Silver-catalyzed decarboxylative radical allylation of α,α-difluoroarylacetic acids for the construction of CF2-allyl bonds

Article abstract of DOI:10.1039/d0ob02546a

An efficient silver-catalyzed method of decarboxylative radical allylation of α,α-difluoroarylacetic acids to build CF₂-allyl bonds has been developed. Using allylsulfone as an allyl donor, α,α-difluorine substituted arylacetic acids bearing various functional groups are successfully allylated to access a series of 3-(α,α-difluorobenzyl)-1-propylene compounds in moderate to excellent yields in aqueous CH₃CN solution under the mild conditions. Experimental studies disclosed that the α-fluorine substitution of arylacetic acid has a great influence on free radical activity and reactivity.

Full text of DOI:10.1039/d0ob02546a

Organic &
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Silver-catalyzed decarboxylative radical allylation
of α,α-difluoroarylacetic acids for the construction
of CF2–allyl bonds†
Cite this: Org. Biomol. Chem., 2021,
19, 2023
Pingyang Wang,a Pengcheng Du,a Qianqian Sun,a Jianhua Zhang,b Hongmei Dengc
a,d
and Haizhen Jiang
*
An efficient silver-catalyzed method of decarboxylative radical allylation of α,α-difluoroarylacetic acids to
build CF2–allyl bonds has been developed. Using allylsulfone as an allyl donor, α,α-difluorine substituted
arylacetic acids bearing various functional groups are successfully allylated to access a series of 3-
(α,α-difluorobenzyl)-1-propylene compounds in moderate to excellent yields in aqueous CH3CN solution
under the mild conditions. Experimental studies disclosed that the α-fluorine substitution of arylacetic
acid has a great influence on free radical activity and reactivity.
Received 21st December 2020,
Accepted 2nd February 2021
DOI: 10.1039/d0ob02546a
rsc.li/obc
increasing attention.4 Because gem-difluoromethylene moieties
are usually considered a bioisostere to an ethereal oxygen
Introduction
Alkyl radical allylation reactions are one of the most prominent atom or a carbonyl group, the introduction of gem-difluoro-
reactions in synthetic chemistry to construct C(sp3)-allyl bonds methylene moieties can effectively alter their chemical, physi-
because allyl moieties serve as a versatile precursor for further cal and biological properties and can dramatically improve the
functionalization to access various purposeful compounds.1 metabolic stability and oral bioavailability of the parent com-
The construction of C(sp3)-allyl bonds mainly focuses on pounds.5 Furthermore, a variety of gem-difluoromethylene-
adding a carbon-centered radical to a suitable allylic reagent. linked compounds with biological significance can be
Thus, a number of radical precursors such as alkyl or aromatic obtained through further functionalization of CF2–allyl
carboxylate2 and a variety of allyl donors have been developed bonds.6 Therefore, it is highly desirable to develop new
successively for exploring the radical allylation reactions, and methods for constructing CF2–allyl bonds.
significant advances have been made in this field.3 However,
CF2–allyl bonds can be constructed through the reaction of
some fluoroalkyl radicals, such as CF3, CF2, perfluoroalkyl rad- aryldifluoromethyl radicals generated in situ from aryldifluoro-
icals, etc., which usually play the role of electrophiles due to methyl halides (fluoride, chloride or bromide) with allyl metal
the influence of fluorine substituents, were completely compounds such as allyltrimethylsilane or allylstannanes
different from alkyl radicals in terms of reactivity. Besides, (Scheme 1(a)).7 Most advances have mainly benefited from the
there is also a scarcity of suitable CF2-containing building efficiency of allylstannanes. However, the use of allylstannanes
block resources. Therefore, the construction of CF2–allyl bonds has significant limitations due to its toxicity. The aryldifluoro-
has been less explored via difluoroalkyl radical allylation reac- methyl radicals derived from aryldifluoromethyl bromides, as
tions in fluorine chemistry. However, with brilliant character- one of the most straightforward methods to access structurally
istics of gem-difluoromethylene compounds being increasingly
discovered, the research on introduction of gem-difluoro-
methylene moieties into organic molecules has received
aDepartment of Chemistry, Shanghai University, Shanghai, 200444, PR China.
E-mail: hzjiang@shu.edu.cn
bKey Laboratory of Advanced Display and System Application, Ministry of Education,
Shanghai University, Shanghai, 200072, PR China
cLaboratory for Microstructures, Shanghai University, Shanghai, 200444, PR China
dKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, 200032, PR China
†Electronic supplementary information (ESI) available: Experimental details and
copies of NMR spectra. See DOI: 10.1039/d0ob02546a
Scheme 1 The construction of CF2–allyl bonds.
