Ag-Catalyzed Chemoselective Decarboxylative Mono- and gem-Difluorination of Malonic Acid Derivatives

Article abstract of DOI:10.1021/jacs.9b00681

Malonic acid derivatives have been successfully applied in a Ag-catalyzed decarboxylative fluorination reaction, providing an unprecedented route to either gem-difluoroalkanes or α-fluorocarboxylic acids by the judicious selection of base and solvent. This reaction features the use of readily available starting materials, tunable chemoselectivity and good functional group compatibility as well as gram-scale synthetic capability. The advantage of using malonic acid derivatives in this radical decarboxylative functionalization is further highlighted by the facile transformations of the α-fluorocarboxylic acid to valuable fluorine-containing compounds. Preliminary mechanistic studies suggest that an α-carboxylic acid radical is involved in this reaction.

Full text of DOI:10.1021/jacs.9b00681

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Communication
Ag-Catalyzed Chemoselective Decarboxylative Mono-
and gem-Di-Fluorination of Malonic Acid Derivatives
Zhen Wang, Cong-Ying Guo, Cheng Yang, and Jian-Ping Chen
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 25 Mar 2019
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Page 1 of 6
Journal of the American Chemical Society
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Ag-Catalyzed Chemoselective Decarboxylative Mono- and gem-Di-
Fluorination of Malonic Acid Derivatives
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Zhen Wang, Cong-Ying Guo, Cheng Yang, Jian-Ping Chen*
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China
Supporting Information Placeholder
dedicated toward the incorporation of gem-difluoromethylene
group into small molecules. However, achievements have mainly
a) Radical decarboxylative functionalization (RDF) of monocarboxylic acid
ABSTRACT: Malonic acid derivatives have been successfully
applied in a Ag-catalyzed decarboxylative fluorination reaction,
providing an unprecedented route to either gem-difluoroalkanes or
α-fluorocarboxylic acids by the judicious selection of base and
solvent. This reaction features the use of readily available starting
materials, tunable chemoselectivity and good functional group
compatibility as well as gram-scale synthetic capability. The
advantage of using malonic acid derivatives in this radical
decarboxylative functionalization is further highlighted by the
facile transformations of the α-fluorocarboxylic acid to valuable
fluorine-containing compounds. Preliminary mechanistic studies
suggest that an α-carboxylic acid radical is involved in this
reaction.
- CO2
R1 COOH
R1 R2
R1
R2 = F, Cl, Br, N3, Bpin, OH,
CF3, alkynyl, allyl, Ar, alkyl etc.
monocarboxylic acids
alkyl radical
b) Double Hunsdiecker and oxidative decarboxylation reactions of malonic acid derivatives
HgO (stoichiometric)
Br2
Pb(OAc)4 (stoichiometric)
or Electrolysis
O
Br
R1 R2
HOOC
COOH
Br
R1 R2
R1
R2
c) Photoredox hydrodecarboxylation of malonic acid derivatives
Mes-Acr-Ph (cat.)
PhS-SPh (cat.)
HOOC
COOH
H
H
R1 R2
R1 R2
KOt-Bu
450 nm LEDs
Carboxylic acids are appealing starting materials because of their
stability, broad availability and low cost. Recently, the
development of novel transformations with carboxylic acids as
starting materials has attracted much attention.1 Among them,
radical decarboxylative functionalization (RDF) has emerged as a
powerful strategy to efficiently construct carbon-carbon and
carbon-heteroatom bonds (Scheme 1a).2 The strength of this
methodology lies in its ability to generate alkyl radicals through a
radical decarboxylation and capture the carbon radicals under mild
conditions. Nevertheless, the carboxylic acids used in RDFs have
been predominantly restricted to monocarboxylic acids. Malonic
acid derivatives are classical building blocks, which can be readily
accessible via alkylations of malonic ester and subsequent
hydrolysis;3 however, the corresponding RDFs of malonic acids
have rarely been reported. Early studies demonstrated that
disubstituted malonic acid derivatives could undergo double
Hunsdiecker or oxidative decarboxylation reactions in the presence
of excess toxic metals or under electrochemical conditions
(Scheme 1b).4,5 A notable example was reported by the Nicewicz
group, who applied gem-dicarboxylic acids in a photoredox
hydrodecarboxylation reaction, but the increased oxidation
potential caused by the second carboxylic acid moiety through
hydrogen bonding makes them challenging substrates, and a strong
base was necessary for this transformation (Scheme 1c).6 Being
aware that the utilization of malonic acid derivatives in RDF
remains largely elusive, especially in a catalytic manner, we are
particularly interested in exploring their novel radical
decarboxylative reactions and exploiting malonic acid as a
promising synthon in organic synthesis.
