Chemoselective Mono- And Difluorination of 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1021/acs.joc.9b01808

By altering the amount of Selectfluor, the highly selective mono- and difluorination of 1,3-dicarbonyl compounds has been achieved, affording a variety of 2-fluoro- and 2,2-difluoro-1,3-dicarbonyl compounds in good to excellent yields. The reaction can be readily performed in aqueous media without any catalyst and base, which features practical and convenient fluorination. Importantly, a gram-scale reaction, transformation of 2-fluoro-1,3-diphenylpropane-1,3-dione to 4-fluoro-1,3,5-triphenyl-1H-pyrazole, and chlorination and bromination of 1,3-dicarbonyl compounds are realized to further exhibit its synthetic utility.

Full text of DOI:10.1021/acs.joc.9b01808

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Article
Chemoselective mono- and difluorination of 1,3-dicarbonyl compounds
Lin Tang, Zhen Yang, Jingchao Jiao, Ying Cui, Guo-Dong Zou,
Qiuju Zhou, Yu-Qiang Zhou, Wei-Hao Rao, and Xiantao Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01808 • Publication Date (Web): 23 Jul 2019
Downloaded from pubs.acs.org on July 23, 2019
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Chemoselective mono- and difluorination of 1,3-dicarbonyl
compounds
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Lin Tang,*a,b Zhen Yang,a Jingchao Jiao,a Ying Cui,a Guodong Zou,a Qiuju Zhou,c Yuqiang
Zhou,*a Weihao Rao,a Xiantao Ma*a
a College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000,
P. R. China.
b
Henan Key Laboratory of Utilization of Non-metallic Mineral in the Sourth of Henan, Xinyang
464000, P. R. China
c Analysis & Testing Center, Xinyang Normal University, Xinyang 464000, P. R. China.
E-mail: lintang@xynu.edu.cn; xiantaoma@126.com; yqzhou@xynu.edu.cn
ABSTRACT: By altering the amount of Selectfluor, the highly selective mono- and
difluorination of 1,3-dicarbonyl compounds has been achieved, affording a variety of
2-fluoro- and 2,2-difluoro-1,3-dicarbonyl compounds in good to excellent yields. The
reaction can be readily performed in aqueous media without any catalyst and base, which
features a practical and convenient fluorination. Importantly, a gram-scale reaction,
transformation
of
2-fluoro-1,3-diphenylpropane-1,3-dione
to
4-fluoro-1,3,5-triphenyl-1H-pyrazole and chlorination and bromination of 1,3-dicarbonyl
compounds are realized to further exhibit its synthetic utility
.
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Introduction
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The fluorine introduction into organic compounds frequently leads to a profound effect that
fluorine-containing scaffolds have distinctive chemical and biological properties.1 In this context,
a growing interest in the exploration of new and efficient methods for fluorinating various
molecules has been prompted in the last decades. For instance, the construction of C(sp2)-F via
transition metal-catalyzed fluorination of arenes bearing BF3K,2 halogen,3 B(OR)2,4 OTf5 and
other leaving groups6 is successfully reported. In the meantime, a great achievement has been
gained in the aspect of direct C(sp2)-H fluorination of arenes with different fluorine sources.7 On
the other hand, C(sp3)-H fluorination of benzyl,8 allyl,9 ketones10 and other unactivated
compounds11 has also been widely developed for C(sp3)-F construction. However, the existing
fluorination involves transition metal catalysts, alkaline additives, excess fluorine sources or poor
regioselectivity. Therefore, exploring a more straightforward, practical and convenient
fluorination is in high demand. Recent approaches in transition metal-free fluorination of arenes,
ketones and alkenes, mainly relying on electrophilic substitution, have been also achieved.12 In
sharp contrast to the existing electrophilic fluorination, transition metal-free radical fluorination
has been rarely reported until now.13
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Due to integrating the properties of 1,3-dicarbonyl compounds and fluorinated molecules,
fluorine-containing 1,3-dicarbonyl compounds are extensively employed as valuable skeletons for
the synthesis of biologically active molecules.14 The indirect fluorination of 1,3-dicarbonyl
compounds has been successfully realized for C(sp3)-CF3 formation by use of trifluoroacetic
acid,15 trifluoroiodomethane16 and Umemoto’s reagent17 as the trifluoromethyl sources (Scheme
1a). The difluoromethylation of 1,3-dicarbonyl compounds for the selective formation of
O-CF2H,18 C(sp3)-CF2H19 and C(sp3)-CF2SO2Ph20 has also been widely developed (Scheme 1b).
Additionally, the direct fluorination, principally relying on electrophilic substitution of
1,3-dicarbonyl compounds with different fluorine sources, can enable a straightforward C(sp3)-F
construction (Scheme 1c).21 The aforementioned electrophilic fluorination methods avoid the
involvement of transition metalcatalysts, however, they usually suffer from limitations of fluorine
source availability, substrate scope or strongly alkaline conditions. For example, Zajc and Zupan
reported 1,3-diketone monofluorination with expensive xenon difluoride as the fluorine source.21a
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Zhang group developed a highly efficient monofluorination of β-keto amides in the solvent of
PEG-400, however, β-keto ester and ketone were inactive substrates in the reaction.21b
Subsequently, Zhang group realized difluorination of β-keto amides in the presence of K2CO3.21c
Additionally, difluoromethylation of β-ketoesters was recently reported by using LiOH as the
base.19e Furthermore, the control of α-position regioselectivity in the direct fluorination of
1,3-dicarbonyl compounds can be easily achieved, but the selective synthesis of 2-mono- and
2,2-difluoriated 1,3-dicarbonyl compounds remains a challenging issue because the conventional
electrophilic fluorination methods usually afforded a mixture of 2-mono- and 2,2-difluoriated
products . To enhance the product selectivity, the development of a novel radical fluorination of
1,3-dicarbonyl compounds is highly desirable. As our continuous interest in fluorination
reactions22 and green synthetic method in aqueous media,23 we want to disclose a practical,
convenient and precise radical fluorination for the highly selective synthesis of 2-fluoro- and
2,2-difluoro-1,3-dicarbonyl compounds in the solvent of CH3CN and water under catalyst- and
base-free conditions (Scheme 1d).
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Scheme 1. Indirect and direct fluorination of 1,3-dicarbonyl compounds.
