Synthesis of α,α-difluorobenzoyl oxygen heterocycles via the radical reaction of 2-iodo-2,2-difluoroacetophenones with unsaturated acids or unsaturated alcohols

Article abstract of DOI:10.1016/j.jfluchem.2017.06.003

A convenient and facile method for the direct synthesis of α,α-difluorobenzoyl lactones or cyclic ethers via the radical cyclization reaction of 2-iodo-2,2-difluoroacetophenone with unsaturated acids or alcohols was reported.

Full text of DOI:10.1016/j.jfluchem.2017.06.003

JournalofFluorineChemistry200(2017)41–46
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Full Length Article
Synthesis of α,α-difluorobenzoyl oxygen heterocycles via the radical
reaction of 2-iodo-2,2-difluoroacetophenones with unsaturated acids or
unsaturated alcohols
⁎
Heng Chena, Jiexiong Wanga, Jingjing Wua,b, , Yujia Kuanga, Fanhong Wua,⁎
a
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
A convenient and facile method for the direct synthesis of α,α-difluorobenzoyl lactones or cyclic ethers via the
radical cyclization reaction of 2-iodo-2,2-difluoroacetophenone with unsaturated acids or alcohols was reported.
α-α-Difluorobenzoyl oxygen heterocycle
2-Iodo-2,2-difluoroacetophenone
Radical addition
Unsaturated acids
Unsaturated alcohols
1. Introduction
by polyfluoroalkylation of unsaturated acid or alcohol with different
polyfluoroalkyl iodides [8]. However, some of the reactions only afforded
Molecules containing an α,α-difluoroketone unit are valuable for
developing novel drugs in medicinal chemistry because they could be
readily formed into hydrates and mimic tetrahedral intermediates in-
volved in peptide hydrolysis [1]. Several α,α-difluoroketones have been
reported to serve as drugs and biological probes, such as lubiprostone,
GABA agonist and inhibitor of HIV-1 aspartic protease. Meanwhile, the
α,α-difluoroketones can be used as fluorinated building blocks for
further functionalization [2]. Despite the importance of α,α-di-
fluoroketone derivatives, more efficient and general synthetic methods
are still needed [3].
the adduct products and the sequent cyclization to give the desired poly-
fluoroalkylated oxygen heterocycles is needed. As part of our continued
research in expanding the structural diversity of the fluoroalkylated
oxygen heterocycles, we tried to synthesize α,α-difluorobenzoyl oxygen
heterocycles by using difluoromethyl acetophenones as difluoroacetyla-
tion agent. Herein, we report the direct synthesis of α,α-difluorobenzoyl
lactones and α,α-difluorobenzoyl cyclic ethers via the radical reaction of
2-iodo-2,2-difluoroacetophenone with unsaturated acids or unsaturated
alcohols initiated by 2,2-azobisisobutyronitrile (AIBN) (Scheme 1).
Recent reports show that the methodologies for the synthesis of α,α-
difluoroketone derivatives mainly rely on direct fluorination methods
and building block fluorination. Radical addition of polyfluoroalkyl
iodides to unsaturated compounds could be an alternative strategy for
polyfluoroalkylated derivatives [4], 2-iodo-2,2-difluoroacetophenones
could also be used as free radicals to introduce α,α-difluorobenzoyl
group to diverse compounds. However, the radical addition of 2-iodo-
2,2-difluoroacetophenones has not been fully investigated. Burton re-
ported the addition of 2-iodo-2,2-difluoroacetophenones to olefins
using UV irradiation or Pd catalyst [5], while copper catalyst was used
for the addition of 2-iodo-2,2-difluoroacetophenones to alkenes by Chai
[6].
2. Results and discussion
Our group has previously reported that the reaction of 2-iodo-2,2-
difluoroacetophenones with 4-pentenoic acids or 5-hexenoic acid could
directly give the cyclic products α,α-difluorobenzoyl γ-butyrolactones
or δ-valerolactones by using AIBN as initiator in CH3CN without any
base (Table 1) [9].
We envisioned that the reaction of 2-iodo-2,2-difluoroacetophenones
with unsaturated alcohols could also afford the cyclic ethers under a si-
milar reaction condition. However, only low yield of cyclic ether 5a was
obtained when 2,2-difluoro-2-iodo-1-phenylethanone 1a reacted with
pent-4-en-1-ol 4a, and a large amount of the starting material 1a was
recovered (Table 2, entry 1). The change of solvents has no significant
impact on the yield of compound 5a (entry 2). The result might be as-
cribed to the different nucleophilic ability between carboxyl and hydroxyl
Our group is interested in constructing polyfluoroalkylated oxygen
heterocycles due to their wide application in both natural and synthetic
products with various bioactivities [7] and has reported their preparation
⁎
Corresponding authors at: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
E-mail addresses: wujj@sit.edu.cn (J. Wu), wfh@sit.edu.cn (F. Wu).
http://dx.doi.org/10.1016/j.jfluchem.2017.06.003
Received 25 March 2017; Received in revised form 4 June 2017; Accepted 5 June 2017
0022-1139/©2017ElsevierB.V.Allrightsreserved.