d) This work:
F
F
R1 R2
R1
R2
HOOC
HOOC
COOH
AgNO3 (cat.)
R1 R2
malonic acid derivatives
Selectfluor
base, solvent
-carboxylic acid radical
key intermediate
F
COOH
R1 R2
e) Representative drugs containing a gem-difluoromethylene group
F
F
NH2
O
F
F
N
HO
N
O
HO
O
HN
O
Me
N
F
O
O
N
N
OH
F
OH
N
Maraviroc
HIV-1 therapeutic agent
Tafluprost
ocular hypertension drug
Gemcitabine
chemotherapy drug
Scheme 1. Radical Decarboxylative Functionalization and
Representative Drugs Containing a gem-Difluoromethylene
Group
been made in the formation of aryl-CF2R bonds,8 but methods for
the synthesis of gem-difluoroalkanes (Csp3-CF2-Csp3) are less
developed.
Conventional
approaches
for
preparing
difluoroalkylated alkanes include deoxyfluorination of ketones and
hydrofluorination
difluoroalkanes can be obtained via
difluoroalkylation or a nickel-catalyzed tandem difluoroalkylation-
arylation of activated alkenes.11,12 Despite recent advances, the
limitations of the aforementioned methods such as harsh reaction
conditions, poor functional group tolerance, poor availability of
starting materials and limited scope have impeded their
applications in organic synthesis to a certain extent. Given their
of
alkynes.9,10
Alternatively,
gem-
a
light-induced
gem-Difluoromethylene group is a valuable fluorinated motif
that is widely present in pharmaceuticals and biologically active
compounds (Scheme 1e).7,8 As a result, great efforts have been
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
significance in medicinal chemistry, the exploration of a general
and practical approach for the efficient synthesis of gem-
difluoroalkanes is highly desirable.
CH3CN/H2O/n-Hex (1/1/3) in the presence of AgNO3 (30 mol%)
by using PhCO2Na (3.0 equiv) as the base (entry 15). When the
base was changed to K2HPO4, the reaction in CPME/H2O (1/1) at
room temperature exclusively provided α-fluorocarboxylic acid 3a
in an isolated yield of 54% (entry 14). This tunable
chemoselectivity realized by simply varying the reaction conditions
offers an expedient way of selectively introducing fluorine atoms
into small molecules. Control experiments showed that the solvent
had a substantial impact on the chemoselectivity of this reaction
(entries 15 and 16) and the silver catalyst was essential for these
transformations (entries 17 and 18).
1
2
3
4
5
6
7
8
Although the application of monocarboxylic acids in radical
decarboxylative fluorinations has been well-documented,13 to the
best of our knowledge, the generation of α-carboxylic acid radicals
through radical decarboxylation of malonic acid derivatives and
subsequent trapping of the resulting radicals with a fluorine reagent
is unprecedented. Herein, we describe the successful application of
malonic acid derivatives in a silver-catalyzed decarboxylative
fluorination. The chemoselectivity of this reaction was tunable,
providing valuable access to either gem-difluoroalkanes or α-
fluorocarboxylic acids (Scheme 1d).
