Radical Difunctionalization of Alkenes with Iododifluoromethyl Ketones Under Ni-Catalysis

Article abstract of DOI:10.1002/cctc.201901395

Ni-catalyzed radical difunctionalization of alkenes with iododifluoromethyl ketones was realized for the synthesis of α,α-difluoroketones. This reaction can also be used for the construction of analogs containing 5-membered heterocycles through radical ad

Full text of DOI:10.1002/cctc.201901395

Accepted Article
Title: Radical difunctionalization of alkenes with iododifluoromethyl
ketones under Ni-catalysis
Authors: Tianyu Zhang, Jun Pan, Jin Duan, Jingjing Wu, Wei Zhang,
and Fanhong Wu
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10.1002/cctc.201901395
ChemCatChem
FULL PAPER
Radical difunctionalization of alkenes with iododifluoromethyl ketones under Ni-
catalysis
Tianyu Zhang,[a] Jun Pan,[a] Jin Duan,[a] Jingjing Wu,*[a] Wei Zhang,[b] Fanhong Wu*[a]
Abstract: Ni-catalyzed radical difunctionalization of alkenes with
iododifluoromethyl ketones was realized for the synthesis of α,α-
difluoroketones. This reaction can also be used for the construction
of analogs containing 5-membered heterocycles through radical
addition and sequenced cyclization reactions.
Introduction
Due to an increased number of compounds containing α,α-
difluoroketo motif found to have biological activities,[1] the
development of synthetic methods for making α,α-difluoroketone
molecules have received much recent attention.[2] Addition of
perfluoroalkyl (Rf) radicals derived from RfI to alkenes is an
[4]
established method by using AIBN[3] and Na2S2O4 as radical
initiators, and under photoredox[5] or transition-metal catalysis[6].
However, the addition reactions of difluoroalkyl (RCF2) radicals
are not fully explored yet,[7] especially those derivatived from
Scheme 1. Ni-catalyzed reaction of iododifluoromethyl ketones and alkenes
difluoroacyl iodides (RCOCF2I).[8]
We have recently reported
a
series of 2-iodo-2,2-
for radical
difluoroketone-based reactions
Results and Discussion
benzoyldifluoromethylation with alkynes using AIBN as initiator
or under Pd-catalyzed conditions,[9] as well as aldol reactions
with aldehydes.[10] Since Ni-catalyzed radical fluoroalkylation
reactions has been emerged as a powerful tool for the synthesis
of fluorinated molecules,[11] we envisoned that RCOCF2 radicals
generated from RCOCF2I could be used in addition reactions
with alkenes. Hence, report here is our effort on the
development of Ni-catalyzed radical addition of 2-iodo-2,2-
difluoroketones with alkenes for the synthesis of different gem-
difluromethylene-containing scaffolds (Scheme 1). It is worth
noting that these scaffolds are prepared by catalyst-promoted
difunctionalization reactions, which is an efficinet and green
synthetic technique. Other than the desired difluromethylene, the
second group could be readily used for further transformations.
Optimization of reaction and substrate scope screening
In our initial investigation, 2,2-difluoro-2-iodo-1-phenylethanone
1a was used as the difluoromethylation agent and 1-octene 2a
as the substrate for the NiCl2 (5 mol%)-catalyzed reaction in 1,4-
dioxane at 100 °C under nitrogen. The desired product 2,2-
difluoro-4-iodo-1-phenyldecan-1-one 3a was obtained in 24%
yield when 1,10-phen (6mol%) was used as a ligand in the
presence of KOAc (Table1, entry 1). Exploring other Ni
catalysts (Table1, entries 1-7) indicated that Ni(acac)2 was the
best one (Table1, entry 7). Screening of ligands and bases
(Table1, entries 8-16) showed that 1,10-phen and K2CO3 were
the most suitable ligand and base respectively (Table1, entry 12).
Then, the solvent investigation (Table1, entries 17-20) showed
that cyclopentyl methyl ether (CPME) is also a suitable solvent
for this reaction. Since CPME is more environmental friendly
than 1,4-dioxane, we chose CPME as the reaction solvent
(Table 1, entry 17). Further examination showed that Ni(0) and
Raney Ni were not suitable catalysts for the reaction which gave
lower yields of 3a (Table 1, entries 21 and 22). Thus, the
optimized reaction condition was to use Ni(acac)2 as catalyst in
the presence of 1,10-phen and K2CO3 in CPME at 100 °C under
nitrogen (Table 1, entry 16). Two control reactions showed that
the reaction could proceeded without base or ligand and gave
the product 3a in lower yield accompanied with unreacted
starting material 1a respectively (Table 1, entries 23 and 24). It's
worth noting that the product 3a could be obtained in 48% yield
just in the presence of base without Ni catalyst and ligand when
the reaction time was extended to 24 h (Table 1, entry 25).
[a] Tianyu Zhang, Jun Pan, Jin Duan, Assist. Prof. Jingjing Wu, Prof.