Results and Discussion
In terms of transition metal-catalyzed radical fluorination, we hypothesized AgI- or CuI-catalyzed
fluorination of 1,3-dicarbonyl compounds via
a
single-electron transfer process.24
3-Oxo-N-phenylbutanamide (1a) was employed as the model substrate to investigate the reaction
conditions (Table 1). The influence of fluorine sources on the reaction was initially evaluated
under the catalysis of AgNO3 as shown in entries 1-5. Selectfluor afforded monofluorinated
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product 2a in 61% yield, however, other fluorine sources, such as N-fluorobenzenesulfonimide
(NFSI), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (FTPT), tetrabutylammonium
fluoride (TBAF) and CsF, could not react with 1a in the solvent of DMF. The obtained results
indicate Selectfluor was an efficient fluorine source. However, the almost same results were
observed by altering the transition metal catalysts (Entries 6-9), which suggests that maybe the
transition metal catalysts are not necessary. Therefore, the reaction was performed smoothly
without any transition metal catalyst (Entry 10). Subsequently, we tested different solvents in the
presence of Selectfluor (Entries 11-15). Although good yields of 2a could be achieved in the
solvents of CH3CN, 1,4-dioxane and EtOH, di-fluorinated product 3a was also afforded in low
yields. It is necessary to develop a highly selective fluorination of 1a because separating 2a from
3a is very difficult. Interestingly, an excellent selectivity was observed when water was employed
as the solvent, even though only a low yield of 2a was obtained (Entry 15). To improve the
reaction selectivity, mixed solvents of DMF-H2O, CH3CN-H2O and EtOH-H2O were used as
shown in entries 16-18. Pleasingly, the reaction presented an excellent activity and selectivity,
affording 2a in 90% yield in CH3CN-H2O (Entry 17). When the reaction time was decreased to 4
hours, 93% of 2a could be achieved (Entry 19).
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Table 1. Optimization of the reaction conditionsa
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aReaction conditions: 1a (0.25 mmol), catalyst (0.025 mmol), F source (0.275 mmol),
b
solvent (1.0 mL), room temperature. Yield was determined by 19F NMR spectroscopy;
isolated yield in parenthese.
After confirming the optimal conditions, we then explored the generality of the selective
monofluorination of 1,3-dicarbonyl compounds (Table 2). Substrates of acetoacetamides bearing
electron-donating groups of methoxyl and ethoxyl offered the corresponding products in good
yields of 71% and 66%, respectively (2b and 2c). However, 2e and 2h could be obtained in
excellent yields when methyl and chlorine that represented weak electronic effect appeared on the
benzene ring. The single-crystal X-ray diffraction analysis unambiguously established the
structure of 2h (see the Supporting Information for detailed X-ray crystallography data). Slightly
low yields of the ortho-substituted products 2d (vs 2b), 2f (vs 2e) and 2i (vs 2h) were afforded due
to the steric hindrance. Interestingly, versatile carbamoyl and carboxyl could be well tolerated in
the absence of a base, yielding the desired products 2k and 2l in acceptable yields. Furthermore,
aliphatic β-keto amides 1m, 1n and 1o were also efficient substrates. When acetyl was changed to
isobutyryl or benzoyl, the product 2p and 2q was obtained in 94% and 95% yields, respectively.
More importantly, a satisfactory result was achieved when β-keto ester and ketone served as the
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substrates (2t and 2u), which indicates a broad substrate scope of the monofluorination reaction. It
was a pity that malononitrile was not an efficient substrate (2x).
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Table 2 Substrate scope of monofluorination of 1,3-dicarbonyl compoundsa,b
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aReaction conditions:
1 (0.25 mmol), F source (0.275 mmol), CH3CN-H2O (1:1, 1.0 mL),
room temperature, 4 h. bIsolated yield.
The result acquired in Table 1 presented that the difluorinated product 3a was constructed in a low
yield. Encouraged by this result, we tried optimizing the reaction conditions to develop a
difluorination method (Figure 1). Moderate yields of 3a could be achieved at 4 hours when 2.1,
2.3 and 2.5 equivalent of Selectfluor were employed. The yields were rapidly increased when the
reaction time was prolonged from 4 hours to 8 hours. We are pleased that an excellent yield of 94%
was obtained at 16 hours under 2.1 equivalent of Selectfluor.
Figure 1. The effect of Selectfluor and reaction time on the difluorination of 1a.
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Having successfully achieved the monofluorination of 1,3-dicarbonyl, the substrate scope of the
difluorination of 1,3-dicarbonyl compounds was extended according to the conditions of figure 1
(Table 3). Various acetoacetamides with electron-donating and -withdrawing groups on the
benzene ring offered the corresponding products 3b-3i in excellent yields, regardless of the steric
hindrance of ortho-substituents. Other acetoacetamides, such as 1p, 1q and 1r, could also afford
the desired products in 85-99% yields. In addition, β-keto ester (1t), ketones (1u and 1v) and
β-keto amide bearing N-heterocycle (1w) were also efficient substrates. The structure of 3h was
confirmed by single-crystal X-ray diffraction analysis (see the Supporting Information for detailed
X-ray crystallography data).
Table 3. Substrate scope of difluorination of 1,3-dicarbonyl compoundsa,b
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aReaction conditions: 1 (0.25 mmol), F source (0.525 mmol), CH3CN-H2O (1:1, 1.0 mL), room
temperature, 16 h. bIsolated yield.
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To testify the synthetic generality of this protocol, scale-up experiments were carried out. 6 Mmol
of 1a could readily afford the desired products 2a and 3a in 88% (1.03 g) and 91% (1.16 g) yields,
respectively, under the standard conditions (Scheme 2). Furthermore, 2u was easily converted to
valuable bioactive molecules of 4-fluoro-1,3,5-triphenyl-1H-pyrazole (4u) through condensation
in the presence of phenylhydrazine (Scheme 3).
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Scheme 2. A gram-scale synthesis.
Scheme 3. Further transformations of 2u to 4u.
Moreover, the chlorination and bromination of 1,3-dicarbonyl compounds were also realized in
the presence of 1-chloropyrrolidine-2,5-dione (NCS) and 1-bromopyrrolidine-2,5-dione (NBS).25
We are pleased to observe that the products of chlorinated and brominated 1,3-dicarbonyl
compounds were efficiently obtained in moderate yields without further optimization (Scheme
4).26
Scheme 4. Chlorination and bromination of 1,3-dicarbonyl compounds.
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In summary, we have described highly efficient and selective mono- and difluorination of
1,3-dicarbonyl compounds by virtue of Selectfluor as the oxidant and fluorine source. This
protocol offers facile and accurate access to 2-fluoro- and 2,2-difluoro-1,3-dicarbonyl compounds
in good to excellent yields. By taking advantage of the metal-free fluorination strategy,
chlorination and bromination of 1,3-dicarbonyl compounds can be also achieved. This fluorination
has a broad substrate scope and can be carried out smoothly in aqueous media under catalyst- and
base-free conditions. Further studies on the application of the reaction are currently underway in
our laboratory.