9
Table 2. Scope of Decarboxylative gem-Difluorinationa-c
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12
13
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15
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59
60
HOOC COOH
F
F
F
COOH
AgNO3 (30 mol%)
+
Inspired by Li’s elegant work on the Ag-catalyzed
decarboxylative fluorination of monocarboxylic acids,13a we
commenced our study with the reaction of 2-(4-chlorophenethyl)-
2-ethylmalonic acid (1a) and Selectfluor in the presence of AgNO3
(20 mol%)in aqueous acetone or acetonitrile at 55 °C. Delightfully,
gem-difluorinated product 2a and monofluorinated product 3a were
produced after 12 h, albeit in low yields and poor ratios of 2a/3a
(Table 1, entries 1 and 2). Next, we examined the effect of base on
this reaction. Generally, the addition of base could promote the
formation of 2a (entries 4-9), except for KOH (entry 3). When
PhCO2K or PhCO2Na were employed, 2a was produced as the
major product in a 31% yield with the ratio of 2a/3a being 84/16
(entries 6 and 7). The investigation of the solvents with PhCO2Na
as the base revealed that the solvent played an important role in
controlling the chemoselectivity (entry 7 vs entries 10-13).
Interestingly, when biphasic systems (CH2Cl2/H2O or CPME/H2O)
were employed, the monofluorinated product 3a was generated
exclusively (entries 10 and 13).
R1
R2
PhCO2Na, Selectfluor
R1
R2
R1
R2
1
2
3
CH3CN/H2O/n-hexane
F
F
F
F
F F
F
F
Ph
Cl
Cl
Cl
2bd
2 3
/
2dd,e
2 3
/
2a
, 60%;
2c
, 51%;
2 3
/ > 95/5
, 69%;
> 95/5
, 77%;
> 95/5
2 3
/
> 95/5
F
F
F
F
F
F
F
F
F
F
Ph
Ph
Ph
Ph
2ff
2 3
/
2gf
, 55%;
2e
, 60%;
2h
2 3
/
, 80%;
> 95/5
, 72%;
> 95/5
2 3
/
> 95/5
2 3
/
= 90/10
O
F
F
F
F
O
F
N
O
F
HOOC
O
O
2ih
2 3
/
2jd
2 3
/
2kf
2 3
/
2lf
2 3
/
, 66%;
> 95/5
, 77%;
> 95/5
, 55%;
> 95/5
, 69%;
> 95/5
F
F
F
F
F
F
F
O
S
F
BzN
Table 1. Optimization of Reaction Conditionsa
CN
, 62%;
O
Cl
2nf
2 3
/
2od
2 3
/
, 79%;
> 95/5
2pg,i, 81%;
2/3 = 90/10
2m
2 3
/
, 85%;
> 95/5
= 90/10
AgNO3 (20 mol%)
Selectfluor (4.0 equiv.)
COOH
F
COOH
F
O
N
O
Br
F
F
F
F
+
F
F
COOH
F
Base, Solvent
55 °C
Ph
F
Cl
Cl
Cl
F
O
OH
1a
2a
ratio
3a
O
H
2sf
2 3
/
2qf
2 3
/
2rf
2 3
/
2ti,j
2 3
, 21%;
/ = 54/46
, 35%;
> 95/5
, 58%;
= 95/5
, 74%;
> 95/5
base
solvent
(V/V)
2a
3a
yield
(%)b
yield
(%)b
entry
(equiv)
(2/ 3)
unsuccessful substrates
HOOC COOH
-
Acetone/H2O (1/1)
CH3CN/H2O (1/1)
Acetone/H2O (1/1)
Acetone/H2O (1/1)
Acetone/H2O (1/1)
Acetone/H2O (1/1)
Acetone/H2O (1/1)
Acetone/H2O (1/1)
Acetone/H2O (1/1)
DCM/H2O (1/1)
1
2
48/52
21/79
32/68
76/24
71/29
84/16
84/16
59/41
63/37
0/100
21/79
27/73
4/96
10
4
11
15
13
5
COOH
COOH
COOH
COOH
AcHN
-
COOH
COOH
1w
Ph
Ph
EtO
5
KOH (2.0)
3
6
Br
Et
1v
1x
1u
K3PO4 (2.0)
K2HPO4 (2.0)
PhCO2K (2.0)
PhCO2Na (2.0)
K2CO3 (2.0)
Et3N (2.0)
4
16
17
31
31
10
17
0
5
6
aReaction condition: 1 (0.2 mmol), AgNO3 (0.06 mmol), Selectfluor (1.2 mmol), PhCO2Na (0.5
mmol), CH3CN (0.6 mL), H2O (0.6 mL), n-hexane (1.8 mL), 55 °C, under N2. bIsolated yield. cThe
2/3 ratio was determined by 19F NMR. dK2HPO4 (0.4 mmol) instead of PhCO2Na. e19F NMR yield
6
6
7
6
f
with 4-fluorobenzoic acid as the internal standard. PhCO2Na (0.7 mmol), CH3CN (1.0 mL), H2O
(1.0 mL) and n-hexane (3.0 mL) as solvent, rt. gAgNO3 (0.04 mmol), K2HPO4 (0.6 mmol). hK2CO3
(0.6 mmol), DCE (2.0 mL) and H2O (2.0 mL). iCH3CN (2.0 mL) and H2O (2.0 mL) were used as the
solvent. jSelectfluor (1.6 mmol), K2HPO4 (0.8 mmol).