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diverse difluoromethyl radical intermediates under visible- fluorine. Thus, the net impact of electronic effects (involving
light-induced Ru catalysis, have also been applied in the con- π-donor conjugation interaction with the radical carbon center
struction of CF2–allyl bonds (Scheme 1(b)).8 In an effort to and the fluorine’s σ-inductive electron-withdrawing effect) in
obviate the high cost and hazardous organotin contaminants, this structure endowed the aryl difluoromethylene radical with
inexpensive transition metal-catalyzed radical allylation slightly electron-rich property relative to the CF3 radical.
methods have gradually attracted attention and have been Speculatively, the electron-rich aryldifluoromethyl radicals
developed in the field of construction of CF2–allyl bonds.
could react better with the electron-deficient activated double
The alkyl radical allylation reaction is effective at building bond in allyl sulfones to construct CF2–allyl bonds. Herein, we
C(sp3)-allyl bonds by decarboxylation of aliphatic carboxylic continue to study the activity of aryldifluoromethyl radicals
acids.9 However, in fluorine chemistry, fluoroalkyl radicals from decarboxylation of α,α-difluoroarylacetic acid to investi-
such as CF3 radical are pyramidal σ-radicals, which are tra- gate the effect of α-fluorine substitution of arylacetic acid on
ditionally added to electron-rich alkenes, while addition of the reactivity and to explore the aryldifluoromethyl radical ally-
these fluoroalkyl radicals to electron-deficient alkenes is elec- lation reaction with allyl sulfones under silver-catalyzed con-
tronically unfavorable.10 Therefore, seeking suitable fluor- ditions (Scheme 1(c)).
oalkyl radicals was the key to construct CF2–allyl bonds.
Decarboxylative functionalization of α,α-difluoroarylacetic
acids has been applied for the synthesis of gem-difluoro-
Results and discussion
methylene compounds.11 Our previous research on the reac-
tion of diarylisonitriles and α,α-difluoroaryl carboxylate potass- We first examined the decarboxylative radical allylation reac-
ium salt has indicated that aryldifluoromethyl radicals can be tion using the available α,α-difluorophenylacetic acid 1a and
generated from the readily available α,α-difluoroaryl carboxy- allyl sulfone 2a as model substrates in the presence of AgNO3
late potassium salt through a silver-catalyzed oxidative decar- as a catalyst and K2S2O8 as an oxidant in a solution of 1 : 1 (v/v)
boxylative process.11c Aryldifluoromethyl radicals, which are acetone and H2O as reported by Hashmi (Table 1, entry 1).11b
different from CF3 radicals, can have a planar or near-planar To our disappointment, the decarboxylative allylation reaction
geometry because of their special structure with a phenyl did not take place. However, when the acetone solvent was
moiety bonded to the carbon radical,12 which results in a good replaced by DMSO, the reaction provided the desired com-
match of the size of the semioccupied molecular orbital pound 3aa in 37% 19F NMR yield (the chemical shift was in
(SOMO) of a carbon radical with the lone pair 2p orbital of −95.37 ppm) (entry 2). 3aa was isolated and the structure was
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Oxidant (equiv.)
2a (equiv.)
Solvent (v/v)
Yieldb (%)
1c
AgNO3
AgNO3
AgNO3
AgNO3
—
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
—
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
t-BuOOH (1.5)
PhI(OAc)2 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.0)
K2S2O8 (0.5)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
3.0
3.5
2.0
Acetone/H2O
DMSO/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
0
2c
37
57
70
0
3c
4
5
6
7
8
9
AgNO3
Ag2CO3
AgOAc
AgOTf
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
0
68
69
63
0
10d
11
12e
13
14
15f
16g
17
18
19
20h
4
57
82
60
65
78
89
92
91
84
a Reaction conditions: 1a (0.2 mmol), 2a, AgNO3 (20 mol%) and oxidant in 2.5 mL of aqueous CH3CN solution (CH3CN : H2O = 3 : 7) at 50 °C for
12 h under a N2 atmosphere. b Yields determined by 19F NMR analysis with PhCF3 as the internal standard. c Solvent 2 mL (v/v = 1 : 1). d tert-Butyl
hydroperoxide (70% solution in water). e K2CO3 (1.0 equiv.) was added. f AgNO3 (10 mol%) was added. g AgNO3 (30 mol%) was added. h Under an
air atmosphere.
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Table 2 Scope of α,α-difluoroarylacetic acids and allyl sulfonesa,b
confirmed by NMR, IR and HR-MS. Encouraged by this result,
we continued to optimize the reaction solvents. It was found
that the decarboxylative allylation product 3aa was also formed
in 57% 19F NMR yield in a solution of 1 : 1 (v/v) CH3CN and
H2O (entry 3). Further examination of solvents showed that the
amount of water has a great influence on the reaction activity.
The reaction provided the highest yield when adding 2.5 mL of
mixed solvent of 3 : 7 (v/v) CH3CN and H2O to the reaction
system when 1a was used at the 0.2 mmol scale (entry 4).
Control experiments revealed that the catalyst and oxidant
were required to carry out the decarboxylative radical allylation
reaction (entries 5 and 6). Switching the catalyst to Ag2CO3,
AgOAc or AgOTf led to a decrease in the yields of 3aa (entries
7–9). The yield of 3aa was decreased regardless of the amount of
AgNO3 being increased or decreased (entries 15 and 16). When
K2S2O8 was replaced by t-BuOOH or PhI(OAc)2, 3aa was not
detected (entry 10) or was obtained in only 4% yield (entry 11).
When K2CO3 was added as an additive to the reaction mixture
under the optimized conditions, the yield of 3aa decreased from
70 to 57% (entry 12 compared to entry 4). Additionally, when 1
equiv. of oxidant K2S2O8 was employed, the reaction efficiency
was higher than that of using 1.5 or 0.5 equiv. of K2S2O8 (entry
13 compared to entries 4 and 14). Increasing the amount of sub-
strate 2a could significantly improve the reaction efficiency
(entries 17–19). Additionally, the reaction could also provide 3aa
in a yield of 84% under an air atmosphere (entry 20). Oxygen
could inhibit the reaction to a certain extent.
