Copper-Catalyzed Three-Component Reactions of 2-Iodo-2,2-difluoroacetophenones, Alkynes, and Trimethylsilyl Cyanide

Article abstract of DOI:10.1002/ejoc.202001650

A Cu(I)-catalyzed three-component reaction of 2-iodo-2,2-difluoroacetophenones, alkynes, and TMSCN is described. The reaction provided a facile method for the synthesis of difluoroacyl-substituted nitriles, which might be served as potentially useful fluo

Full text of DOI:10.1002/ejoc.202001650

Communications
doi.org/10.1002/ejoc.202001650
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Copper-Catalyzed Three-Component Reactions of 2-Iodo-
2,2-difluoroacetophenones, Alkynes, and Trimethylsilyl
Cyanide
Pingjie Wu,[a] Cheng Zheng,[a] Xia Wang,[a] Jingjing Wu,*[a, b] and Fanhong Wu*[a]
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sequently, Zhu et al. and Zhang et al. independently reported
the palladium-catalyzed difunctionalization of alkynes with
ethyl difluoroiodoacetate and B2pin2.[6c,d] A Pd (0)-catalyzed
three-component reactions of 2-iodo-2,2-difluoroacetophe-
nones, alkynes, and arylboronic acids was also reported by our
group. The application of more difluoroalkylation reagents will
facilitate the development of synthetic approaches for varieties
of useful fluoroalkylated compounds.[6e]
A
Cu(I)-catalyzed three-component reaction of 2-iodo-2,2-
difluoroacetophenones, alkynes, and TMSCN is described. The
reaction provided facile method for the synthesis of
a
difluoroacyl-substituted nitriles, which might be served as
potentially useful fluoroorganic intermediates for further trans-
formation in drug discovery. This method has broad substrate
scope, good efficiency, and excellent stereoselectivity. Prelimi-
nary mechanistic investigation indicated that a radical-mediated
process was involved in this cyanodifluoroalkylation reaction.
In addition, nitriles are versatile organic intermediates,[7]
which can be easily converted into other functional organic
compounds with potential applications such as ketones,
carboxylic acids, amides and triazoles etc. Despite the impor-
tance of nitriles in the field of organic synthesis, the develop-
ment of concise approaches to fluorine-containing nitriles
remains a challenging task. Liang’s group reported the synthesis
of β-trifluoromethylated acrylonitriles via copper-catalyzed
difunctionalization of alkynes with Togni reagent and trimeth-
ylsilyl cyanide (TMSCN).[8] They next disclosed a copper powder-
mediated reaction with ethyl difluoroiodoacetate, alkynes, and
TMSCN for the synthesis of β-difluoroalkylated acrylonitriles.[9] In
2019, Bao’s group has developed a copper-catalyzed cyanoper-
fluoroalkylation of alkynes with perfluoroalkyl iodides and
Difluoromethylene compounds have been widely used in
medicinal chemistry and agrochemistry due to that the
difluorinated moieties could significantly enhance their lip-
ophilicity, metabolic stability, and bioavailability.[1] Therefore,
substantial efforts have been made on the development of
difluoroalkylation reactions for the construction of α,α-difluor-
oketone molecules.[2] In a general way, the difluoroalkylation
methods mainly include metal-mediated cross-coupling reac-
tions of difluoroalkylated reagents with halogenated aromatic
hydrocarbons, or olefins,[3] and radical addition reactions of
difluoroalkylated reagents with unsaturated hydrocarbons,[4]
etc.
As we know, alkynes were vital industrial raw materials, and
their excellent performance in functionalization was widely
concerned.[5] Among them, the difunctionalization of alkynes for
the synthesis of organofluorine compounds via three-compo-
nent reactions has made significant advancements.[6] Liang et al.