Fanhong Wu
School of Chemical and Environmental Engineering,
Shanghai Institute of Technology
Shanghai 201418, China
E-mails: wujj@sit.edu.cn; wfh@sit.edu.cn
[b] Prof. Wei Zhang
Department of Chemistry
University of Massachusetts Boston
100 Morrissey Boulevard
Boston MA 02125, USA
E-mail: wei2.zhang@umb.edu
Supporting information for this article is given via a link at the end of the
document.(Please delete this text if not appropriate)
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Table 1. Optimization of Reaction Conditions[a]
internal alkene cyclohexene could be employed in the reaction
to give the compound 3r in moderate yield. However, the
reaction of phenylethylenes only gave a trace amount of
product and most starting material was unreacted. When
naphthalenyl iododifluoromethyl ketone was reacted with 1-
octene, both the addition product 3s and cyclization product 3t
were obtained in almost 1:1 ratio. A gram-scale reaction of 1a
and 2a was carried out under the optimized conditions to afford
3a in 80% yield by using decreased amount of Ni catalyst (1
mol%) (Scheme 2).
Entry
Catalyst
Ligand
Base
Solvent
Yield [%][b]
1
2
NiCl2
NiCl2(dppf)
NiCl2(dppp)
NiBr2(DME)
NiCl2(PPh3)2
NiCl2glyme
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(COD)2
Raney Ni
Ni(acac)2
Ni(acac)2
-
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
xantphos
dppf
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
K3PO4
Et3N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CPME
24
16
9
3
4
44
67
71
83
75
20
63
0
Table 2. Scope of the radical addition fluoroalkylation[a],[b]
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25[c]
bpy
TCHP
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
-
92
72
60
56
0
TMEDA
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
90
45
31
11
trace
13
38
55
48
DMF
DMA
NMP
CPME
CPME
CPME
K2CO3
K2CO3
CPME
-
CPME
[a]
Reaction conditions: 1a (1 mol), 2a (1.2 mmol), base (2 mmol), catalyst (5
mol%), ligand (6 mol%), and solvent (4 mL) in a sealed Schlenk tube, 100 °C
[b]
for 5-8 h under N2.
Yields were determined by 19F NMR analysis using
trifluorotoluene as an internal standard. [c] Reaction for 24 h.
To explore the substrate scope, different 2-iodo-2,2-
difluoroketones 1 were investigated in combination with several
unactivated alkenes 2 under the optimized reaction conditions
(Table 2). Aryl 2-iodo-2,2-difluoroketones bearing electron-
donating or -withdrawing groups were tested to give diverse
difluoroalkyl ketones（3a-k）in excellent yields except 3j (42%
yield). The product 3j was formed along with several unknown
byproducts. It was observed that 2,2-difluoro-2-iodo-1-(p-
tolyl)ethan-1-one reacted with 2a affording 2,2-difluoro-4-iodo-1-
(p-tolyl)decan-1-one 3g with a high yield of 91%. The aliphatic
and heterocyclic 2-iodo-2,2-difluoroketones were also suitable
fluorinated agents to give desired products 3I-3n in good yields.
Furthermore, various unactivated alkenes were used in the
reactions under the optimized conditions giving products in good
yields (3o-r). 2,5-Dihydrofuran was found to be a good substrate
and produced the product 3q in 65% yield. Moreover, the
____________________________________________________________
[a]
Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), Ni(acac)2 (0.05 mmol),
1,10-phen (0.06 mmol), K2CO3 (2 mmol), CPME (4 mL), 100°C for 5-8 h under
N2. [b] Isolated yield.
Scheme 2. A gram-scale reaction
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Control reactions and proposed reaction mechanism
Post-modifications for cyclization- difunctionalization
Several control reactions were carried out to understand the
mechanism of the Ni-catalyzed difluoroalkylation reaction
(Scheme 3). When the radical scavenger 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added to the reaction, the radical
difluorination process was inhibited, and the TEMPO-CF2COPh
adduct 13 was detected (δ -71.85 for compound 13, see the
Supporting Information) (Scheme 3a). A radical clock reaction
using (1S)-(-)-β-Pinene 14 as the radical probe was also
conducted, thus giving the ring-opened diene 15 in 72%
yield (Scheme 3b). The two reactions indicated that the
generation of the PhCOCF2∙ radical might be involved in the
reaction process.
We have previously reported the AIBN-initiated radical reactions
of 2-iodo-2,2-difluoroacetophenones with
unsaturated
acids/alcohols for preparing cyclic esters and ethers.[12] We
wonder if the Ni-catalyzed radical reaction of similar substrates
could also yield the cyclization products. Gratifyingly, lactone 7
and cyclic ether 8 were obtained in good yields when 1a was
reacted with 2,2-dimethylpent-4-enoic acid 4 or pent-4-en-1-ol 5,
respectively (Table 3). N-Methyl-N-phenylmethacrylamide 6 was
also used in the reaction, which provided PhOCF2-containing
indolinone 9 in 71% yield. Since indolinone is a privileged
heterocyclic scaffold found in bioactive natural products and
synthetic compounds,[13] this reaction provides an alternative
route to acesss fluorinated indolinons.
