Copper(I)-Catalyzed Cyanoperfluoroalkylation of Alkynes

Article abstract of DOI:10.1021/acs.orglett.9b02648

A highly chemoselective and regioselective copper-catalyzed radical cyanoperfluoroalkylation of alkynes is described. This three-component reaction directly uses commercially available alkynes, perfluoroalkyl iodides, and trimethylsilyl cyanide as the reaction partners and delivers a variety of perfluoroalkylated cyanoalkenes in good yields. Broad substrate scope and good functional group tolerance are observed. The perfluoroalkylated cyanoalkenes that are produced can be readily transformed into useful fluoroalkylated derivatives.

Full text of DOI:10.1021/acs.orglett.9b02648

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(I)-Catalyzed Cyanoperfluoroalkylation of Alkynes
Muhammad Israr,†,‡ Haigen Xiong,†,‡ Yajun Li,† and Hongli Bao*,†,‡
†State Key Laboratory of Structural Chemistry, Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for
Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of Matter, University of Chinese Academy of
Sciences, 155 Yangqiao Road West, Fuzhou, Fujian 350002, People’s Republic of China
‡University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
S
* Supporting Information
ABSTRACT: A highly chemoselective and regioselective copper-
catalyzed radical cyanoperfluoroalkylation of alkynes is described.
This three-component reaction directly uses commercially available
alkynes, perfluoroalkyl iodides, and trimethylsilyl cyanide as the
reaction partners and delivers a variety of perfluoroalkylated
cyanoalkenes in good yields. Broad substrate scope and good
functional group tolerance are observed. The perfluoroalkylated
cyanoalkenes that are produced can be readily transformed into useful fluoroalkylated derivatives.
Scheme 1. Perfluoroalkylative Difunctionalization of
Alkynes with Perfluoroalkyl Iodides
ecause of the special properties of organofluorine
1
Bcompounds,
the efficient introduction of fluoroalkyl
moieties into generally used chemical building blocks has
increasingly attracted the attention of chemists. Fluoroalky-
lated compounds are commonly used in medicinal chemistry,
agrochemistry, and materials science.2,3 To date, substantial
efforts have been made to synthesize fluoroalkylated aromatic
molecules.4 Efficient approaches to fluoroalkylated alkenes are,
however, less developed, presumably due to the lack of general
and catalytic strategies. Commonly, fluoroalkylated alkenes can
be achieved through Heck-type fluoroalkylation of alkenes5 or
cross-coupling of prefunctionalized fluoroalkyl species with
alkenyl halides,6 but such processes can principally only
introduce fluoroalkyl groups into the target molecules. In
contrast, fluoroalkylative difunctionalization of alkynes pos-
sesses the fascinating capability to introduce both a fluoroalkyl
group and an additional functionality, forming functionalized
fluoroalkylated alkenes in a step-economic strategy.
In recent years, together with the progress on hydro-,7 oxy-,8
carbo-,8d,9 or aminotrifluoromethylation10 of alkynes with
Togni or Umemoto reagents or others, several catalytic
approaches for the synthesis of fluoroalkylated alkenes via an
alkyne difunctionalization process have been explored.11 In
2014, Hu et al. reported an iron-catalyzed atom-transfer radical
addition (ATRA) reaction of alkynes with perfluoroalkyl
iodides to afford β-fluoroalkyl vinyl iodides (Scheme 1a).
These products are highly reactive and can be easily converted
into other functionalized fluoroalkyl-containing motifs.12
Subsequently, Nevado et al. and Liang et al. independently
established excellent methods for the synthesis of fluoroalky-
lated alkenes through palladium-catalyzed three-component
reactions with alkynes, perfluoroalkyl iodides or ethyl
difluoroiodoacetate, and arylboronic acids (Scheme 1b).13,14
Taking advantage of the palladium catalysis with fluoroalkyl
iodides, the Wu group disclosed an interesting procedure for
the synthesis of perfluoroalkylated enynes from perfluoroalkyl
iodides and alkynes (Scheme 1c).15 In addition, cyanodi-
fluoroalkylation of alkynes was explored. This reaction occurs
in the presence of a stoichiometric amount of copper powder
with only ethyl difluoroiodoacetate as the difluoroalkyl
source.16 Although some progress has been achieved, however,
methods for perfluoroalkylative difunctionalization of alkynes
are still limited. Recently, we reported an iron-catalyzed radical
Received: July 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02648
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
relay process for the carboazidation of alkenes and alkynes with
fluoroalkyl iodides17 as the fluoroalkyl source. With our
interest in radical difunctionalization of alkenes as well as
alkynes,18 we were eager to explore the possibility of the
fluoroalkylative difunctionalization of alkynes. Herein, we
report a copper-catalyzed cyanoperfluoroalkylation of alkynes
(Scheme 1d), providing facile and general access to a wide
range of fluoroalkylated cyanoalkenes.