Having found the optimal conditions for the synthesis of
3aa (Table 1, entry 18), we next explored the scope and limit-
ation of this decarboxylative allylation method with allyl
sulfone 2a as the allylating reagent. As shown in Table 2, a
broad range of α,α-difluoroarylacetic acids bearing either elec-
tron-donating or electron-withdrawing groups at different posi-
tions of the phenyl ring underwent efficient decarboxylative
a Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), K2S2O8 (0.2 mmol)
and AgNO3 (20 mol%) in 2.5 mL of aqueous CH3CN solution
(CH3CN : H2O = 3 : 7) at 50 °C for 12 h under a N2 atmosphere.
b Isolated yields.
allylation, furnishing the corresponding products. The col, although they were transition-metal-sensitive in a variety
α,α-difluoroarylacetic acids with electron-donating groups on of transition metal-catalyzed cross-coupling reactions.
the phenyl ring transformed smoothly into the desired pro- Furthermore, the reduction-sensitive nitrile and cyano groups
ducts 3a in high yields (Table 2, 3ba and 3ca) in the mixed were well tolerated (3ea and 3fa). When 2,2-difluoro-2-
solvent of CH3CN and H2O, which were higher than the (naphthalen-1-yl)acetic acid (1l) was used to investigate the
reported yields in pure H2O solvent.13 When the steric effect of the reaction, it was found that the yield of the
α,α-difluoroarylacetic acids bearing strong electron-withdraw- desired product 3la was 40%, accompanied by the intra-
ing groups such as trifluoromethyl or cyano were employed, molecular cyclization product 3la′ in 32% yield. Therefore,
the reaction also afforded the desired products 3da and 3fa in another α,α-difluoroarylacetic acid with large steric hindrance,
77 and 74% yields, respectively. This might be attributed to 2,2-difluoro-2-mesitylacetic acid (1m), was employed, and the
the activation of the ester group on the double bond of the reaction provided 3ma in 87% yield. This result indicated that
substrate, so that the radicals could also smoothly attack the there is no obvious steric effect on the phenyl difluoromethyl-
electron-deficient activated double bond. However, when the ene radical allylation reaction. However, α,α-difluoroaryl
nitro group was used as a substituent, the yield of the product heterocyclic acetic acid might not be a good radical precursor
3ea was only 45%, which might be due to the fact that the in this decarboxylative allylation. When 2,2-difluoro-2-(pyridin-
nitro group inhibited the generation of free radicals. The 2-yl)acetic acid was employed, the reaction did not work, while
α,α-difluoroarylacetic acids with halogens such as F, Cl or Br at 2,2-difluoro-2-(thiophen-2-yl)acetic acid was unstable after
the 2-, 3- or 4-position all provided the products in excellent hydrolysis of the corresponding ethyl 2,2-difluoro acetate. The
yields. In particular, para-bromo-α,α-difluoroarylacetic acids protocol is suitable not only for α,α-difluoroarylacetic acid but
gave the desired product 3ia in the highest yield among all also for α,α-difluoroalkylacetic acid because the reaction gave
halogen-containing substrates. Additionally, halogen func- the desired product 3na in 55% yield when 2,2-difluorobuta-
tional groups were well tolerated in this silver-catalyzed proto- noic acid (1n) was used.
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The generality of this catalytic decarboxylative allylation of
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difluoroarylacetic acids toward different allylating agents was
also explored. When 2-methyl, phenyl or 2-unsubstituted
group allyl sulfone served as the allyl donor, the decarboxyla-
tive allylation of para-bromo-α,α-difluoroarylacetic acid 1i pro-
ceeded to give the expected products in yields of 32, 17 and
52% (3ic, 3id and 3ib), respectively. This could indicate that
the allylating agent is suitable not only for an electron-
deficient activated alkene with an ester group but also for
alkenes with electron-donating methyl or phenyl (3ic or 3id) in
our protocol. The allyl sulfone with an unsubstituted group at
position 2 also proved to be a suitable partner (3ib). When the
sulfone group in allyl sulfone was replaced by an ester group,
the reaction provided the desired product in only 6% 19F NMR
yield.
The effect of α-fluorine substitution of arylacetic acid on
the reactivity was also explored. α,α-Difluorophenylacetic acid
1a has an advantage over α-monofluoronated and non-fluori-
nated α-phenyl acetic acids in the reactivity and provided the
desired product in an isolated yield of 87%.
α-Monofluoronated phenyl acetic acid 1o provided 3oa in 37%
isolated yield. However, non-fluorinated α-phenyl acetic acid
provided 3pa in only 9% isolated yield. The reason could be
that it was easy to decarboxylate α,α-difluorophenylacetic acid
1a to form phenyldifluoromethyl radicals due to the effect of
two α-fluorine atoms under silver-catalyzed conditions.
Additionally, the phenyldifluoromethyl radical produced
in situ has a slightly electron-rich property because it has a
π-donor conjugate interaction and a σ-induced electron-with-
drawing effect of fluorine due to the influence of fluorine sub-
stituents; thus, addition of the phenyldifluoromethyl radical to
the electron-deficient double bond in allyl sulfone is electroni-
cally favourable. However, non-fluorinated α-phenyl acetic acid
1p is the most difficult to decarboxylate and produces an elec-
trophilic radical that is difficult to add to the electron-deficient
double bond in allyl sulfone.