8
7
9
10
18
15
16
25
PhCO2Na (2.0)
PhCO2Na (2.0)
PhCO2Na (2.0)
PhCO2Na (2.0)
K2HPO4 (4.0)
10
11
12
13
14c
15d
16d
17e
18e
CH3CN/H2O (1/1)
n-Hex/H2O (1/1)
CPME/H2O (1/1)
CPME/H2O (1/1)
4
With the optimal conditions established, the substrate scope of
decarboxylative gem-difluorination was examined (Table 2).
Generally, for disubstituted malonic acids, the reaction proceeded
smoothly, affording gem-difluorinated compounds 2 in moderate to
good yields with excellent chemoselectivities. The reactions of
simple dialkyl-substituted gem-dicarboxylic acids exclusively
produced gem-difluoroalkanes 2a-2g in 51-77% yields. Increasing
the steric hindrance at the α-position of the malonic acids had no
obvious deleterious effects on the reactivity or selectivity (2a-2c).
Aryl- and alkyl-substituted malonic acids were tolerated in this
transformation, and two fluoro substituents could be effectively
installed at the benzylic position (2h and 2i). In addition, cyclic
malonic acids were also suitable substrates, furnishing 2o and 2p
in good yields. Notably, malonic acids bearing functional groups,
including phthalimide (2j), ester (2k), ether (2q), sulfone (2n),
benzoic acid (2i), cyanide (2m), amide (2p) and ketone (2l and 2r)
were well tolerated in this system, providing gem-difluoro
compounds 2 in 55-85% yields with excellent chemoselectivities.
6
1
56 (54)
2/98
1
PhCO2Na (3.0) CH3CN/H2O/n-Hex (1/1/3)
69 (60)
100/0
7/93
0
14
0
PhCO2Na (3.0)
K2HPO4 (4.0)
CPME/H2O (1/1)
CPME/H2O (1/1)
1
0
0
0
PhCO2Na (3.0) CH3CN/H2O/n-Hex (1/1/3)
0
0
aReaction conditions: 1a (0.1 mmol), AgNO3 (0.02 mmol), Selectfluor (0.4 mmol), base, solvent
(2 mL), 55 °C, 12 h under N2. b19F NMR yield with 4-fluorobenzoic acid as the internal standard,
isolated yield in parentheses. cSelectfluor (0.2 mmol), rt. d1a (0.1 mmol), AgNO3 (0.03 mmol),
Selectfluor (0.6 mmol), base, solvent (1.5 mL). eWithout AgNO3. CPME = cyclopentyl methyl ether;
n-Hex = n-hexane.
Based on the above findings, an extensive study of the reaction
parameters was conducted to further improve the yields.
