated estrone derivative 6s was obtained in excellent yield,
thus offering a facile access to perfluoroalkylated natural
product estrone derivatives, which are of great interest in the
life sciences. The treatment of menthol-based substrate 1t
afforded perfluoroalkylated compound 6t in excellent yield,
which further highlights the significance of this protocol.
To gain further insight into the perfluoroalkylation,
mechanism studies were conducted (see the Supporting
Information). When the stoichiometric CuI was subjected to
the treatment with 3 in toluene at 80 °C, a cuprates species
was produced (as determined by 19F NMR) and used as an RF
source for subsequent transformation. These experiments lend
strong credence for the proposed mechanism of trans-
metalation.
The desired product also could be accessed on gram-scale
with high efficiency through a one-pot process (Scheme 5).
For instance, 6a was generated in 89% yield under the one-pot
gram-scale operation. In respect to the advantages of RF−I, we
believe that perfluoroalkylation reactions will be prompted by
this process with RFI.
On the basis of these results and previous reports,20−22
a
plausible reaction mechanism involving a CuI/CuIII catalytic
cycle is proposed (Scheme 7). The reaction begins with the
transmetalation between perfluoroalkylzinc reagent 3 and
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Letter
Junlan Li − School of Chemistry and Chemical Engineering,
Hefei University of Technology, Anhui 230000, China
Yaomei Liu − School of Chemistry and Chemical Engineering,
Hefei University of Technology, Anhui 230000, China
Fangpei Yan − School of Chemistry and Chemical Engineering,
Hefei University of Technology, Anhui 230000, China
Hua Xiao − School of Food and Biological Engineering, Hefei
University of Technology, Anhui 230000, China
Scheme 7. Proposed Mechanism
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00906
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
[CuILn] (I) which may be generated through the in situ
formation. Subsequently, oxidative addition of alkynyl
bromides 1 with [(RF)mCuI]Ln (II) would provide the key
copper intermediate III, which undergoes a reductive
elimination to afford the desired product 6 and regenerate
the [CuILn] species simultaneously.
In summary, we have successfully established a one-pot
perfluoroalkylation reaction of alkynyl bromides and terminal
alkynes by using perfluoroalkyl iodides as an RF source through
an extremely low copper catalytic loading under mild reaction
conditions, providing practical access to RF-containing alkynes.
Furthermore, various functional groups were well tolerated in
the reaction affording the corresponding perfluoroalkylated
products in good to excellent yields. These reactions proceed
in good yields on both small and large scales.
■
This work was financially supported by the Fundamental
Research Funds for the Central Universities
(JZ2020HGTB0018 and PA2020GDSK0067), the National
Natural Science Foundation of China (Grant No. 21971050),
and the Start-up Foundation of Hefei University of
Technology. We are also grateful to Dr. Yanbo Yu for his
generous help in revising the manuscript..
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00906.
Experimental details, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Shilu Fan − School of Chemistry and Chemical Engineering,
Hefei University of Technology, Anhui 230000, China; Key
Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0003-0315-
7874; Email: shilu.fan@hfut.edu.cn
Yi-Si Feng − School of Chemistry and Chemical Engineering,
Hefei University of Technology, Anhui 230000, China;
orcid.org/0000-0002-1646-0955; Email: fengyisi@
hfut.edu.cn
Yuan-Yuan Zhu − School of Chemistry and Chemical
Engineering, Hefei University of Technology, Anhui 230000,
China; orcid.org/0000-0002-3142-0396;
Email: yyzhu@hfut.edu.cn
Authors
Chenggong Zheng − School of Chemistry and Chemical
Engineering, Hefei University of Technology, Anhui 230000,
China
Kaiting Zheng − School of Chemistry and Chemical
Engineering, Hefei University of Technology, Anhui 230000,
China
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