Scheme 3 Proposed reaction mechanism.
On the basis of the above experimental results, as well as
our previous report that the formation of ArCF2 radical species
is independent of AgNO3 and the oxidant K2S2O8,11c a possible
mechanism for the reaction is proposed in Scheme 3. Ag(I) is
initially oxidized by the persulfate (K2S2O8) to generate the
highly reactive Ag(II) cation in situ, which could obtain an elec-
tron from α,α-difluoroarylacetic acid to produce Ag(I). The
α,α-difluoroarylacetic acid transforms into an aryldifluoro-
methyl carboxyl radical cation by a single-electron transfer
process. Quick decarboxylation of the aryldifluoromethyl car-
boxyl radical cation with the loss of CO2 provides the corres-
ponding aryldifluoromethyl radical. Then, addition of the aryl-
difluoromethyl radical to the double bond of allyl sulfone fol-
lowed by β-elimination leads to the product and realizes the
decarboxylative radical allylation of α,α-difluoroarylacetic acid.
•
Finally, oxidation of the PhSO2 radical gives rise to PhSO3H
•−
under the action of the radical anion SO4 in the presence of
water.9b
Conclusions
In conclusion, we have developed a mild and effective strategy
to construct CF2–allyl bonds through silver-catalyzed decarbox-
ylative allylation of α,α-difluoroarylacetic acids with allyl sul-
fones in aqueous CH3CN solution. The aryl difluoromethylene
radical generated in situ by silver catalysis could be smoothly
added to the double bonds with different activities in allyl sul-
fones to obtain 3-(α,α-difluorobenzyl)-1-propylene compounds,
which could be easily further functionalized into biologically
significant gem-difluoromethylene-linked compounds. The
protocol features a broad scope of substrates, good functional
group compatibility, and mild reaction conditions.
Experimental studies also disclosed that α-fluorine substi-
tution of arylacetic acid has a great influence on free radical
activity and reactivity.
To gain more insight into the reaction mechanism, control
experiments were carried out. When α,α-difluoroarylacetic acid
1a was employed under the standard conditions without allyl
sulfone 2a, the phenyl difluoromethylene radical self-coupling
product 5 was obtained and was isolated in 14% yield; the
result showed that the phenyl difluoromethylene radical
existed in the reaction system. Therefore, we inferred that a
radical process is probably involved. However, when 3 equiv. of
TEMPO was added to the reaction system, no adduct was
observed (Scheme 2).
Experimental
General procedure for the synthesis of compounds 3
α,α-Difluoroarylacetic acids (0.20 mmol), AgNO3 (20 mol%,
0.04 mmol), K2S2O8 (1.0 equiv., 0.20 mmol) and allyl sulfones
(3.0 equiv., 0.60 mmol) were placed in a 10 mL round-bottom
Scheme 2 Control experiments.
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flask. 2.5 ml of solvent CH3CN/H2O (v/v = 3 : 7) were then −95.94 (t, J = 15.9 Hz). 13C NMR (125 MHz, CDCl3) δ 166.1,
2
3
added under a nitrogen atmosphere. The solution was stirred 148.9, 142.9 (t, JC–F = 27.0 Hz), 132.0 (t, JC–F = 4.1 Hz), 131.3,
3
1
at 50 °C for 12 h. The resulting mixture was cooled down to 126.8 (t, JC–F = 6.1 Hz), 123.7, 120.6 (t, JC–F = 245.5 Hz), 61.3,
2
room temperature and extracted with EA (5 mL × 4). The com- 40.3 (t, JC–F
bined organic phase was dried over anhydrous Na2SO4. After C13H14F2NO2 [M + H]+ 286.0891, found: 286.0895.
the removal of the solvent under reduced pressure, the crude Ethyl 4-(4-cyanophenyl)-4,4-difluoro-2-methylenebutanoate
= 28.3 Hz), 14.2. HRMS (ESI) calcd for
1
product was purified by silica gel column chromatography (3fa). 39.3 mg, 74% yield, light yellow oil. H NMR (500 MHz,
(petroleum ether/ethyl acetate) to afford pure difluoroallylated CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 6.40
arenes.
(s, 1H), 5.79 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.20 (t, J = 15.8 Hz,
Ethyl 4,4-difluoro-2-methylene-4-phenylbutanoate (3aa). 2H), 1.19 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ
41.9 mg, 87% yield, light yellow oil. 1H NMR (500 MHz, CDCl3) −96.40 (t, J = 15.8 Hz). 13C NMR (125 MHz, CDCl3) δ 166.1,
δ 7.48–7.43 (m, 2H), 7.42–7.37 (m, 3H), 6.37 (s, 1H), 5.75 (s, 141.2 (t, JC–F = 27.0 Hz), 132.3, 132.0 (t, JC–F = 4.1 Hz), 131.2,
2
3
3
1
1H), 4.07 (q, J = 7.1 Hz, 2H), 3.22 (t, J = 15.9 Hz, 2H), 1.20 (t, J = 126.4 (t, JC–F = 6.2 Hz), 120.6 (t, JC–F = 245.4 Hz), 118.1, 114.1
7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ −95.37 (t, J = 15.9 (t, JC–F = 1.7 Hz), 61.3, 40.3 (t, JC–F = 28.4 Hz), 14.2. HRMS
4
2
Hz). 13C NMR (125 MHz, CDCl3) δ 166.4, 136.8 (t, JC–F = 26.3 (ESI) calcd for C14H13F2NNaO2 [M + Na]+ 288.0806, found:
2
3
3
Hz), 132.8 (t, JC–F = 3.9 Hz), 130.4, 129.9, 128.3, 125.3 (t, JC–F 288.0808.