Our investigation started with phenylacetylene (1a, 1 equiv),
C4F9I (2a, 2 equiv), and TMSCN (3a, 2 equiv) as model
substrates, lauroyl peroxide (LPO, 4a, 2 equiv) as the radical
initiator, anhydrous MeOH as the solvent, CuTc (copper
thiophene carboxylate, 10 mol %) as the catalyst, and L1 (20
mol %) as the ligand (Table 1). In a preliminary experiment,
solvents, temperature, and loadings of reagent and reactant
were then screened (see Tables S1−S6 for details). First, a
variety of copper salts and also copper powder were tested
(Table 1, entries 2−9). Cu(I) salts, Cu(II) salts, and copper
powder produced 5a and 5a′ with similar selectivity, and
Cu(CH3CN)4BF4 offered the best result, forming 5a in 80%
NMR yield and 5a′ in only 8% NMR yield (Table 1, entry 5).
Examination of ligands L2−L6 (Table 1, entries 10−14) and
changing the solvent (Table 1, entries 15−18) failed to show
any improvement in the selectivity and the yield of 5a. Without
metal catalyst or ligand, both the desired product 5a and
ARTA product 5a′ were almost not formed (Table 1, entries
19 and 20). After considerable effort, the competitive
chemoselectivity between 5a and 5a′ was limited, and only a
small amount of the ATRA side product 5a′ was formed when
using Cu(CH3CN)4BF4 as the catalyst and L1 as the ligand
(Table 1, entry 5).
a
Table 1. Reaction Condition Optimization
With the established procedure in hand, the scope of alkynes
in their cyanoperfluoroalkylation was investigated. As
described in Scheme 2, a series of terminal phenylacetylenes
a,b
Scheme 2. Substrate Scope of Alkynes
b
entry
catalyst
CuTc
CuBr
ligand
solvent
yield (%) of 5a/5a′
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
-
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CH3CN
THF
75/14
68/15
68/19
74/17
CuI
Cu(CH3CN)4PF6
Cu(CH3CN)4BF4
CuBr2
CuCl2
Cu(OAc)2
c
80(76) /8
67/24
66/22
68/18
68/22
42/18
65/29
39/22
64/30
57/33
58/21
61/24
14/59
62/31
9
Cu powder
10
11
12
13
14
15
16
17
18
19
20
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
EtOH
MeOH
MeOH
Cu(CH3CN)4BF4
trace
a
Reaction conditions: 1 (0.3 mmol, 1 equiv), 2a (2 equiv), 3a (2
equiv), 4a (2 equiv), Cu(CH3CN)4BF4 (10 mol %), L1 (20 mol %),
a
Reaction conditions: 1a (0.3 mmol, 1 equiv), 2a (2 equiv), 3a (2
equiv), 4a (2 equiv), catalyst (10 mol %), ligand (20 mol %), solvent
b
MeOH (1 mL), 70 °C, 5 h. Isolated yields.
b
(1 mL), at 70 °C, 5 h. Determined by 1H NMR with 1,4-
dimethoxybenzene as an internal standard. Isolated yield in
c
parentheses.
with various substituents on the aromatic ring were found to
be appropriate candidates, affording the desired products (5a−
5t) in good yields with excellent chemo-, regio-, and
stereoselectivity. A range of functional groups, such as alkyl
(5b−5g), halogen (5h−5l), an ether (5m−5o), a free
aldehyde (5p), an ester (5q), and a ketone (5t), tolerated
the reaction conditions. Generally, phenylacetylenes bearing an
electron-donating group gave higher yields than those bearing
an electron-withdrawing group, and the substituent can be
attached on the ortho-, meta-, or para-position of the phenyl
the desired cyanoperfluoroalkylation product (5a) was
observed in 75% yield, determined from NMR data. However,
an ATRA side product (5a′) was also formed in 14% NMR
yield (Table 1, entry 1). Production of 5a′ is a process which is
significantly competitive with the reaction producing the
desired product. In order to improve the chemoselectivity and
to exclude the generation of the ATRA product (5a′), the
reaction conditions with respect to metal catalysts, ligands,
B
DOI: 10.1021/acs.orglett.9b02648
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ring. Moreover, the thiophene ring, an example of a
heterocyclic ring, was also tolerated (5u−5v). However,
internal alkynes were not good reaction partners for this
reaction, and in cases where the terminal was blocked by a
methyl group, only 21% yield of 5w was obtained. It should be
mentioned, in general, that substrates with an electron-
donating group can only afford a trace amount of the side
products, while other substrates provide the side products in
approximately less than 10% yields. Notably, 1-octyne, as an
alkyl acetylene, but-3-yn-1-ylbenzene, as an arylalkyl acetylene,
2-ethynylquinoline, and 3-ethynylpyridine all failed to provide
the desired products.
the cyano group, product 5a could be selectively transformed
into a fluoroalkylated amide19 (7) or a fluoroalkylated
aldehyde20 (8) in 80% and 78% yield, respectively. Upon
treatment with sodium azide and ammonium chloride, the
cyanofluoroalkylation product (5a) afforded in 69% yield a
fluoroalkylated triazole21 (9) which can be easily converted to
N-methylated fluoroalkylated triazole21 (10) in 74% yield.