Experimental Section
General information: Proton nuclear magnetic resonance (1H NMR) spectra, carbon nuclear
magnetic resonance (13C{1H} NMR) spectra and 19F fluorine spectra (19F NMR) were recorded on
a JNM-ECZ600R/S3 (1H NMR 600 MHz, 13C{1H} NMR 150 MHz, 19F NMR 564 MHz). HRMS
were recorded on a MicroMass Waters Xevo G2-XS QTof. GC and MS samples were recorded on
an Agilent 7890A-5975C GC-MS system. Melting points were determined on a Beijing Tech
Instrument Co., LTD X-4 melting point apparatus and were uncorrected. The X-ray diffraction
data were collected at room temperature on a Bruker D8 QUEST ECO diffractometer with
graphite-monochromated MoKα radiation (λ = 0.71073 Å) for products 2h and 3h. Unless
otherwise indicated, all reagents were purchased commercially without further purification.
Typical reaction procedure for the synthesis of 2: 1a (0.25 mmol, 44.3 mg) and Selectfluor
(0.275 mmol, 97.4 mg) were respectively added to the solvent of CH3CN and H2O (v : v = 1 : 1,
1.0 mL) in a Schlenk tube. The mixture was sealed and then stirred at room temperature for 4 h.
When the reaction was finished, the mixture was extracted by appropriate ethyl acetate. The
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obtained organic phase was evaporated to remove the solvent and the resulting residue was further
purified by flash column chromatography to afford the product 2a (45.4 mg, 93%).
Typical reaction procedure for the synthesis of 3: 1a (0.25 mmol, 44.3 mg) and Selectfluor
(0.525 mmol, 186.0 mg) were respectively added to the solvent of CH3CN and H2O (v : v = 1 : 1,
1.0 mL) in a Schlenk tube. The mixture was sealed and then stirred at room temperature for 16 h.
When the reaction was finished, the mixture was extracted by appropriate ethyl acetate. The
obtained organic phase was evaporated to remove the solvent and the resulting residue was further
purified by flash column chromatography to afford the product 3a (50.0 mg, 94%).
Gram-scale synthesis of 2a: 1a (6 mmol, 1.06 g) and Selectfluor (6.6 mmol, 2.34 g) were
respectively added to the solvent of CH3CN and H2O (v : v = 1 : 1, 24 mL) in a Schlenk tube. The
mixture was sealed and then stirred at room temperature for 4 h. When the reaction was finished,
the mixture was extracted by appropriate ethyl acetate. The obtained organic phase was
evaporated to remove the solvent and the resulting residue was further purified by flash column
chromatography using petroleum ether/ethyl acetate (v : v = 5 : 1) to afford the product 2a (1.03g,
88%).
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Gram-scale synthesis of 3a: 1a (6 mmol, 1.06 g) and Selectfluor (12.6 mmol, 4.46 g) were
respectively added to the solvent of CH3CN and H2O (v : v = 1 : 1, 24 mL) in a Schlenk tube. The
mixture was sealed and then stirred at room temperature for 16 h. When the reaction was finished,
the mixture was extracted by appropriate ethyl acetate. The obtained organic phase was
evaporated to remove the solvent and the resulting residue was further purified by flash column
chromatography using petroleum ether/ethyl acetate (v : v = 5 : 1) to afford the product 3a (1.16g,
91%).
Typical reaction procedure for the synthesis of 4u: 2u (0.20 mmol, 48.4 mg) and
phenylhydrazine (0.30 mmol, 32.4 mg) were respectively added to the solvent of EtOH (1mL) in a
Schlenk tube. The mixture was sealed and then stirred at 80 oC for 6 h under an oil bath. When the
reaction was finished, the mixture was evaporated to remove the solvent and the resulting residue
was further purified by flash column chromatography using petroleum ether/ethyl acetate (v : v =
15 : 1) to afford the product 4u (32.6 mg, 52%).
2-fluoro-3-oxo-N-phenylbutanamide (2a)21b
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This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 45.4 mg, 93% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.09 (s, 1H), 7.54-7.52 (m, 2H),
7.37-7.34 (m, 2H), 7.19-7.16 (m, 1H), 5.42 (d, J = 49.3 Hz, 1H), 2.44 (d, J = 2.9 Hz, 3H); 13C{1H}
NMR (150 MHz, CDCl3): δ [ppm] = 199.3 (d, J = 19.7 Hz), 161.2 (d, J = 19.2 Hz), 136.2,
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CF
CF
129.3, 125.6, 120.3, 92.9 (d, J
-191.1 (d, J = 46.8 Hz).
= 201.4 Hz), 26.8; 19F NMR (564 MHz, CDCl3): δ [ppm] =
CF
2-fluoro-N-(4-methoxyphenyl)-3-oxobutanamide (2b)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: white solid,
m.p. = 60-62 oC; 39.9 mg, 71% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.01 (s, 1H), 7.43
1
(d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.40 (d, J = 49.3 Hz, 1H), 3.79 (s, 3H), 2.43 (d, J =
3.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.3 (d, J CF = 19.5 Hz), 161.0 (d, J CF
= 19.3 Hz), 157.3, 129.2, 122.1, 114.4, 92.5 (d, J CF = 201.2 Hz), 55.6, 26.8; 19F NMR (564 MHz,
CDCl3): δ [ppm] = -191.2 (d, J = 49.2 Hz).
N-(4-ethoxyphenyl)-2-fluoro-3-oxobutanamide (2c)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: colorless
oil; 39.5 mg, 66% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 7.96 (s, 1H), 7.41 (d, J = 9.0 Hz,
2H), 6.86 (d, J = 8.9 Hz，2H), 5.40 (d, J = 49.3 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 2.43 (d, J = 2.9
Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.3 (d, J
=
CF
19.4 Hz), 161.0 (d, J = 19.4 Hz), 156.7, 129.1, 122.0, 115.0, 92.5 (d, J = 201.1 Hz), 63.8,
CF
CF
26.8, 14.9; 19F NMR (564 MHz, CDCl3): δ [ppm] = -191.2 (d, J = 52.1 Hz).