Table 3. Synthesis of PhCOCF2-containing heterocyclic compounds[a]
Scheme 3. Control reactions
On the basis of the above control experiments and previous
reports, [15] we proposed a plausible reaction mechanism for the
radical addition of alkenes with 2-iodo-2,2-difluoroketone 1
(Scheme 4). Both of Hu’s group and Studer’s group disclosed
that base could initiate the radical reaction in an unknown way.
[15] We also found that the radical adduct could be formed only in
the presence of K2CO3 (Table 1, entry 25). In the presence of
Ni(acac)2, the Ni catalyst might somehow act in concert with
K2CO3 to accelerate the generation of the benzoyldifluoroalkyl
radical from 1 (Table 1, entry 24), which is similar to both Hu’s
and Studer’s reports. [15] Moreover, the addition of ligand could
further active the 2-iodo-2,2-difluoroketone 1 and give higher
yield of 3a (Table 1, entry 17). Accordingly, we proposed that
benzoyldifluoroalkyl (RCOCF2) radical A is generated from
benzoyldifluoroalkylation agent 1 in the presence of Ni catalyst,
ligand and base (step 1). The RCOCF2 radical A adds to the
alkene to generate alkyl radical B (step 2), which can react with
another molecule of benzoyldifluoroalkylation agent 1 to produce
the addition product 3 and regenerate RCOCF2 radical A (step
3).
[a]
Reaction conditions: 1a (1.0 mmol), alkene (1.2 mmol), Ni(acac)2 (0.05
mmol), 1,10-phen (0.06 mmol), K2CO3 (2 mmol), CPME (4 mL), 100 °C, under
N2 for 8 h. [b] Reaction for 20 h.
The Wu and Jiang groups recently reported a Pd-catalyzed
reaction of RfI with olefins through radical addition and then
cyclization to afford the fluoroalkylated 2,3-dihydrobenzofuran.[14]
Since Ni-catalyst is more affordable than Pd-catalyst, we would
like to explore the possibility of using a Ni-catalyst to replace the
Pd-catalyst. Fortunately, our effort to construct Csp3−CF2 and
C−O bonds through radical bifuctionalization was successful and
gave difluoroalkylated 2,3-dihydrobenzofurans 11a-c in good
yields (Table 4). In this reaction, TMEDA insead of K2CO3 was
used as the base.
Table 4. Synthesis of difluoromethylated 2,3-dihydrobenzofuran [a].
[a]
Reaction conditions: 1a (1.0 mmol), alkene (1.2 mmol), Ni(acac)2 (0.05
mmol), 1,10-phen (0.06 mmol), TMEDA (2 mmol), CPME (4 mL), 100 °C,
under N2 for 5-8 h.
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Conclusions
In summary, we have developed an operationally simple and
higly efficient Ni-catalyzed radical difunctionaliztion reaction of
alkenes and 2-iodo-2,2-difluoroketones. The reaction is not only
good for the synthesis of 1,2-difluroalkylated and iodinated
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difluoroalkylated tetrahydrofuran, dihydrobenzofuran, and
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Further synthetic applications of the Ni-catalyzed radical reaction
for the construction of diversity difluorinated compounds are
currently underway in our laboratory and will be reported in due
course.
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Experimental Section
General catalytic reaction procedures: An oven-dried Schlenk
tube was charged with Ni(acac)2 (0.05 mmol), 1,10-phen (0.06
mmol) and K2CO3 or TMEDA (2 mmol). The tube was evacuated
and backfilled with nitrogen (repeated three times). Then a 2-
iodo-2,2-difluoroacetophenone 1 (1.0 mmol) and an alkene 2
(1.2 mmol) in CPME (4.0 mL) were added into the tube. The
reaction mixture was stirring at 100 °C for 5-8 h. After
completion of the reaction as indicated by TLC, the reaction was
quenched with an appropriate amount of water, and the reaction
mixture was extracted with EtOAc (3 x 15 mL). The combined
organic layers were washed with saturated brine, dried over
Na2SO4, and concentrated in vacuum to give the crude product
3. It was purified by silica-gel column chromatography (100:1
petroleum ether/EtOAc) to afford the desired product .
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We are grateful for financial supports from the National Natural
Science Foundation of China (Nos. 21672151, 21602136).
Keywords: Ni-catalyst • 2-iodo-2,2-difluoroketones • alkenes •
radical • difunctionalization
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Radical difunctionalization of
alkenes with iododifluoromethyl
ketones under Ni-catalysis
Tianyu zhang,[a] Jun Pan,[a] Jin Duan,[a]
Jingjing Wu,*[a] Wei Zhang,[b] Fanhong
Wu*[a]
Page No. – Page No.
Nickel-catalyzed radical
difucntionalization of alkenes with
iododifluoromethyl ketones through
1,2-addition or addition and
cyclization sequences
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