1
2
= 6.2 Hz), 121.4 (t, JC–F = 244.3 Hz), 61.1, 40.5 (t, JC–F = 29.0
Hz), 14.1. HRMS (ESI) calcd for C13H14F2NaO2 [M + Na]+ (3ga). 42.7 mg, 83% yield, light yellow oil. H NMR (500 MHz,
263.0854, found: 263.0857. CDCl3) δ 7.46–7.41(m, 2H), 7.10–7.04(m, 2H), 6.37 (s, 1H), 5.75
Ethyl 4,4-difluoro-4-(4-fluorophenyl)-2-methylenebutanoate
1
Ethyl 4,4-difluoro-2-methylene-4-(p-tolyl)butanoate (3ba). (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.19 (t, J = 16.0 Hz, 2H), 1.21 (t,
45.7 mg, 90% yield, light yellow oil. 1H NMR (500 MHz, CDCl3) J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ −94.28 (t, J = 15.7
δ 7.34 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.36 (s, 1H), Hz), −111.27–111.34 (m). 13C NMR (125 MHz, CDCl3) δ 166.3,
1
4
2
5.74 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.20 (t, J = 15.9 Hz, 2H), 163.6 (dt, JC–F = 249.1 Hz, JC–F = 1.9 Hz), 132.8 (td, JC–F
=
2.36 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) 27.1 Hz, JC–F = 3.5 Hz), 132.7 (t, JC–F = 4.1 Hz), 130.6, 127.5
4
3
δ −94.75 (t, J = 15.9 Hz). 13C NMR (125 MHz, CDCl3) δ 166.5, (dt, JC–F = 8.6 Hz, JC–F = 6.2 Hz), 121.2 (t, JC–F = 244.5 Hz),
3
3
1
2
3
2
2
139.9, 134.0 (t, JC–F = 26.5 Hz), 132.9 (t, JC–F = 3.8 Hz), 130.3, 115.4 (d, JC–F = 21.9 Hz), 61.2, 40.5 (t, JC–F = 29.2 Hz), 14.2.
129.0, 125.2 (t, JC–F = 6.1 Hz), 121.6 (t, JC–F = 244.0 Hz), 61.1, HRMS (ESI) calcd for C13H14F3O2 [M + H]+ 259.0946, found:
3
1
2
40.5 (t, JC–F = 29.3 Hz), 21.4, 14.2. HRMS (ESI) calcd for 259.0943
C14H16F2NaO2 [M + Na]+ 277.1010, found: 277.1011.
Ethyl 4-(4-chlorophenyl)-4,4-difluoro-2-methylenebutanoate
Ethyl 4,4-difluoro-4-(4-methoxyphenyl)-2-methylenebutanoate (3ha). 48.5 mg, 88% yield, light yellow oil. H NMR (500 MHz,
(3ca). 43.7 mg, 81% yield, light yellow oil. H NMR (500 MHz, CDCl3) δ 7.40–7.34 (m, 4H), 6.37 (s, 1H), 5.75 (s, 1H), 4.08 (q, J
1
1
CDCl3) δ 7.37 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.35 = 7.1 Hz, 2H), 3.19 (t, J = 15.7 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H).
(s, 1H), 5.72 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.19 19F NMR (470 MHz, CDCl3) δ −95.12 (t, J = 15.8 Hz). 13C NMR
4
(t, J = 15.7 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz, (125 MHz, CDCl3) δ 166.3, 136.1(t, JC–F = 2.0 Hz), 135.3 (t,
3
CDCl3) δ −93.57 (t, J = 15.8 Hz). 13C NMR (125 MHz, CDCl3) δ 2JC–F = 27.0 Hz), 132.5 (t, JC–F = 4.1 Hz), 130.7, 128.6, 126.9 (t,
3
2
1
2
166.5, 160.7, 132.9 (t, JC–F = 3.8 Hz), 130.3, 129.0 (t, JC–F
=
3JC–F = 6.2 Hz), 121.1 (t, JC–F = 244.7 Hz), 61.2, 40.4 (t, JC–F
=
3
1
26.9 Hz), 126.8 (t, JC–F = 6.1 Hz), 121.6 (t, JC–F = 243.8 Hz), 29.0 Hz), 14.2. HRMS (ESI) calcd for C13H13ClF2NaO2 [M +
113.6, 61.1, 55.4, 40.5 (t, JC–F = 29.7 Hz), 14.1. HRMS (ESI) Na]+ 297.0464, found: 297.0461.
2
calcd for C14H17F2O3 [M + H]+ 271.1146, found: 271.1140.