2-fluoro-N-(2-methoxyphenyl)-3-oxobutanamide (2d)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: colorless
oil; 38.3 mg, 68% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.67 (s, 1H), 8.31-8.29 (m, 1H),
7.12-7.09 (m, 1H), 6.98-6.95 (m, 1H), 6.91-6.89 (m, 1H), 5.39 (d, J = 49.1 Hz, 1H), 3.89 (s, 3H),
2.44 (d, J = 3.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.1 (d, J CF = 19.3 Hz),
161.0 (d, J CF = 19.3 Hz), 148.4, 126.1, 125.2, 121.1, 120.0, 110.3, 93.1 (d, J CF = 201.8 Hz), 55.9,
26.7; 19F NMR (564 MHz, CDCl3): δ [ppm] = -191.0 (d, J = 49.3 Hz).
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2-fluoro-3-oxo-N-(p-tolyl)butanamide (2e)21b
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This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 49.1 mg, 94% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.03 (s, 1H), 7.40 (d, J = 9.0 Hz,
2H), 7.14 (d, J = 9.0 Hz，2H), 5.39 (d, J = 49.2 Hz, 1H), 2.44 (d, J = 3.0 Hz, 3H), 2.32 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.3 (d, J CF = 19.3 Hz), 161.0 (d, J CF = 19.3 Hz),
135.4, 133.7, 129.8, 120.3, 93.0 (d, J CF = 201.2 Hz), 26.8, 21.0; 19F NMR (564 MHz, CDCl3): δ
[ppm] = -191.1 (d, J = 46.4 Hz).
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2-fluoro-3-oxo-N-(o-tolyl)butanamide (2f)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 46.5 mg, 89% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 7.95 (s, 1H), 7.81 (d, J = 8.0 Hz,
1H), 7.26-7.20 (m, 2H), 7.14-7.11 (m, 1H), 5.43 (d, J = 49.1 Hz, 1H), 2.45 (d, J = 3.0 Hz, 3H),
2.27 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.6 (d, J CF = 19.3 Hz), 161.2 (d, J
CF = 18.9 Hz), 134.0, 130.8, 129.4, 127.1, 126.2, 122.8, 93.0 (d, J CF = 201.3 Hz), 26.6, 17.6; 19F
NMR (564 MHz, CDCl3): δ [ppm] = -191.6 (d, J = 50.3 Hz).
N-(2,4-dimethylphenyl)-2-fluoro-3-oxobutanamide (2g)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
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m.p. = 55-57 oC; 50.2 mg, 90% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 7.89 (s, 1H), 7.60
(d, J = 8.7 Hz, 1H), 7.04-7.01 (m, 2H), 5.43 (d, J = 49.2 Hz, 1H), 2.44 (d, J = 3.0 Hz, 3H), 2.29 (s,
3H), 2.21 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.6 (d, J CF = 19.3 Hz), 161.3
(d, J CF = 19.0 Hz), 136.1, 131.5, 131.3, 129.8, 127.5, 123.2, 93.1 (d, J CF = 201.2 Hz), 26.8, 21.0,
17.5; 19F NMR (564 MHz, CDCl3): δ [ppm] = -191.6 (d, J = 51.3 Hz).
N-(4-chlorophenyl)-2-fluoro-3-oxobutanamide (2h)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
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m.p. = 60-62 oC; 52.1 mg, 91% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.00 (s, 1H), 7.49
(d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 5.41 (d, J = 49.2 Hz, 1H), 2.45 (d, J = 2.9 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.3 (d, J CF = 19.1 Hz), 161.3 (d, J CF = 19.1 Hz),
134.8, 130.7, 129.4, 121.5, 92.8 (d, J CF = 201.0 Hz), 26.8; 19F NMR (564 MHz, CDCl3): δ [ppm]
= -191.4 (d, J = 49.0 Hz).
N-(2-chlorophenyl)-2-fluoro-3-oxobutanamide (2i)21b
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This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 51.5 mg, 90% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.63 (s, 1H), 8.32-8.30 (m, 1H),
7.41-7.40 (m, 1H), 7.31-7.28 (m, 1H), 7.13-7.10 (m, 1H), 5.42 (d, J = 49.3 Hz, 1H), 2.45 (d, J =
3.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 199.1 (d, J CF = 19.1 Hz), 161.2 (d, J CF
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= 18.8 Hz), 133.2, 129.4, 127.9, 126.0, 123.7, 121.6, 92.8 (d, J = 201.2 Hz), 26.8; 19F NMR
CF
(564 MHz, CDCl3): δ [ppm] = -191.6 (d, J = 49.0 Hz).
N-(2,5-dichlorophenyl)-2-fluoro-3-oxobutanamide (2j)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 53.9 mg, 82% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.64 (s, 1H), 8.42 (d, J = 2.5 Hz,
1H), 7.33 (d, J = 8.6 Hz, 1H), 7.11-7.09 (dd, J = 8.6, 2.5 Hz, 1H), 5.42 (d, J = 49.2 Hz, 1H), 2.45
(d, J = 3.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 198.9 (d, J CF = 19.2 Hz), 161.3
(d, J CF = 19.2 Hz), 134.0, 133.8, 130.1, 125.9, 121.7, 121.6, 92.6 (d, J = 201.2 Hz), 26.8; 19F
CF
NMR (564 MHz, CDCl3): δ [ppm] = -192.0 (d, J = 48.9 Hz).
4-(2-fluoro-3-oxobutanamido)benzamide (2k)
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 2:1) to offer the product: colorless
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oil; 25.6 mg, 43% yield; H NMR (600 MHz, d6-DMSO): δ [ppm] = 10.64 (s, 1H), 7.89 (s, 1H),
7.85 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 5.69 (d, J = 48.0 Hz, 1H), 2.30 (d,
J = 3.4 Hz, 3H); 13C{1H} NMR (150 MHz, d6-DMSO): δ [ppm] = 200.2 (d, J CF = 21.1 Hz), 167.2,
162.5 (d, J = 20.6 Hz), 140.2, 130.1, 128.4, 119.4, 92.8 (d, J = 194.2 Hz), 26.4; 19F NMR
CF
CF
(564 MHz, d6-DMSO): δ [ppm] = -190.7 (d, J = 52.2 Hz); HRMS (ESI-TOF): calcd. for
C11H12FN2O3 [M+H]+ 239.0832, found 239.0815.