Moreover, the cyanofluoroalkylation product (5a) can react
with methyl acrylate in the presence of a base and a reducing
agent to afford a Michael addition product22 (11) with a
quaternary carbon center in 61% yield.
Preliminary experiments (Scheme 5) were performed to
further understand the mechanism of this cyanofluoroalkyla-
Inspired by these results, we further investigated the scope of
perfluoroalkyl iodides. As shown in Scheme 3, a variety of
Scheme 5. Preliminary Mechanistic Studies
a,b
Scheme 3. Substrate Scope of Perfluoroalkyl Iodides
a
Reaction conditions: 1a (0.3 mmol, 1 equiv), 2 (2 equiv), 3a (2
equiv), 4a (2 equiv), Cu(CH3CN)4BF4 (10 mol %), L1 (20 mol %),
b
MeOH (1 mL), 70 °C, 5 h. Isolated yields.
perfluoroalkyl iodides, including n-C3F7I, n-C6F13I, n-C8F17I,
and n-C10F21I, and other fluoroalkyl iodides, such as C4F8I2
and FSO2CF2CF2OCF2CF2I, all reacted smoothly to afford the
corresponding products (6a−6f) with good yields and
excellent regioselectivity. Interestingly, only one terminal of
C4F8I2 reacted to afford the corresponding product 6f, leaving
another one untouched. These results imply that the reaction
generally tolerates various fluoroalkyl iodides which can be
used directly as feedstock reagents for the radical cyano-
fluoroalkylation of alkynes. However, the reactions failed with
CF3I (balloon) and ICF2COOEt as the fluoroalkyl iodides.
To demonstrate the potential of this alkyne cyanofluor-
oalkylation reaction, compound 5a was transformed into many
useful products (Scheme 4). Owing to the general capability of
tion reaction. When the radical scavenger TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy) was added under the standard
conditions, no product (5a) was formed and an adduct
TEMPO-C11H23 (12) was detected by GC−MS analysis,
suggesting a radical process (Scheme 5a). Upon the addition of
BHT (butylated hydroxytoluene) to the reaction mixture
under the standard conditions, the yield of product 5a fell
sharply to 31% (Scheme 5b). Furthermore, a control
experiment was carried out without the addition of LPO to
the standard reaction conditions. No 5a was detected in this
case, indicating that LPO is crucial for the cyanofluoroalky-
lation reaction (Scheme 5c). Finally, side product 5a′ was
supposed to be the reaction intermediate. However, upon
treatment of 5a′ under the standard reaction conditions, an
almost quantitative yield of 5a′ was recovered. This reaction
excludes the possibility of 5a′ as the reaction intermediate
(Scheme 5d).
Scheme 4. Synthetic Applications
On the basis of these preliminary findings and previously
reported papers,13,17d a plausible mechanism was proposed and
is shown in Scheme 6. First, the L1Cu(I) catalyst (A)
Scheme 6. Possible Radical Pathway
C
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Asymmetric fluorination, trifluoromethylation, and perfluoroalkyla-
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undergoes a SET process with LPO to deliver an undecyl
radical, a molecule of CO2, and a L1Cu(II) complex (B),
which undergoes a ligand exchange with TMSCN to form a
L1Cu(II)CN23/L1Cu(II)NC18h species (C). The undecyl
radical reacts with a fluoroalkyl iodide via a radical relay
process to provide a fluoroalkyl radical, which subsequently
attacks an alkyne forming a vinyl radical intermediate. Then
the vinyl radical reacts with the copper(II) species (C) to
produce the desired cyanofluoroalkylation product and the
regenerated active L1Cu(I) species (A). This procedure is
expected to be much faster than I atom abstraction from the
fluoroalkyl iodide, forming the ATRA type product.
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cyanoalkenes. This protocol features a wide scope of alkynes
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simple operation. Moreover, owing to the general capability of
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further transformed into many useful derivatives, and this
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and α-Heteroaryl-Substituted α,α-Difluoromethyl Phenyl Sulfones.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02648.
General procedure, optimization of reaction conditions,
characterization data, and copies of NMR spectra for all
novel compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hlbao@fjirsm.ac.cn.
ORCID
Yajun Li: 0000-0001-6690-2662
Hongli Bao: 0000-0003-1030-5089
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key R&D Program of China (Grant
No. 2017YFA0700103), the NSFC (Grant Nos. 21672213,
21871258), the Strategic Priority Research Program of the
Chinese Academy of Sciences (Grant No. XDB20000000), the
Haixi Institute of CAS (Grant No. CXZX-2017-P01), the
Natural Science Foundation of Fujian Province (Grant No.
2018J05037), and the CAS-TWAS president program of the
UCAS for financial support.
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