Ethyl 4-(4-bromophenyl)-4,4-difluoro-2-methylenebutanoate
1
Ethyl 4,4-difluoro-2-methylene-4-(4-(trifluoromethyl)phenyl) (3ia). 58.2 mg, 91% yield, light yellow oil. H NMR (500 MHz,
butanoate (3da). 47.6 mg, 77% yield, light yellow oil. H NMR CDCl3) δ 7.53 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 6.37
1
(500 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, (s, 1H), 5.75 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.18 (t, J =
2H), 6.39 (s, 1H), 5.78 (s, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.22 (t, J 15.8 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz,
= 15.8 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ −95.33 (t, J = 15.8 Hz). 13C NMR (125 MHz, CDCl3) δ
2
3
CDCl3) δ −62.95 (s), −96.03 (t, J = 15.8 Hz). 13C NMR 166.3, 135.8 (t, JC–F = 27.0 Hz), 132.5 (t, JC–F = 4.0 Hz), 131.6,
(125 MHz, CDCl3) δ 166.0, 140.2 (t, JC–F = 26.8 Hz), 132.2 (t, 130.7, 127.2 (t, 3JC–F = 6.1 Hz), 124.3 (t, 4JC–F = 2.1 Hz), 121.1 (t,
2
3JC–F = 4.2 Hz), 132.1 (q, 2JC–F = 32.1 Hz), 130.8, 125.9 (t, 3JC–F
=
1JC–F = 244.8 Hz), 61.2, 40.4 (t, JC–F = 28.9 Hz), 14.2. HRMS
2
6.2 Hz), 125.3 (q, JC–F = 3.7 Hz), 123.7 (q, JC–F = 272.3 Hz), (ESI) calcd for C13H13BrF2NaO2 [M + Na]+ 340.9959, found:
3
1
1
2
120.7 (t, JC–F = 245.1 Hz), 61.1, 40.3 (t, JC–F = 28.6 Hz), 14.0. 340.9954.
HRMS (ESI) calcd for C14H14F5O2 [M + H]+ 309.0914, found:
309.0911.
Ethyl 4-(2-bromophenyl)-4,4-difluoro-2-methylenebutanoate
(3ja). 57.3 mg, 90% yield, light yellow oil. H NMR (500 MHz,
1
Ethyl 4,4-difluoro-2-methylene-4-(4-nitrophenyl)butanoate CDCl3) δ 7.64 (d, J = 7.9 Hz, 1H), 7.48 (dd, J = 7.8, 1.6 Hz, 1H),
1
(3ea). 25.8 mg, 45% yield, light yellow oil. H NMR (500 MHz, 7.32 (t, J = 7.6 Hz, 1H), 7.28–7.23 (m, 1H), 6.36 (s, 1H), 5.75 (s,
CDCl3) δ 8.26 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 9.0 Hz, 2H), 6.41 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.45 (t, J = 16.1 Hz, 2H), 1.21 (t, J =
(s, 1H), 5.80 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.23 (t, J = 15.9 Hz, 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ −94.34 (t, J = 16.1
2
2H), 1.19 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ Hz). 13C NMR (125 MHz, CDCl3) δ 166.3, 135.5 (t, JC–F = 25.6
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3
3
3
Hz), 134.8, 132.6 (t, JC–F = 3.8 Hz), 131.3, 131.0, 128.2 (t, JC–F 27.6 Hz), 22.1 (t, JC–F = 6.6 Hz), 20.7, 14.1. HRMS (ESI) calcd
= 9.1 Hz), 127.3, 120.8 (t, JC–F = 246.5 Hz), 120.1 (t, JC–F = 3.7 for C16H21F2O2 [M + H]+ 283.1509, found: 283.1516.
1
4
2
Hz), 61.1, 38.4 (t, JC–F = 27.1 Hz), 14.2. HRMS (ESI) calcd for
Ethyl 4,4-difluoro-2-methylenehexanoate (3na). 21.3 mg,
55% yield, light yellow oil. H NMR (500 MHz, CDCl3) δ 6.39
C13H13BrF2NaO2 [M + Na]+ 340.9959, found: 340.9956.
1
Ethyl 4-(3-bromophenyl)-4,4-difluoro-2-methylenebutanoate (s, 1H), 5.81 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.92 (t, J = 16.2 Hz,
1
(3ka). 56.4 mg, 88% yield, light yellow oil. H NMR (500 MHz, 2H), 1.92–1.78 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.5
CDCl3) δ 7.60 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.8 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ −99.62 – −99.79 (m).
3
Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.39 (s, 1H), 5.77 (s, 1H), 4.08 13C NMR (125 MHz, CDCl3) δ 166.7, 133.1 (t, JC–F = 4.3 Hz),
1
2
(q, J = 7.1 Hz, 2H), 3.18 (t, J = 15.9 Hz, 2H), 1.22 (t, J = 7.1 Hz, 129.9, 123.9 (t, JC–F = 242.3 Hz), 61.1, 37.3 (t, JC–F = 26.6 Hz),
3H). 19F NMR (470 MHz, CDCl3) δ −95.60 (t, J = 15.9 Hz). 13C 29.4 (t, 2JC–F = 25.8 Hz), 14.1, 6.4 (t, 3JC–F = 5.6 Hz). HRMS (ESI)
NMR (125 MHz, CDCl3) δ 166.3, 138.9 (t, 2JC–F = 26.8 Hz), 133.1 calcd for C9H15F2O2 [M + H]+ 193.1040, found: 193.1037.