2-(2-fluoro-3-oxobutanamido)benzoic acid (2l)
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 2:1) to offer the product: white solid,
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m.p. = 156-158 C; 38.8 mg, 65% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 11.8 (s, 1H),
8.69-8.67 (m, 1H), 8.17-8.15 (m, 1H), 7.64-7.61 (m, 1H), 7.23-7.20 (m, 1H), 5.40 (d, J = 49.4 Hz,
1H), 2.45 (d, J = 3.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 198.9 (d, J CF = 20.6
Hz), 162.4, 162.2 (d, J
= 20.5 Hz), 140.3, 135.7, 132.1, 124.2, 120.8, 115.3, 93.2 (d, J
=
CF
CF
202.7 Hz), 26.7; 19F NMR (564 MHz, CDCl3): δ [ppm] = -191.0 (d, J = 49.4 Hz); HRMS
(ESI-TOF): calcd. for C11H11FNO4 [M+H]+ 240.0672, found 240.0662.
2-fluoro-N-methyl-3-oxobutanamide (2m)27
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This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 21.2 mg, 64% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 6.39 (s, 1H), 5.39 (d, J = 49.3 Hz,
1H), 2.88 (d, J = 5.0 Hz, 3H), 2.39 (d, J = 2.9 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm]
= 199.3 (d, J = 19.3 Hz), 163.9 (d, J = 19.0 Hz), 93.2 (d, J = 199.7 Hz), 26.8, 26.2; 19F
CF
CF
CF
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NMR (564 MHz, CDCl3): δ [ppm] = -193.1 (d, J = 49.1 Hz).
2-fluoro-N,N-dimethyl-3-oxobutanamide (2n)27
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
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oil; 30.1 mg, 82% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 5.49 (d, J = 49.9 Hz, 1H), 3.10
(d, J = 1.6 Hz, 3H), 3.00 (d, J = 1.3 Hz, 3H), 2.34 (d, J = 2.9 Hz, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ [ppm] = 202.1 (d, J CF = 20.5 Hz), 163.7 (d, J CF = 19.9 Hz), 91.6 (d, J CF = 200.1 Hz),
37.1 (d, J CF = 4.6 Hz), 36.3, 26.3; 19F NMR (564 MHz, CDCl3): δ [ppm] = -188.4 (d, J = 50.1 Hz)
N,N-diethyl-2-fluoro-3-oxobutanamide (2o)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
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oil; 39.0 mg, 89% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 5.40 (d, J = 50.1 Hz, 1H),
3.42-3.32 (m, 4H), 2.32 (d, J = 4.0 Hz, 3H), 1.19 (t, J = 14.2 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 202.2 (d, J CF = 23.9 Hz), 163.1 (d, J CF = 23.5 Hz),
91.7 (d, J
= 194.5 Hz), 41.8 (d, J
= 4.2 Hz), 40.9, 26.2, 14.3, 12.7; 19F NMR (564 MHz,
CF
CF
CDCl3): δ [ppm] = -187.9 (d, J = 49.8 Hz).
2-fluoro-4-methyl-3-oxo-N-phenylpentanamide (2p)21b
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 52.4 mg, 94% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.12 (s, 1H), 7.54-7.52 (m, 2H),
7.36-7.33 (m, 2H), 7.18-7.15 (m, 1H), 5.53 (d, J = 49.2 Hz, 1H), 3.29-3.24 (m, 1H), 1.20 (d, J =
6.7 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 205.9 (d, J CF
= 18.8 Hz), 161.5 (d, J CF = 18.9 Hz), 136.3, 129.3, 125.5, 120.2, 91.6 (d, J CF = 201.0 Hz), 37.4,
18.5, 17.2 (d, J CF = 2.0 Hz); 19F NMR (564 MHz, CDCl3): δ [ppm] = -193.2 (d, J = 50.3 Hz).
2-fluoro-3-oxo-N,3-diphenylpropanamide (2q)28
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
m.p. = 86-88 oC; 61.0 mg, 95% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.16-8.14 (m, 3H),
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7.67-7.64 (m, 1H), 7.54-7.51 (m, 4H), 7.34-7.31 (m, 2H), 7.17-7.14 (m, 1H), 6.26 (d, J = 49.1 Hz,
1H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 190.4 (d, J CF = 17.3 Hz), 161.9 (d, J CF = 18.9
Hz), 136.3, 134.9, 133.6, 130.0, 129.2, 128.9, 125.5, 120.2, 91.4 (d, J = 198.3 Hz); 19F NMR
CF
(564 MHz, CDCl3): δ [ppm] = -190.0 (d, J = 49.1 Hz).
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2-fluoro-N-octyl-3-oxo-3-phenylpropanamide (2r)
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
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m.p. = 65-67 C; 60.1 mg, 82% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.63 (s, 1H),
8.02-8.00 (m, 2H), 7.71-7.68 (m, 1H), 7.57-7.54 (m, 2H), 6.44 (d, J = 47.8 Hz, 1H), 3.10-3.04 (m,
2H), 1.40-1.35 (m, 2H), 1.28-1.23 (m, 2H), 1.22-1.18 (m, 8H), 0.85-0.83 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 191.5 (d, J CF = 18.2 Hz), 163.6 (d, J CF = 18.4 Hz),
134.1, 133.9, 129.1, 128.6, 90.6 (d, J CF = 200.0 Hz), 44.0, 38.4, 31.2, 28.7, 28.6, 26.1, 22.0, 13.9;
19F NMR (564 MHz, CDCl3): δ [ppm] = -192.2 (d, J = 47.7 Hz); HRMS (ESI-TOF): calcd. for
C17H25FNO2 [M+H]+ 294.1869, found 294.1883.
2-fluoro-N-(naphthalen-2-yl)-3-oxo-3-phenylpropanamide (2s)
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
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m.p. = 111-113 C; 69.1 mg, 90% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.51 (s, 1H),
8.29-8.26 (m, 1H), 8.17-8.16 (m, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.69-7.66
(m, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.56-7.47 (m, 5H), 6.30 (d, J = 48.9 Hz, 1H); 13C{1H} NMR
(150 MHz, CDCl3): δ [ppm] = 190.0 (d, J CF = 17.1 Hz), 162.2 (d, J CF = 17.3 Hz), 134.9, 133.6,
131.8, 131.8, 130.0, 129.0, 127.6, 127.0, 126.4, 124.1, 124.0, 120.1, 120.1, 120.1, 90.6 (d, J
199.1 Hz); 19F NMR (564 MHz, CDCl3): δ [ppm] = -190.0 (d, J = 49.0 Hz); HRMS (ESI-TOF):
calcd. for C19H15FNO2 [M+H]+ 308.1087, found 308.1101.