Ultimately, the gem-difluorinated compound 2a could be obtained
predominantly in an isolated yield of 60% by the reaction of 1a (0.1
mmol) with Selectfluor (0.6 mmol) in a mixed solvent of
ACS Paragon Plus Environment

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Journal of the American Chemical Society
Secondary alcohol partially survived to afford product 2s in 35%
To demonstrate the practical utility of this unprecedented
decarboxylative fluorination, gram-scale reactions were carried out
(Scheme 2a). From the same starting material 1p, gem-
difluoroalkane 2p and α-fluorocarboxylic acid 3p were obtained in
good yields and excellent selectivities. Notably, α-fluorocarboxylic
acids 3 are of particular versatility, as the remaining carboxylic acid
group provides spacious room for further elaboration. The utility of
the α-fluorocarboxylic acid has been showcased by the facile
conversions of compound 3p to a series of valuable fluorine-
containing building blocks, such as gem-chloro fluoroalkane 4,2a,18
tertiary propargylic fluoride 52b,19 and γ-fluoride Michael adduct
62g via radical decarboxylative functionalization (Scheme 2b).
These results clearly demonstrate the potential applications of this
protocol for the late-stage diversification of fluorinated bioactive
compounds.
1
2
3
4
5
6
7
8
yield, along with 33% yield of corresponding ketone product.14
Alkynyl and alkenyl groups (1u and 1v) were not compatible with
such oxidative conditions. Only oxidative decarboxylation
products were observed for the α-heteroatom substituted malonic
acids (1w and 1x).5 Furthermore, the decarboxylative gem-
difluorination of monosubstituted malonic acid was also examined;
unfortunately, product 2t was obtained in a low yield with poor
chemoselectivity.15
Subsequently, we turned our attention to extending the substrate
scope of decarboxylative monofluorination. As illustrated in Table
3, the substrates that can participate in the decarboxylative gem-
difluorination are also suitable for this monofluorination reaction,
predominately producing α-fluorocarboxylic acids in 30-92%
yields;16 the exception is aryl-substituted malonic acids, which only
produced gem-difluorides (2h and 2i). We attribute the different
chemoselectivity of aryl-substituted malonic acids in this system to
the reaction rate of the second decarboxylative fluorination being
accelerated due to the stabilization of the corresponding benzylic
radical. In contrast to the decarboxylative gem-difluorination,
introduction of sterically encumbered groups at the α-position of
the malonic acids compromised the reaction efficiency (3c vs 3b
and 3e vs 3d), but 3c and 3e could still be obtained in synthetically
useful yields. Generally, methods for accessing tertiary α-
fluorocarboxylic acid derivatives rely on electrophilic fluorination
of the corresponding ester enolates and subsequent hydrolysis;17
however, the harsh reaction conditions of these protocols showed
limited functional group compatibility. In comparison, our mild
reaction conditions for α-fluorocarboxylic acids accommodate a
variety of functional groups, such as aryl halide (3a-3c, 3o and 3r),
phthalimide (3j), ester (3k), ether (3q), sulfone (3n), cyanide (3m),
amide (3p), ketone (3l and 3r), alcohol (3s) and alkyne (3u).
Substrates 1v-1x are not viable for this transformation. Pleasingly,