4
3
(t, JC–F = 1.5 Hz), 132.4 (t, JC–F = 3.9 Hz), 130.9, 130.1, 128.6
Ethyl
4-fluoro-2-methylene-4-phenylbutanoate
(3oa).
3
3
1
(t, JC–F = 6.4 Hz), 124.1 (t, JC–F = 6.1 Hz), 122.5, 120.6 (t, JC–F 16.5 mg, 37% yield, light yellow oil. 1H NMR (500 MHz, CDCl3)
2
= 245.3 Hz), 61.3, 40.5 (t, JC–F = 28.6 Hz), 14.2. HRMS (ESI) δ 7.42–7.29 (m, 5H), 6.30 (s, 1H), 5.69 (s, 1H), 5.71–5.58 (m,
calcd for
340.9953.
C
13H13BrF2NaO2 [M
+
Na]+ 340.9959, found: 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.91–2.89 (m, 1H), 2.89–2.81 (m,
1H), 1.31 (t, J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ
Ethyl 4,4-difluoro-2-methylene-4-(naphthalen-1-yl)butanoate −176.27 (m). 13C NMR (125 MHz, CDCl3) δ 166.8, 139.9 (d,
(3la). 23.5 mg, 40% yield, light yellow oil. H NMR (500 MHz, 2JC–F = 19.8 Hz), 135.8 (d, 3JC–F = 3.2 Hz), 128.6, 128.6, 128.5 (d,
1
CDCl3) δ 8.38 (d, J = 8.5 Hz, 1H), 7.94–7.87 (m, 2H), 7.66 (d, J = 4JC–F = 1.8 Hz), 125.6 (d, JC–F = 6.9 Hz), 92.7 (d, JC–F = 173.2
3
1
2
7.1 Hz, 1H), 7.61 (ddd, J = 8.6, 6.8, 1.4 Hz, 1H), 7.54 (ddd, J = Hz), 61.1, 40.4 (d, JC–F = 25.0 Hz), 14.3. HRMS (ESI) calcd for
8.0, 6.9, 1.0 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.43 (s, 1H), 5.78 C13H16FO2 [M + H]+ 223.1134, found: 223.1139.
(s, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 16.6 Hz, 2H), 1.13 (t,
Ethyl 2-methylene-4-phenylbutanoate (3pa). 3.6 mg, 9%
J = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3) δ −92.19 (t, J = 16.6 yield, light yellow oil.1H NMR (500 MHz, CDCl3) δ 7.32–7.24
Hz). 13C NMR (125 MHz, CDCl3) δ 166.5, 134.2, 132.9 (t, 4JC–F
=
=
(m, 2H), 7.22–7.17 (m, 3H), 6.16 (d, J = 1.4 Hz, 1H), 5.50 (q, J =
1.3 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.82–2.77 (m, 2H),
2
4
3.0 Hz), 132.3 (t, JC–F = 24.1 Hz), 131.1, 130.9, 129.6 (t, JC–F
3
2.3 Hz), 129.0, 127.1, 126.1, 125.0 (t, JC–F = 4.4 Hz), 124.6, 2.66–2.59 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).13C NMR (125 MHz,
124.5 (t, 3JC–F = 9.3 Hz), 122.3 (t, 1JC–F = 245.2 Hz), 61.1, 40.6 (t, CDCl3) δ 167.1, 141.5, 140.2, 128.5, 128.4, 125.9, 125.1, 60.7,
2JC–F = 27.5 Hz), 14.1. HRMS (ESI) calcd for C17H17F2O2 [M + 34.9, 33.9, 14.2. HRMS (ESI) calcd for
C13H17O2 [M +
H]+ 291.1196, found: 291.1199.
Ethyl
H]+205.1228, found: 205.1233.
3,3-difluoro-1-((phenylsulfonyl)methyl)-2,3-dihydro-
1-Bromo-4-(1,1-difluorobut-3-en-1-yl)benzene (3ib). 25.6 mg,
1H-phenalene-1-carboxylate (3la′). 27.8 mg, 32% yield, white 52% yield, colourless oil. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J
1
solid, m.p. = 168–169 °C. H NMR (500 MHz, CDCl3) δ 7.97 (d, = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 5.71 (ddt, J = 17.3, 10.3,
J = 8.2 Hz, 1H), 7.96–7.92 (m, 3H), 7.84 (d, J = 8.2 Hz, 1H), 7.71 7.1 Hz, 1H), 5.24–5.10 (m, 2H), 2.87 (td, J = 15.7, 7.1 Hz, 2H). 19
F
(d, J = 7.4 Hz, 1H), 7.65–7.57 (m, 2H), 7.57–7.50 (m, 2H), NMR (470 MHz, CDCl3) δ −95.06 (t, J = 15.7 Hz). 13C NMR
2
7.50–7.45 (m, 1H), 4.44 (dq, J = 10.7, 7.1 Hz, 1H), 4.35 (dq, J = (125 MHz, CDCl3) δ 136.1 (t, JC–F = 27.0 Hz), 131.7, 128.8 (t,
10.8, 7.1 Hz, 1H), 4.15 (dd, J = 14.7, 1.4 Hz, 1H), 3.90 (d, J = 3JC–F = 5.3 Hz), 127.0 (t, JC–F = 6.2 Hz), 124.2 (t, JC–F = 2.2 Hz),
14.8 Hz, 1H), 3.64 (ddd, J = 15.0, 10.6, 6.6 Hz, 1H), 3.34 (dddd, 121.6 (t, 1JC–F = 243.5 Hz), 121.0, 43.7 (t, 2JC–F = 28.3 Hz). HRMS
J = 32.3, 15.0, 5.8, 1.2 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H).19F NMR (ESI) calcd for C10H10BrF2 [M + H]+ 246.9934, found: 246.9937.