=
CF
ethyl 2-fluoro-3-oxo-3-phenylpropanoate (2t)21d
This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 6:1) to offer the product: colorless
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oil; 46.2 mg, 88% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.03 (d, J = 8.6 Hz, 2H),
7.65-7.63 (m, 1H), 7.52-7.49 (m, 2H), 5.86 (d, J = 48.7 Hz, 1H), 4.32-4.28 (m, 2H), 1.26 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 189.7 (d, J CF = 20.1 Hz), 165.1 (d, J CF
= 20.2 Hz), 134.7, 133.5 (d, J CF = 2.4 Hz), 129.7 (d, J CF = 3.6 Hz), 129.0, 90.1 (d, J CF = 196.4
Hz), 62.9, 14.1; 19F NMR (564 MHz, CDCl3): δ [ppm] = -190.2 (d, J = 48.8 Hz).
2-fluoro-1,3-diphenylpropane-1,3-dione (2u)21d
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This compound was prepared according to the typical procedure for the synthesis of 2 and purified
by column chromatography (petroleum ether / ethyl acetate = 15:1) to offer the product: light
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yellow solid, m.p. = 62-64 C; 58.1 mg, 96% yield; H NMR (600 MHz, CDCl3): δ [ppm] =
8.10-8.09 (m, 4H), 7.63-7.60 (m, 2H), 7.52-7.47 (m, 4H), 6.54 (d, J = 49.1 Hz, 1H); 13C{1H}
NMR (150 MHz, CDCl3): δ [ppm] = 191.2 (d, J CF = 20.1 Hz), 134.7, 130.0, 130.0, 128.9, 96.7 (d,
J CF = 197.9 Hz); 19F NMR (564 MHz, CDCl3): δ [ppm] = -186.7 (d, J = 49.0 Hz).
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2,2-difluoro-3-oxo-N-phenylbutanamide (3a)21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
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m.p. = 84-86 C; 50.0 mg, 94% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.15 (s, 1H),
7.56-7.54 (m, 2H), 7.38-7.35 (m, 2H), 7.22-7.19 (m, 1H), 2.50 (t, J = 1.6 Hz, 3H); 13C{1H} NMR
(150 MHz, CDCl3): δ [ppm] = 196.3 (t, J = 28.3 Hz), 159.0 (t, J = 27.0 Hz), 135.6, 129.4,
CF
CF
126.2, 120.5, 109.1 (t, J CF = 265.0 Hz), 25.4; 19F NMR (564 MHz, CDCl3): δ [ppm] = -114.3.
2,2-difluoro-N-(4-methoxyphenyl)-3-oxobutanamide (3b) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: light
yellow solid, m.p. = 66-68 oC; 58.9 mg, 97% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.23
(s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 2.48 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3): δ [ppm] = 196.4 (t, J = 28.2 Hz), 158.9 (t, J = 26.9 Hz), 157.6,
CF
CF
128.6, 122.3, 114.4, 110.9, 109.2 (t, J CF = 264.8 Hz), 55.5, 25.4; 19F NMR (564 MHz, CDCl3): δ
[ppm] = -114.3.
N-(4-ethoxyphenyl)-2,2-difluoro-3-oxobutanamide (3c) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: white solid,
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m.p. = 92-94 oC; 63.0 mg, 98% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.01 (s, 1H), 7.43
(d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.01 (q, J = 7.0 Hz, 2H), 2.50 (t, J = 1.6 Hz, 3H),
1.40 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 196.4 (t, J CF = 28.2 Hz),
158.7 (t, J CF = 26.8 Hz), 157.0, 128.4, 122.2, 115.0, 109.2 (t, J CF = 264.7 Hz), 63.9, 25.5, 14.9;
19F NMR (564 MHz, CDCl3): δ [ppm] = -114.3.
2,2-difluoro-N-(2-methoxyphenyl)-3-oxobutanamide (3d) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: light
yellow solid, m.p. = 65-67 oC; 52.8 mg, 87% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.72
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(s, 1H), 8.30-8.28 (m, 1H), 7.16-7.13 (m, 1H), 7.00-6.97 (m, 1H), 6.93-6.91 (m, 1H), 3.91 (s, 3H),
2.51 (t, J = 1.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 196.2 (t, J CF = 28.2 Hz),
158.7 (t, J CF = 26.9 Hz), 148.5, 125.8, 125.5, 121.2, 120.1, 110.3, 109.1 (t, J CF = 264.6 Hz), 56.0,
25.5; 19F NMR (564 MHz, CDCl3): δ [ppm] = -114.3.
9
2,2-difluoro-3-oxo-N-(p-tolyl)butanamide (3e) 21c
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11
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This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
1
m.p. = 70-72 oC; 53.3 mg, 94% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.04 (s, 1H), 7.42
(d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 2.50 (t, J = 1.6 Hz, 3H), 2.33 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3): δ [ppm] = 196.3 (t, J = 28.1 Hz), 158.7 (t, J = 26.9 Hz), 136.0, 133.0,
CF
CF
129.9, 120.5, 109.1 (t, J
= 264.7 Hz), 25.5, 21.1; 19F NMR (564 MHz, CDCl3): δ [ppm] =
CF
-114.3.
2-fluoro-3-oxo-N-(o-tolyl)butanamide (3f) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 51.1 mg, 90% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 7.95 (s, 1H), 7.73 (d, J = 8.0 Hz,
1H), 7.26-7.22 (m, 2H), 7.18-7.15 (m, 1H), 2.52 (t, J = 1.6 Hz, 3H), 2.29 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3): δ [ppm] = 196.5 (t, J = 28.0 Hz), 159.2 (t, J = 26.8 Hz), 133.3, 130.9,
CF
CF
130.1, 127.1, 126.9, 123.3, 109.2 (t, J CF = 264.6 Hz), 25.5, 17.5; 19F NMR (564 MHz, CDCl3): δ
[ppm] = -114.2.
N-(2,4-dimethylphenyl)-2,2-difluoro-3-oxobutanamide (3g) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 53.0 mg, 88% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 7.89 (s, 1H), 7.55 (d, J = 8.6 Hz,
1H), 7.04-7.03 (m, 2H), 2.51 (t, J = 1.6 Hz, 3H), 2.30 (s, 3H), 2.23 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3): δ [ppm] = 196.5 (t, J CF = 28.1 Hz), 159.2 (t, J CF = 26.8 Hz), 136.9, 131.6, 130.6,
130.3, 127.6, 123.5, 109.3 (t, J = 264.6 Hz), 25.4, 21.0, 17.5; 19F NMR (564 MHz, CDCl3): δ
CF
[ppm] = -114.3.