reported a novel method for the synthesis of fluoroalkylated
alkenes through palladium-catalyzed three-component reac-
tions with alkynes, ethyl difluoroiodoacetate, and arylboronic
acids.[6a] In 2017, Zhao’s group disclosed a palladium-catalyzed
reaction of alkynes with diphenylphosphine oxides and ethyl
difluoroiodoacetate, providing an attractive approach for the
formation of (E)-γ,γ-difluoroalkenylphosphines oxides.[6b] Sub-
TMSCN to produce
a
variety of perfluoroalkylated
cyanoalkenes.[10] In recent years, our group has utilized RCOCF2I
as difluoroalkylating reagents and employed them in different
reactions for the construction of diverse difluoroacyl
alkenes.[6e,11] With our continued interest in the introduction of
the difluoroacyl group synchronously with other functional
groups into alkynes, herein, we reported a copper-catalyzed
reaction of 2-iodo-2,2-difluoroacetophenones, alkyne, and
trimethylsilyl cyanide (TMSCN) that achieves cyanodifluoroalky-
lation of simple abundant alkynes with high stereoselectivity via
multicomponent radical cascade process (Scheme 1).
In our initial investigation, the reaction of 2-iodo-2,2-
difluoroacetophenone 1a, phenylacetylene 2a with TMSCN was
chosen as a model reaction to optimize the reaction conditions.
°
The reaction was conducted in anhydrous MeOH at 70 C with
[a] P. Wu, C. Zheng, X. Wang, Prof. J. Wu, F. Wu
Shanghai Engineering Research Center of Green Fluoropharmaceutical
Technology
Shanghai Institute of Technology
201418 Shanghai, P. R. China
E-mail: wujj@sit.edu.cn
lauryl peroxide (LPO) as the radical initiator, and L1 as the
ligand catalyzed by Cu(CH3CN)4BF4 under the nitrogen (Table 1,
entry 1). As expected, results showed that the desired difluor-
oalkyl-substituted acrylonitrile 3aa was observed in 73% GC
wfh@sit.edu.cn
[b] Prof. J. Wu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry
Chinese Academy of Sciences
200032 Shanghai, P. R. China
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001650
Scheme 1. Synthesis of difluoroacyl-substituted nitriles catalyzed by copper.
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doi.org/10.1002/ejoc.202001650
2a (1.5 equiv) with TMSCN (2.0 equiv) in the presence of
Cu(CH3CN)4PF6 (10 mol%), L1 (20 mol%), and LPO (2.5 equiv) in
Table 1. Optimization of the reaction conditions for cyanodifluoroalkyla-
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4
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tion of alkynes.[a]
°
MeOH (1.0 mL) at 70 C for 5 h (Table 1, entry 7). Additional
control experiments confirmed that copper-metal catalyst, L1,
and LPO were all crucial for this reaction (Table 1, entries 22–
24).
6
With the optimized reaction conditions in hand, we next
evaluated the substrate scope of the reaction by employing
structurally varied 2-iodo-2,2-difluoroacetophenones. As shown
in Table 2, aryl 2-iodo-2,2-difluoroketones bearing electron-
donating or -withdrawing groups are all compatible to deliver
cyanodifluoroalkylation products (3aa–3ja) in moderate to
excellent yields. The substrates containing electron-withdrawing
groups give a relatively low yield. Substituent groups were
tolerated at the para- and meta- positions of the benzene ring
(3ba–3da, 3ha). Unfortunately, the ortho-substituent sub-
strates failed to give the desired products. Furthermore, 2-iodo-
2,2-difluoroacetophenones derived from heterocyclic arenes,
such as thiophene 1i, reacted smoothly with 2a to afford the
compound 3ia in excellent yield. Pleasingly, we found that the
reaction with 1,1-difluoro-1-iodo-4-phenylbutan-2-one 1k and
2a proceeded well to provide 4,4-difluoro-5-oxo-2,7-diphenyl-
hept-2-enenitrile 3ka with a high yield of 81%. When ethyl
iododifluoroacetate was used as the substrate, the desired
compound 3la was not achieved, instead, the compound 3ma
was obtained through a transesterification reaction.
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Entry Cat.