3
4
(470 MHz, CDCl3) δ −75.24 (ddd, J = 268.3, 32.2, 10.4 Hz),
1-Bromo-4-(1,1-difluoro-3-methylbut-3-en-1-yl)benzene (3ic).
1
−93.81 (dt, J = 268.1, 5.9 Hz). 13C NMR (125 MHz, CDCl3)δ 16.9 mg, 32% yield, colourless oil. H NMR (500 MHz, CDCl3)
4
4
171.4 (d, JC–F = 1.7 Hz), 142.1, 133.6, 131.3 (d, JC–F = 3.0 Hz), δ 7.54 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 4.91 (s, 1H),
3
2
130.4 (t, JC–F = 1.3 Hz), 129.3, 129.1, 128.3(dd, JC–F = 25.3, 4.71 (s, 1H), 2.82 (t, J = 16.3 Hz, 2H), 1.72 (s, 3H). 19F NMR
23.4 Hz), 127.8, 126.9 (d, JC–F = 3.6 Hz), 126.9 (d, JC–F = 3.6 (470 MHz, CDCl3) δ −93.48 (t, J = 16.3 Hz). 13C NMR (125 MHz,
4
4
4
3
3
2
Hz), 126.3, 126.0 (d, JC–F = 2.9 Hz), 125.4, 123.1 (dd, JC–F
=
=
CDCl3) δ 137.2 (t, JC–F = 3.7 Hz), 136.3 (t, JC–F = 27.1 Hz),
1
4
6.5, 2.9 Hz), 118.6 (dd, JC–F = 238.4, 234.6 Hz), 63.4 (d, JC–F
131.6, 127.0 (t, 3JC–F = 6.2 Hz), 124.1 (t, 4JC–F = 2.2 Hz), 122.0 (t,
5.0 Hz), 63.0, 49.6 (d, JC–F = 10.4 Hz), 35.7 (dd, JC–F = 26.7, 1JC–F = 244.9 Hz), 117.5, 47.2 (t, JC–F = 27.6 Hz), 23.6 (t, JC–F
=
3
2
2
4
24.9 Hz), 14.1. HRMS (ESI) calcd for C23H21F2O4S [M + H]+ 1.7 Hz). HRMS (ESI) calcd for C11H12BrF2 [M + H]+ 261.0090,
431.1128, found: 431.1124.
found: 261.0097.
Ethyl 4,4-difluoro-4-mesityl-2-methylenebutanoate (3ma).
1-Bromo-4-(1,1-difluoro-3-phenylbut-3-en-1-yl)benzene (3id).
49.2 mg, 87% yield, light yellow oil. 1H NMR (500 MHz, CDCl3) 10.8 mg, 17% yield, colourless oil. H NMR (500 MHz, CDCl3)
δ 6.86 (s, 2H), 6.43 (s, 1H), 5.82 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), δ 7.49 (d, J = 8.7 Hz, 2H), 7.32–7.24 (m, 7H), 5.45 (s, 1H), 5.13
3.21 (t, J = 16.5 Hz, 2H), 2.43 (t, J = 4.4 Hz, 6H), 2.27 (s, 3H), (s, 1H), 3.35 (t, J = 15.3 Hz, 2H). 19F NMR (470 MHz, CDCl3) δ
1.26 (t, J = 7.1 Hz, 3H).19F NMR (470 MHz, CDCl3) δ −87.4− −93.13 (t, J = 15.3 Hz). 13C NMR (125 MHz, CDCl3) δ 140.9,
1
−87.6 (m). 13C NMR (125 MHz, CDCl3) δ 166.6, 138.8, 136.3 (t, 140.2 (t, JC–F = 4.2 Hz), 136.0 (t, JC–F = 27.1 Hz), 131.5, 128.4,
3
2
4
2
3
4
3JC–F = 3.1 Hz), 132.7 (t, JC–F = 2.2 Hz), 131.0, 130.7 (t, JC–F
=
=
127.7, 127.1 (t, JC–F = 6.2 Hz), 126.4, 124.1(t, JC–F = 2.1 Hz),
1
2
1
2
23.5 Hz), 130.5, 123.9 (t, JC–F = 246.6 Hz), 61.0, 39.8 (t, JC–F
121.8 (t, JC–F = 245.2 Hz), 119.4, 44.8 (t, JC–F = 28.3 Hz).
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HRMS (ESI) calcd for C16H14BrF2 [M + H]+ 323.0247, found:
323.0244.
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Conflicts of interest
The authors declare that they have no known competing finan-
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to influence the work reported in this paper.
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Acknowledgements
We are grateful to the Ministry of Science and Technology of
the People’s Republic of China (2017YFB0404700) and the
Science Foundation of Shanghai Municipal Commission of
Sciences and Technology (15230724800) for their financial
support. We also thank the Instrumental Analysis and
Research Center of Shanghai University for assistance.
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