N-(4-chlorophenyl)-2-fluoro-3-oxobutanamide (3h) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
1
m.p. = 85-87 oC; 55.6 mg, 90% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.05 (s, 1H), 7.51
(d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 2.52 (t, J = 1.6 Hz, 3H); 13C{1H} NMR (150 MHz,
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CDCl3): δ [ppm] = 196.3 (t, J CF = 28.1 Hz), 159.0 (t, J CF = 26.8 Hz), 134.1, 131.4, 129.5, 121.7,
109.0 (t, J CF = 264.5 Hz), 25.5; 19F NMR (564 MHz, CDCl3): δ [ppm] = -114.2.
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7
8
N-(2-chlorophenyl)-2,2-difluoro-3-oxobutanamide (3i) 21c
9
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
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19
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by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
1
oil; 55.5 mg, 90% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.60 (s, 1H), 8.30-8.28 (dd, J =
8.6, 1.5 Hz, 1H), 7.43-7.41 (dd, J = 8.6, 1.6 Hz, 1H), 7.33-7.30 (dt, J = 8.6, 1.5 Hz, 1H), 7.17-7.14
(dd, J = 8.6, 1.6 Hz, 1H), 2.52 (t, J = 1.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] =
195.9 (t, J CF = 28.2 Hz), 159.0 (t, J CF = 26.8 Hz), 132.5, 129.5, 128.1, 126.6, 123.9, 121.9, 108.9
(t, J CF = 264.5 Hz), 25.4; 19F NMR (564 MHz, CDCl3): δ [ppm] = -114.1.
2,2-difluoro-4-methyl-3-oxo-N-phenylpentanamide (3p) 21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: light
1
yellow liquid; 59.6 mg, 99% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.08 (s, 1H),
7.56-7.54 (m, 2H), 7.38-7.35 (m, 2H), 7.22-7.19 (m, 1H), 3.31-3.24 (m, 1H), 1.22 (d, J = 6.8 Hz,
6H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 203.0 (t, J CF = 26.5 Hz), 159.0 (t, J CF = 26.9
Hz), 135.7, 129.4, 126.1, 120.4, 109.5 (t, J
CDCl3): δ [ppm] = -113.2.
= 266.2 Hz), 36.6, 18.0; 19F NMR (564 MHz,
CF
2,2-difluoro-3-oxo-N,3-diphenylpropanamide (3q)21c
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: white solid,
m.p. = 92-94 oC; 67.4 mg, 98% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.19-8.18 (m, 2H),
8.16 (s, 1H), 7.69-7.66 (m, 1H), 7.59-7.57 (m, 2H), 7.54-7.51 (m, 2H), 7.38-7.35 (m, 2H),
7.22-7.19 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 165.4 (t, J CF = 21.7 Hz), 142.9
(t, J = 21.8 Hz), 124.1, 123.6, 120.8, 119.9, 119.0, 118.7, 116.3, 111.8, 104.2 (t, J = 211.9
CF
CF
Hz), 25.4; 19F NMR (564 MHz, CDCl3): δ [ppm] = -107.7.
N-butyl-2,2-difluoro-3-oxo-3-phenylpropanamide (3r)
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 5:1) to offer the product: colorless
oil; 54.2 mg, 85% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.15-8.13 (m, 2H), 7.66-7.63 (m,
1H), 7.51-7.48 (m, 2H), 6.54 (s, 1H), 3.34 (q, J = 6.8 Hz, 2H), 1.58-1.53 (m, 2H), 1.29-1.24 (m,
10H), 0.86 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 187.6 (t, J CF = 26.8
Hz), 161.5 (t, J = 27.0 Hz), 135.0, 131.8, 130.5, 128.9, 111.0 (t, J = 263.4 Hz), 40.1, 31.9,
CF
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29.2, 26.8, 22.8, 14.2; 19F NMR (564 MHz, CDCl3): δ [ppm] = -108.2; HRMS (ESI-TOF): calcd.
for C17H24F2NO2 [M+H]+ 312.1775, found 312.1773.
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7
8
ethyl 2,2-difluoro-3-oxo-3-phenylpropanoate (3t)21d
9
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
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by column chromatography (petroleum ether / ethyl acetate = 6:1) to offer the product: light
1
yellow liquid; 51.9 mg, 91% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.08-8.07 (m, 2H),
7.69-7.66 (m, 1H), 7.54-7.51 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (150 MHz, CDCl3): δ [ppm] = 185.6 (t, J = 27.6 Hz), 161.9 (t, J = 30.1 Hz), 135.2,
CF
CF
131.1, 130.0, 129.1, 109.9 (t, J CF = 262.8 Hz), 63.9, 14.0; 19F NMR (564 MHz, CDCl3): δ [ppm]
= -107.5.
2,2-difluoro-1,3-diphenylpropane-1,3-dione (3u)21d
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 15:1) to offer the product: white
solid, m.p. = 153-155 oC; 50.7 mg, 78% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 7.93-7.91
(m, 4H), 7.59-7.56 (m, 2H), 7.47-7.44 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] =
187.5 (t, J CF = 26.7 Hz), 135.2, 131.7 (t, J CF = 1.3 Hz), 130.4 (t, J CF = 2.7 Hz), 129.1, 112.8 (t, J
CF = 264.2 Hz); 19F NMR (564 MHz, CDCl3): δ [ppm] = -102.6.
2,2-difluoro-1-phenylbutane-1,3-dione (3v)21d
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 8:1) to offer the product: colorless
oil; 42.0 mg, 85% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.07-8.05 (m, 2H), 7.70-7.67 (m,
1H), 7.54-7.51 (m, 2H), 2.44 (t, J = 1.7 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ [ppm] =
196.1 (t, J CF = 27.6 Hz), 187.7 (t, J CF = 27.6 Hz), 135.3, 131.5 (t, J CF = 2.4 Hz), 130.2 (t, J CF
3.2 Hz), 129.0, 111.4 (t, J CF = 264.9 Hz), 25.2; 19F NMR (564 MHz, CDCl3): δ [ppm] = -108.9.
=
2,2-difluoro-3-oxo-3-phenyl-N-(pyridin-2-yl)propanamide (3w)
This compound was prepared according to the typical procedure for the synthesis of 3 and purified
by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product: colorless
oil; 63.5 mg, 92% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 9.30 (s, 1H), 8.36-8.35 (m, 1H),
8.19-8.14 (m, 3H), 7.77-7.74 (m, 1H), 7.68-7.65 (m, 1H), 7.53-7.50 (m, 2H), 7.15-7.12 (m, 1H);
13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 186.7 (t, J CF = 27.8 Hz), 160.0 (t, J CF = 27.8 Hz),
149.8, 148.3, 138.9, 135.2, 131.6, 130.4 (t, J = 2.8 Hz), 129.0, 121.4, 114.8, 110.8 (t, J
=
CF
CF
265.8 Hz); 19F NMR (564 MHz, CDCl3): δ [ppm] = -107.5. HRMS (ESI-TOF): calcd. for
C14H11F2N2O2 [M+H]+ 277.0789, found 277.0796.