the reaction of monosubstituted malonic acid delivered product 3t
in 41% yield with a 2/3 ratio of 21/79.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2p
3p
and
a) Gram-scale synthesis of
F
F
HOOC COOH
2p
F COOH
Table 2
reaction condition for
Table 3
standard condition
4 h
5 h
N
N
N
78% yield;
95% yield;
Bz
2p
Bz
Bz
3p
1p
2p 3p
2p 3p
/ < 5/95
/
> 95/5
1.0 gram
3p
b) Transformations of compound
F
Cl
Ag(Phen)2OTf (10 mol%)
t-BuOCl, CH3CN, 50 °C
N
83%
Bz
4
TIPS
F
COOH
F
AgNO3 (30 mol%)
K2S2O8, TIPS-EBX
N
Bz
3p
CH3CN/H2O, 55 °C
58%
N
Bz
5
6
Table 3. Scope of Decarboxylative Monofluorinationa-c
CO2Et
CO2Et
F
Ir[df(CF3)ppy]2(dtbbpy)PF6 (3 mol%)
Diethyl ethylidenemalonate
HOOC COOH
R1 R2
F
F
F
COOH
AgNO3 (20 mol%)
+
R1
R2
R1
R2
3
K2HPO4, Selectfluor
CPME/H2O
1
2
N
K2HPO4, blue LED
DMF, rt
Bz
F
COOH
Cl
F
COOH
F COOH
F
COOH
Ph
78%
Scheme 2. Synthetic Applications
Cl
Cl
3cd,e
3a
3b
3d
, 76%;
, 54%;
, 61%;
, 30%;
2 3
2 3
2 3
/
< 5/95
/
< 5/95
/
< 5/95
2 3
/
= 22/78
Cl
N
O
F
N
COOH
R1
R2
F
COOH
F
COOH
Ph
2 BF4
8
HOOC
F
N
O
Ph
Ag(II)
HOOC COO
COOH
Ph
Selectfluor
R1 R2
10
11
O
O
path a
-CO2
Selectfluor
3ed
, 60%;
3j
, 92%;
2 3
/
3f
3k
, 63%;
, 47%;
8
2 3
/
< 5/95
2 3
/
< 5/95
< 5/95
2 3
/
= 18/82
Cl
BF4
N
F
HOOC
F
COOH
N
COOH
F
COOH
HOOC
F
path b
F
O
S
O
Ag(I)
HOOC COO
9
R1 R2
R1 R2
7
8
3
CN
O
Cl
base
3l
, 78%;
2 3
/
3m,
2 3
/
3n
2 3
/
3o
74%;
< 5/95
, 80%;
< 5/95
, 58%;
Ag(I)
base
2 3
/ = 17/83;
dr = 3.5/1
< 5/95
Ag(I)
F
COO
R1 R2
12
8
Br
F
COOH
F
COOH
Ph
F
F
COOH
HOOC COOH
F
F
COOH
path b
R1 R2
1
R1 R2
9
BzN
O
OH
3s
O
2
3p
, 87%;
2 3
/
3q
2 3
/
, 80%;
< 5/95
3r
, 78%;
2 3
/
, 78%;
Selectfluor
-CO2
F
COOAg(II)
R1 R2
13
< 5/95
2 3
/
= 9/91;
< 5/95
path a
8
dr = 1/1
O
R1
R2
F
COOH
5
F
Selectfluor
F
8
Ph
COOH
N
F
14
COOH
Et
H
O
3te,f
2 3
3u
, 58%;
2 3
/
3v
, 14%;
2 3
/ < 5/95
, 41%;
< 5/95
Scheme 3. Proposed Mechanism
/
= 21/79
aReaction condition: 1 (0.2 mmol), AgNO3 (0.04 mmol), Selectfluor (0.4 mmol), K2HPO4 (0.8
mmol), CPME (2.0 mL), H2O (2.0 mL), rt under N2. bIsolated yield for the corresponding methyl
ester. cThe ratio of 2/3 was determined by 19F NMR. dAgNO3 (0.06 mmol), Selectfluor (0.8 mmol),
PhCO2Na (0.7 mmol), CPME (9.0 mL), CH3CN (1.0 mL), n-hexane (3.0 mL), H2O (1.0 mL), rt. e55
°C. fAgNO3 (0.06 mmol), Selectfluor (1.2 mmol), CH3CN (0.8 mL), H2O (3.2 mL).
Based upon our experimental results and literature
precedents,13a,20 a tentative reaction mechanism was proposed
(Scheme 3). Initially, facilitated by a weak base, malonic acid 1
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reacts with a catalytic amount of Ag(I) to form malonic acid
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
5
6
7
8
monosilver(I) salt 7,21 which is readily oxidized to Ag(II) 10 by
Selectfluor with concomitant generation of 8; alternatively, the
newly formed Selectfluor radical cation 8 is also capable of
oxidizing Ag(I) to Ag(II).20 Then, the carboxylate anion loses an
electron to Ag(II), and subsequent CO2 extrusion delivers an α-
carboxylic acid radical 11 and regenerates Ag(I). The resulting
radical 11 abstracts a fluorine atom from Selectfluor to give product
3. In the decarboxylative monofluorination, the reaction ceases at
this stage and α-fluorocarboxylic acid 3 is the final product. In the
decarboxylative gem-difluorination, compound 3 would undergo a
second decarboxylative fluorination (3 → 12 → 13 → 14 → 2) to
eventually produce gem-difluorinated product 2.
