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Ag-Catalyzed Chemoselective Decarboxylative Monoand 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 Downloaded from http://pubs.acs.org on March 25, 2019
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Journal of the American Chemical Society
Ag-Catalyzed Chemoselective Decarboxylative Mono- and gem-DiFluorination of Malonic Acid Derivatives 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 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.
dedicated toward the incorporation of gem-difluoromethylene group into small molecules. However, achievements have mainly a) Radical decarboxylative functionalization (RDF) of monocarboxylic acid - CO2
R1 COOH monocarboxylic acids
R2
2
R = F, Cl, Br, N3, Bpin, OH, CF3, alkynyl, allyl, Ar, alkyl etc.
alkyl radical
b) Double Hunsdiecker and oxidative decarboxylation reactions of malonic acid derivatives Br
Br
HgO (stoichiometric) HOOC
R1 R2
COOH Pb(OAc)4 (stoichiometric)
R1 R2
Br2
O R1
or Electrolysis
R2
c) Photoredox hydrodecarboxylation of malonic acid derivatives Mes-Acr-Ph (cat.) PhS-SPh (cat.)
COOH
HOOC
R1 R2
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. 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
R1
R1
H
H
R1 R2
KOt-Bu 450 nm LEDs
d) This work: F HOOC
COOH
AgNO3 (cat.)
HOOC
F
R1 R2
R1 R2
R1 R2
Selectfluor -carboxylic acid radical base, solvent key intermediate malonic acid derivatives
F
COOH
R1 R2
e) Representative drugs containing a gem-difluoromethylene group F F F
F
NH2
O
N HO
HN
O
Me N
HO
O O
N N
Maraviroc HIV-1 therapeutic agent
N
OH
O
Tafluprost ocular hypertension drug
N
O
F
OH F 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 of alkynes.9,10 Alternatively, gemdifluoroalkanes can be obtained via a light-induced difluoroalkylation or a nickel-catalyzed tandem difluoroalkylationarylation 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
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significance in medicinal chemistry, the exploration of a general and practical approach for the efficient synthesis of gemdifluoroalkanes is highly desirable. 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 αfluorocarboxylic acids (Scheme 1d). 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).
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).
Table 2. Scope of Decarboxylative gem-Difluorinationa-c HOOC COOH
Cl
AgNO3 (20 mol%) Selectfluor (4.0 equiv.)
F
COOH
Base, Solvent 55 °C
F
1a
Cl
1
COOH
F F
Cl
Cl
Ph
2a yield (%)b
3a yield (%)b
1
-
Acetone/H2O (1/1)
48/52
10
11
-
CH3CN/H2O (1/1)
21/79
4
15
Ph 2ff , 72%; 2/3 > 95/5
HOOC
F
32/68
6
13
Acetone/H2O (1/1)
76/24
16
5
1u
5
K2HPO4 (2.0)
Acetone/H2O (1/1)
71/29
17
6
6
PhCO2K (2.0)
Acetone/H2O (1/1)
84/16
31
6
7
PhCO2Na (2.0)
Acetone/H2O (1/1)
84/16
31
6
8
K2CO3 (2.0)
Acetone/H2O (1/1)
59/41
10
7
9
Et3N (2.0)
Acetone/H2O (1/1)
63/37
17
10
10
PhCO2Na (2.0)
DCM/H2O (1/1)
0/100
0
18
11
PhCO2Na (2.0)
CH3CN/H2O (1/1)
21/79
4
15
12
PhCO2Na (2.0)
n-Hex/H2O (1/1)
27/73
6
16
4/96
1
25
2/98
1
56 (54)
15d
PhCO2Na (3.0)
CH3CN/H2O/n-Hex (1/1/3)
100/0
69 (60)
0
16d
PhCO2Na (3.0)
CPME/H2O (1/1)
7/93
1
14
17 e
K2HPO4 (4.0)
CPME/H2O (1/1)
0
0
0
18e
PhCO2Na (3.0)
CH3CN/H2O/n-Hex (1/1/3)
0
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
F BzN Cl
2od , 79%; 2/3 > 95/5
Br
2pg,i , 81%; 2/3 = 90/10 O
F F Ph
N
F
O 2ti,j , 21%; 2/3 = 54/46
H
F
OH
2rf , 74%; 2/3 > 95/5
HOOC COOH
Acetone/H2O (1/1)
CPME/H2O (1/1)
F
2sf , 35%; 2/3 > 95/5
unsuccessful substrates
KOH (2.0)
CPME/H2O (1/1)
F
O S O
O
2qf , 58%; 2/3 = 95/5
2lf , 69%; 2/3 > 95/5 F
F
F F
K3PO4 (2.0)
K2HPO4 (4.0)
2kf , 55%; 2/3 > 95/5
2nf , 85%; 2/3 > 95/5
2m, 62%; 2/3 = 90/10
O
O
2jd , 77%; 2/3 > 95/5
F F
F F
F O
F
O 2ih, 66%; 2/3 > 95/5
2h, 80%; 2/3 > 95/5 F
F
N
4
PhCO2Na (2.0)
2gf , 55%; 2/3 = 90/10
O
F F
3
13
F F F
Ph
2e, 60%; 2/3 > 95/5
5
14c
, 77%; 2/3 > 95/5
F
F F
F F Ph
2dd,e
2c, 51%; 2/3 > 95/5
, 69%; 2/3 > 95/5
O
ratio (2/ 3)
R2 3
F F
2bd
2a, 60%; 2/3 > 95/5
3a
solvent (V/ V)
2
Ph Cl
Cl
base (equiv)
R1
F F
F
2a
F COOH
+
R2
R1
F F
F F
+
F F
AgNO3 (30 mol%) PhCO2Na, Selectfluor CH3CN/H2O/n-hexane
CN
entry
2
R2
R1
Table 1. Optimization of Reaction Conditionsa COOH
Page 2 of 6
COOH COOH
Ph Et 1v
AcHN COOH Ph COOH 1w
Br
EtO
COOH COOH
1x
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 with 4-fluorobenzoic acid as the internal standard. fPhCO2Na (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).