H. Chen et al.
JournalofFluorineChemistry200(2017)41–46
Scheme 1. Radical addition of 2-iodo-2,2-difluoroacetophenones to unsaturated acids and alcohols.
group. Therefore, 2,2-difluoro-2-iodo-1-phenylethanone 1a and pent-4-en-
1-ol 4a were used as model reactants for the second optimization of the
free radical cyclization reaction conditions, and the results are shown in
Table 2. Initially, the experiments were conducted in the presence of dif-
ferent initiators or catalysts at 60 °C under a solvent-free condition (entries
3–11). Among several initiators/catalysts tested, AIBN turned out to be the
suitable one for the reaction (entry 11), while others, such as Pd, Ni or Cu
catalyst, were ineffective and less cyclic product 5a could be detected
(entries 3–10).
It’s worth noting that, the addition of base into the reaction could
deprotonate the alcohols [10]. Screening of bases was investigated
(entries 12–18) and the result revealed that 2,6-lutidine was the most
efficient base for the reaction (entry 18). Moreover, increasing reaction
temperature to 80 °C gave higher yield of product 5a while decreasing
reaction temperature obviously diminished the yield (entries 18–20).
When the amount of AIBN was increased to 30 mol%, the target com-
pound 5a was obtained in higher yield (entry 21). However, the yield
would be lower when the amount of 2,2-difluoro-2-iodo-1-pheny-
lethanone 1a was reduced to 1 equiv of 4a (entry 22).
remarkably, 2-iodo-2,2-difluoroacetophenone bearing methoxy group
reacted with pent-4-en-1-ol to afford 2,2-difluoro-1-(4-methoxyphenyl)-
3-(tetrahydrofuran-2-yl) propan-1-one 5g with yield as high as 90%.
Furthermore, the substrates 2,2-difluoro-1-(naphthalen-2-yl)-3-(tetra-
hydrofuran-2-yl)propan-1-one 1h and 2,2-difluoro-3-(tetrahydrofuran-
2-yl)-1-(thiophen-2-yl)propan-1-one 1i, which contain heterocyclic
groups, could also afford the cyclic compounds with lower yield than
those from α,α-difluoroacetophenones. While electron-withdraw
group-substituted iododifluoromethyl acetophenone 2,2-difluoro-2-
iodo-1-(4-(trifluoromethyl)phenyl) ethanone was employed in this re-
action, the reaction efficiency was very poor with no specific product
and most of the starting material was recovered. Furthermore, allyl
alcohol was subjected to the addition reaction aiming at the corre-
sponding epoxy propane. However, no target compound was obtained
and only the reduction product difluoromethyl compound was ob-
served.
3. Conclusion
Having established the optimized method (entry 21), we next probe
the generality and scope of this radical cyclization reaction. Several 2-
iodo-2,2-difluoroacetophenones and different unsaturated alcohols,
such as γ- and δ- hydroxyl olefins, were examined under the optimized
reaction conditions (Table 3). Overall, the radical addition reaction
proceeded smoothly to furnish the α,α-difluorobenzoyl cyclic ethers in
moderate to high yields, and no primary adduct β-iodo(difluoroalkyl)-
alkanoic alcohol was observed. The results showed that 2-iodo-2,2-di-
fluoroacetophenones, which have electron-donating groups in the
benzene ring give higher yield of the corresponding cyclic ethers than
those having halogen atoms, such as fluorine, chlorine. Most
In summary,
a convenient and facile approach for α,α-di-
fluorobenzoyl oxygen heterocycles via the radical cyclization reaction
of 2-iodo-2,2-difluoroacetophenones with unsaturated acids or alcohols
has been developed. The reaction of unsaturated acids was initiated by
AIBN in CH3CN for the synthesis of α,α-difluorobenzoyl lactones, while
the reaction of unsaturated alcohols initiated by AIBN proceeded well
only in the presence of base 2,6-lutidine to afford α,α-difluorobenzoyl
cyclic ethers. Further application of 2-iodo-2,2-difluoroacetophenones
for radical reactions to synthesize structurally diverse α,α-di-
fluoroketones are in progress and will be reported in due course.
Table 1
a,b
Reaction scope of 2-iodo-2,2-difluoroacetophenones and unsaturated acids
.
a
Reaction condition: 1 (1.5 mmol), 2 (1.0 mmol), AIBN (30 mol%), CH3CN (10 mL).
Isolated yield.
b
42