Ligand Initiator Solvent
Yield[b][%] of
3aa/4
1
2
3
Cu(CH3CN)4BF4 L1
CuTc
CuI
LPO
LPO
LPO
LPO
LPO
LPO
LPO
AIBN
ABVN
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
LPO
–
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3CN
DMSO
73/19
70/18
62/24
63/22
59/27
59/26
83/8
27/56
32/54
68/16
34/60
L1
L1
L1
L1
L1
4
5
6
CuBr
CuOAc
CuBr2
7
8
9
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L2
Cu(CH3CN)4PF6 L3
Cu(CH3CN)4PF6 L4
Cu(CH3CN)4PF6 L5
Cu(CH3CN)4PF6 L6
Cu(CH3CN)4PF6 L7
Cu(CH3CN)4PF6 L1
Cu(CH3CN)4PF6 L1
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17
18
19
20[c]
21[d]
22[e]
23[f]
24[g]
CH3COCH3 52/36
DMF
50/38
61/27
57/31
58/29
62/24
55/35
60/24
81/10
80/9
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
Secondly, we examined the reaction scope with respect to
the alkyne component by using 1a as the fluoroalkyl reagent
(Table 3). These alkynes all proceeded efficiently under the
optimized reaction conditions to furnish the corresponding
products (3ab–3ap) in moderate to good yields with excellent
–
L1
–
trace
trace
trace
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6 L1
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv),
TMSCN (0.4 mmol, 2.0 equiv), initiator (0.5 mmol, 2.5 equiv), cat. [Cu]
(10 mol%), ligand (20 mol%), solvent (1.0 mL), at 70 C, 5 h, under N2.
[b] GC yields. [c] LPO (0.4 mmol, 2.0 equiv). [d] LPO (0.6 mmol, 3.0 equiv).
[e] Without Cu(CH3CN)4PF6 catalyst. [f] Without L1 ligand. [g] Without LPO
initiator.
Table 2. Substrate scope of 2-iodo-2,2-difluoroacetophenones.[a,b]
°
yield. Unfortunately, the byproduct 4 was also formed from the
reaction in a 19% GC yield. Encouraged by this preliminary
observation, we attempted to improve the reaction efficiency
and to exclude the generation of the byproduct 4 by optimizing
the reaction conditions. Among the copper-metal catalysts
tested, Cu(CH3CN)4PF6 was found to be the best catalyst
(Table 1, entries 2–7), giving the compound 3aa in a raising
83% yield and 4 in only 8% (Table 1, Entry 7). The desired
product 3aa was obtained in lower yields when AIBN or ABVN
was used as a radical initiator instead of LPO in the reaction
(Table 1, entries 8 and 9). Other solvents such as CH3CN, DMSO,
CH3COCH3 and DMF showed inferior results (Table 1, entries 10–
13). The yield of 3aa was decreased when L2–L7 were tested as
alternative ligands (Table 1, entries 14–19). Increasing or
decreasing the equivalent of LPO did not improve the yield of
3aa (Table 1, entries 22 and 23). Ultimately, the optimized
conditions for the generation of 3aa were determined as 2-
iodo-2,2-difluoroacetophenone 1a (1.0 equiv), phenylacetylene
[a] Reaction conditions: 1 (0.3 mmol, 1.0 equiv), 2a (0.45 mmol, 1.5 equiv),
TMSCN (0.6 mmol, 2.0 equiv), LPO (0.75 mmol, 2.5 equiv), Cu(CH3CN)4PF6
°
(10 mol%), L1 (20 mol%), MeOH (1.5 mL), at 70 C, 5 h, under N2.
[b] Isolated yields.
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Table 3. Substrate scope of alkynes.[a,b]
A reduction reaction was performed to demonstrate the
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synthetic utility of the cyanofluoroalkylation products. The
reaction between compound 3aa and DIBAL proceeded
smoothly to afford the reduced product 5a in 52% yield
(Scheme 2).
Several control experiments were designed to interrogate
the reaction mechanism. The reaction was completely sup-
pressed when the radical scavenger 2,2,6,6-tetramethyl-1-oxy-
lpiperidine (TEMPO) was added under the standard conditions,
which indicates that a radical path might be involved in the
process (Scheme 3a). No desired product 3aa was detected in
the absence of LPO (Scheme 3b). Furthermore, the adduct
product 4 was used to react with TMSCN under the standard
reaction conditions. However, the cyanodifluoroalkylation prod-
uct 3aa was not obtained, and an almost quantitative yield of 4
was recovered. These results suggested that the possibility of 4
as the reaction intermediate was precluded (Scheme 3c).