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4-fluoro-1,3,5-triphenyl-1H-pyrazole (4u)29
5
6
This compound was prepared according to the typical procedure for the synthesis of 4u and
7
8
9
purified by column chromatography (petroleum ether / ethyl acetate = 15:1) to offer the product:
1
colorless oil; 32.6 mg, 52% yield; H NMR (600 MHz, CDCl3): δ [ppm] = 8.10-8.00 (m, 3H),
7.57-7.46 (m, 3H), 7.40-7.35 (m, 7H), 7.34-7.31 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ
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[ppm] = 145.8 (d, J = 252.0 Hz), 140.0, 138.42 (d, J = 6.3 Hz), 135.3 (d, J = 67.4 Hz),
CF
CF
CF
132.6, 130.6 (d, J CF = 69.0 Hz), 129.1, 128.8, 128.7, 128.3, 127.7, 127.3, 126.4, 126.4, 125.0; 19F
NMR (564 MHz, CDCl3): δ [ppm] = -172.3. HRMS (ESI-TOF): calcd. for C21H16FN2 [M+H]+
315.1298, found 315.1279.
2-chloro-3-oxo-N-phenylbutanamide (5a)30
This compound was prepared according to the typical procedure for the synthesis of 2 using
1-chloropyrrolidine-2,5-dione (0.275 mmol, 36.5 mg) instead of Selectfluor as the substrate and
purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product:
colorless oil; 26.9 mg, 51% yield; 1H NMR (600 MHz, d6-DMSO): δ [ppm] = 10.67 (s, 1H), 7.59
(d, J = 7.7 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 5.38 (s, 1H), 2.30 (s, 3H).
2,2-dichloro-3-oxo-N-phenylbutanamide (6a)31
This compound was prepared according to the typical procedure for the synthesis of 2 using
1-chloropyrrolidine-2,5-dione (0.525 mmol, 69.8 mg) instead of Selectfluor as the substrate and
purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product:
colorless oil; 37.9 mg, 62% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.40 (s, 1H), 7.56-7.54
(dd, J = 7.4, 1.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.23-7.21 (tt, J = 7.8, 1.2 Hz, 1H), 2.54 (s, 3H).
2-bromo-3-oxo-N-phenylbutanamide (7a)32
This compound was prepared according to the typical procedure for the synthesis of 2 using
1-bromopyrrolidine-2,5-dione (0.275 mmol, 48.6 mg) instead of Selectfluor as the substrate and
purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product:
colorless oil; 33.8 mg, 53% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.38 (s, 1H), 7.54-7.52
(dd, J = 7.5, 1.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.20-7.17 (tt, J = 7.6, 1.2 Hz, 1H), 2.49 (s, 3H).
2,2-dibromo-3-oxo-N-phenylbutanamide (8a)32
This compound was prepared according to the typical procedure for the synthesis of 2 using
1-bromopyrrolidine-2,5-dione (0.525 mmol, 92.9 mg) instead of Selectfluor as the substrate and
purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to offer the product:
colorless oil; 48.2 mg, 58% yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.56 (s, 1H), 7.50-7.45
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(m, 5H), 2.64 (s, 3H).
5
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(2-fluoroethene-1,1-diyl)dibenzene (W)33
7
8
9
This compound was prepared according to the typical procedure for the synthesis of 2 with the
addition of 1,1-diphenylethylene (0.25 mmol, 45.0 mg) and purified by column chromatography
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1
(petroleum ether) to offer the product: colorless oil; 16.8 mg, 34% yield; H NMR (600 MHz,
CDCl3): δ [ppm] = 7.39-7.32 (m, 8H), 7.25-7.24 (m, 2H), 7.00 (d, J = 83.3 Hz, 1H); 13C{1H}
NMR (150 MHz, CDCl3): δ [ppm] = 145.9 (d, J = 266.9 Hz), 137.1 (d, J = 8.2 Hz), 135.3,
CF
CF
129.9 (d, J CF = 4.1 Hz), 128.8 (d, J CF = 2.5 Hz), 128.6, 128.3, 127.9 (d, J CF = 5.9 Hz), 126.3 (d, J
CF = 5.4 Hz); 19F NMR (564 MHz, CDCl3): δ [ppm] = -128.0 (d, J = 84.1 Hz).
3-oxo-N-phenyl-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)butanamide (11)
This compound was prepared according to the typical procedure for the synthesis of 2 with the
addition of TEMPO (0.625 mmol, 97.5 mg) and purified by column chromatography (petroleum
ether / ethyl acetate = 20:1) to offer the product: mixed state of solid and liquid; 32.3 mg, 39%
yield; 1H NMR (600 MHz, CDCl3): δ [ppm] = 8.18 (s, 1H), 7.53-7.52 (m, 2H), 7.36-7.33 (m, 2H),
7.16-7.13 (m, 1H), 5.01 (s, 1H), 2.37 (s, 3H), 1.56-1.42 (m, 5H), 1.35-1.14 (m, 10H), 1.02 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ [ppm] = 203.4, 165.0, 136.9, 129.3, 125.0, 119.9, 94.4, 60.5,
40.5, 40.3, 32.9, 32.9, 28.7, 20.8, 20.4, 17.0. HRMS (ESI-TOF): calcd. for C19H29N2O3 [M+H]+
333.2178, found 333.2169.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
Copies of H, 13C{1H} and 19F NMR spectra for the products, and X-ray crystallography data of
1
2h and 3h (PDF)
X-ray crystallography data of 2h (CIF)
X-ray crystallography data of 3h (CIF)
AUTHOR INFORMATION
Corresponding Author
E-mail: lintang@xynu.edu.cn; yqzhou@xynu.edu.cn; xiantaoma@126.com
ORCID
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Lin Tang: 10000-0003-0477-2481
Weihao Rao: 0000-0001-6197-0148
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS：
This work was supported by no. 21602190 from the National Natural Science Foundation of
China, no. 172102210456 from the Foundation of Department of Science and Technology of
Henan Province, no. 17A150049 and 18A150049 from the Henan Key Scientific Research Project,
and the Nanhu Scholars Program for Young Scholars of XYNU.
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