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.
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Journal of the American Chemical Society Secondary alcohol partially survived to afford product 2s in 35% 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 gemdifluorination 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 gemdifluorination 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 αfluorocarboxylic 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.
To demonstrate the practical utility of this unprecedented decarboxylative fluorination, gram-scale reactions were carried out (Scheme 2a). From the same starting material 1p, gemdifluoroalkane 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 fluorinecontaining 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. a) Gram-scale synthesis of 2p and 3p F F
HOOC COOH Table 2 reaction condition for 2p 4h 78% yield; 2p/3p > 95/5
N Bz 2p
5h 95% yield; 2p/3p < 5/95
N Bz 1p 1.0 gram
N Bz 3p
b) Transformations of compound 3p F Cl Ag(Phen)2OTf (10 mol%) t-BuOCl, CH3CN, 50 °C 83%
N Bz 4 TIPS
F COOH F
AgNO3 (30 mol%) K2S2O8, TIPS-EBX
N Bz 3p
CH3CN/H2O, 55 °C 58%
N Bz 5
Table 3. Scope of Decarboxylative Monofluorinationa-c HOOC COOH R2
R1
F F
AgNO3 (20 mol%) K2HPO4, Selectfluor CPME/H2O
1 F COOH
+
R2
R1 2
F COOH
F COOH F COOH Ph
Cl
Cl
F COOH Ph
Ph
3cd,e, 30%; 2/3 = 22/78 O
F COOH
N
Ph
3ed , 47%; 2/3 = 18/82 O
HOOC
HOOC F
F COOH
F
O
3p, 87%; 2/3 < 5/95
F COOH
N
F COOH H
O 3te,f , 41%; 2/3 = 21/79 aReaction
5 3u, 58%; 2/3 < 5/95
Selectfluor
3k, 63%; 2/3 < 5/95 COOH
Cl
2 BF4 8
HOOC
HOOC
path b
COOAg(I)
F COOH Ph OH 3s, 78%; 2/3 = 9/91; dr = 1/1
F
11
-CO2
N
R1 R2
HOOC
COOAg(II)
R1 R2 10
path a
Selectfluor 8
Cl
N 9
F
BF4
base
F
HOOC
R1 R2 2
Ag(I)
R1 R2 1
9 -CO2
Selectfluor COOH
base
1
R R2
F
F
8
COOH
8
COOH
R1 R2 3
8
3o, 58%; 2/3 = 17/83; dr = 3.5/1 Br
6
Cl
R1 R2 7
F Ph
N
O O
O 3r, 78%; 2/3 < 5/95
3q, 80%; 2/3 < 5/95
O
COOH
O S O
F COOH
COOH BzN
N
COOH
3n, 80%; 2/3 < 5/95
3m, 74%; 2/3 < 5/95
F
F
F
CN 3l, 78%; 2/3 < 5/95
3d, 76%; 2/3 < 5/95
O 3j, 92%; 2/3 < 5/95
3f, 60%; 2/3 < 5/95
F COOH
F
N Bz
Scheme 2. Synthetic Applications
Cl 3b, 61%; 2/3 < 5/95
3a, 54%; 2/3 < 5/95
CO2Et
Diethyl ethylidenemalonate K2HPO4, blue LED DMF, rt 78%
R2 3
CO2Et
F
Ir[df(CF3)ppy]2(dtbbpy)PF6 (3 mol%)
F COOH R1
F COOH
Table 3 standard condition
F
path b
COOAg(II)
R1 R2 13
COOAg(I)
R1 R2 12
path a
Selectfluor
8
14
Et 3v, 14%; 2/3 < 5/95
Scheme 3. Proposed Mechanism
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 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 αcarboxylic 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. 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 αcarboxylic 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 αcarboxylic 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 αfluorinated 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 origin of this intriguing chemoselectivity is not yet clear,23 a detailed mechanistic study of this reaction is underway in our laboratory. Ph HOOC 15
Table 3 F standard condition Me Ph COOH
F COOH
16 54% yield Table 2 standard condition
N Bz 3p
Me COOH F 17 not observed
(1)
F F (2) N Bz 2p 67% yield
N Bz 3p
F COOH
COOH + Ph
Table 3 standard condition
F F
N Bz 2p 19 < 5% FNMR yield
F COOH (3)
+ N 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 gemdifluoroalkanes 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.
ASSOCIATED CONTENT Supporting Information 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:
[email protected] Notes The authors declare no competing financial interest.
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 Startup 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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Insert Table of Contents artwork here F HOOC
COOH
R1 R2 1 malonic acid derivative R1= Ar, Alkyl; R2 = Alkyl
AgNO3 (cat.) Selectfluor solvent, base
HOOC
F
R1 R2 2 2/3 = 90->95:10-5 35-85% yields
R1 R2
-carboxylic acid radical key intermediate
F
COOH
R1 R2 3 3/2 = 78->95:22-5 30-92% yields
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