Detailed experimental procedures, spectral data, and analytical data
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Jian-Ping Chen: ias_jpchen@njtech.edu.cn
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22
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Notes
The authors declare no competing financial interest.
Although the mechanism of the silver-catalyzed decarboxylative
fluorination of monocarboxylic acids has been well studied,20 the
radical decarboxylation of malonic acid derivatives to generate α-
carboxylic acid radicals in a Ag(I)/Selectfluor system is unknown.
To support the above mechanistic hypothesis, radical clock 15 was
subjected to our standard decarboxylative monofluorination
conditions, and the ring-opening product 16 was obtained in 54%
yield (Scheme 4, eq 1), which suggested the involvement of α-
carboxylic acid radical 11 in this transformation. Moreover, the
successful conversion of 3p to gem-difluoroalkane 2p (eq 2) and
the observation of monofluorinated product 3 as a side product in
the decarboxylative gem-difluorination (Table 2) implied that α-
fluorinated carboxylic acid 3 was the intermediate in the formation
of gem-difluoroalkanes.22 Additionally, 3p could not be converted
to 2p by decarboxylative monofluorination (eq 3). Although the
ACKNOWLEDGMENT
This paper is dedicated to Professor Li-Xin Dai on the occasion of
his 95th birthday. Financial support from the National Natural
Science Foundation of China (21702104), the Natural Science
Foundation of Jiangsu Province, China (BK20170983), and a Start-
up Grant from Nanjing Tech University (39837120) are gratefully
acknowledged. We also appreciate the SICAM Fellowship by
Jiangsu National Synergetic Innovation Center for Advanced
Materials.
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origin of this intriguing chemoselectivity is not yet clear,23
a
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laboratory.
Table 3
standard condition
F
Me
Me
COOH
+
Ph
(1)
(2)
Ph
Ph
COOH
COOH
HOOC
15
F
17
16
54% yield
not observed
F
COOH
F F
Table 2
standard condition
N
N
Bz
3p
Bz
2p
67% yield
F
COOH
F
F
F COOH
Table 3
standard condition
(3)
+
N
N
N
Bz
3p
Bz
2p
< 5% 19FNMR yield
Bz
3p
recovered in 90% yield
Scheme 4. Mechanistic Experiments
In summary, we have successfully developed a silver-catalyzed
decarboxylative fluorination reaction of malonic acid derivatives.
Tunable chemoselectivity was realized by the judicious selection
of base and solvent, which offers an expedient way to access gem-
difluoroalkanes and α-fluorocarboxylic acids. The advantage of
using malonic acid derivatives in RDF was further highlighted by
the facile transformations of the α-fluorocarboxylic acid to some
valuable fluorine-containing compounds. More importantly, this
work constitutes the first example of the generation of α-carboxylic
acid radicals through the decarboxylation of malonic acid
derivatives in a Ag(I)/Selectfluor system. Given the operational
simplicity and good functional group tolerance as well as the use of
readily available starting materials, we believe that the present
protocol will provide a powerful tool for the preparation of valuable
fluorinated compounds.
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Journal of the American Chemical Society
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60
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(23) Since the chemoselectivity was mainly caused by the different
reactivities of α-fluorocarboxylic acid 3 (Scheme 3) in decarboxylative
mono- and gem-difluorination, we speculate that the contrasting reactivity
behavior of 3 under different conditions might be due to different existing
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1
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Insert Table of Contents artwork here
F
F
3
4
5
6
R1 R2
2
HOOC
COOH
R1
R2
2/3
= 90->95:10-5
35-85% yields
HOOC
R1 R2
AgNO3 (cat.)
1
Selectfluor
solvent, base
-carboxylic acid radical
malonic acid derivative
R1= Ar, Alkyl; R2 = Alkyl
7
key intermediate
F
COOH
8
R1 R2
9
3
3/2
= 78->95:22-5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
30-92% yields
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