On the basis of the control experiments above and previous
literature reports,[12] a plausible reaction mechanism is proposed
similar to Bao’s report (Scheme 4).[10] First, LPO reacted with
L1Cu(I) catalyst (A) to form an undecyl radical and an L1Cu(II)
complex (B), which undergoes a ligand exchange with TMSCN
to produce an L1Cu(II)CN species (C). Subsequently, the undecyl
radical reacts with 2-iodo-2,2-difluoroacetophenones through a
radical relay process to afford a benzoyldifluoroalkyl radical
(RCOCF2·), which immediately attacks an alkyne to generate a
vinyl radical intermediate. Finally, the active copper (II) species
(C) reacts with the vinyl radical to produce the desired three-
component products and the regenerated L1Cu(I) species (A).
In summary, we have reported a Cu(I)-catalyzed three-
component reaction of 2-iodo-2,2-difluoroacetophenones, al-
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[a] Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2 (0.45 mmol, 1.5 equiv),
TMSCN (0.6 mmol, 2.0 equiv), LPO (0.75 mmol, 2.5 equiv), Cu(CH3CN)4PF6
°
(10 mol%), L1 (20 mol%), MeOH (1.5 mL), at 70 C, 5 h, under N2.
[b] Isolated yields.
stereoselectivity. The aryl acetylenes bearing electron-withdraw-
ing substituents gave lower yield than those with electron-
donating groups, including Me (3ab, 3af), nÀ C2H5 (3ac), tÀ Bu
(3ad), nÀ C5H11 (3ae), OMe (3ah), Ph (3am) at the para- or
meta- position on the phenyl ring. Furthermore, halogen-
containing substrates turned out to be operational reactants,
yielding the acrylonitrile products (3ag, 3aj–3al) with good
efficiency. Interestingly, 2- or 3-ethynylthiophene derivatives
(2n, 2o) reacted extremely well to provide corresponding
products 3an and 3ao, and even, 2-ethynylthiophene afforded
4,4-difluoro-5-oxo-5-phenyl-2-(thiophen-2-yl) pent-2-enenitrile
(3an) in 79% yield. Notably, the satisfactory yield of the
difluoroalkyl-substituted acrylonitrile 3ap was observed in this
case when ethynylcyclohexene was subjected to the three-
component reaction.
The NOESY experiment was offered to provide the data for
the determination of the stereochemistry of compound 3aa
(See Supporting Information). The spectrum shows that there is
no correlation between hydrogen in C=C bond and hydrogen
in benzene ring, which means that compound 3aa is mainly in
E-configuration. Furthermore, a second signal appears next to
the main product in almost all the 19F NMR-spectra, which
might show that the Z-isomer of the desired compound is also
obtained. The ratio of the two isomers of the cyanodifluoroalky-
lated products 3 is showed in table 2 and table 3 according to
the 19F NMR-spectra.
Scheme 2. The reaction between compound 3aa and DIBAL.
Scheme 3. Mechanistic studies.
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Scheme 4. Proposed mechanism.
kynes, and TMSCN for the synthesis of difluoroacyl-substituted
nitriles, which could be served as important synthons in organic
synthesis. The present method offers several advantages
including broad fluorinated substrate scope, good yields of
products, and excellent stereoselectivity. Preliminary mechanis-
tic investigation indicated that a radical-mediated process was
involved in this cyanodifluoroalkylation reaction.
Acknowledgements
We are grateful for financial supports from the National Natural
Science Foundation of China (Nos. 21672151 and 21602136).
Conflict of Interest
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Liu, X. Feng, Chem. Rev. 2011, 111, 6947–6983; c) W.-B. Wu, J.-S. Yu, J.
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The authors declare no conflict of interest.
Keywords: Copper
·
Homogeneous
catalysis
·
Cyanodifluoroalkylation · Difluoroalkylation · Nitriles · Synthetic
methods
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Manuscript received: December 22, 2020
Revised manuscript received: January 15, 2021
Accepted manuscript online: January 18, 2021
Eur. J. Org. Chem. 2021, 1420–1423
www.eurjoc.org
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