H. Chen et al.
JournalofFluorineChemistry200(2017)41–46
Table 2
Optimization of reaction conditions for the synthesis of compound 5aa.
Entry
Initia./Catal. (mol%)
Base
Solvent
Temp. (°C)
Yield (%)b
1
2
3
4
5
6
7
8
AIBN
AIBN
–
–
–
–
–
–
–
–
–
–
CH3CN
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
80
40
80
12
15–30
23
25
trace
10
trace
24
trace
trace
50
19
53
28
22
trace
23
63
76
trace
90
CH3CN + H2O/ClCH2CH2Cl/THF/DMF/DMSO/1,4-dioxane
Pd(PPh3)4
Pd(OAc)2
PdCl2(PPh3)2
Pd(PCy3)2Cl2
NiCl2
Ni(acac)2
(PPh3)2NiCl2
Ni(dppf)Cl2
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
9
10
11
12
13
14
15
16
17
18
19
20
21
Cs2CO3
NaHCO3
NaOH
K2CO3
Et3N
pyridine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
(30 mol%)
AIBN
22
2,6-lutidine
–
80
65
(30 mol%)
cThe ratio of 1a to 4a is 1:1.
a
Reaction condition: 1a (1.5 mmol), 4a (1.0 mmol), initiator/catalyst (20 mol%), base (1.5 mmol).
Yields determined by GC analysis and based on 4a.
b
Table 3
Reaction scope of 2-iodo-2,2-difluoroacetophenones and unsaturated alcoholsa,b
.
a
Reaction condition: 1 (1.5 mmol), 4 (1.0 mmol), AIBN (30 mol%), 2,6-lutidine (1.5 mmol).
Isolated yield.
b
43

H. Chen et al.
JournalofFluorineChemistry200(2017)41–46
130.8, 127.1, 95.2 (t, JC-F = 325.0 Hz) ppm. HRMS (EI): calcd for
1
4. Experimental
C8H4BrF2IO [M]+: 361.8438, found: 361.8442.
4.1. General
4.2.4. 2,2-Difluoro-2-iodo-1-(4-methoxyphenyl)ethanone (1f)
Light yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.17–8.16 (m,
All reagents were of analytical grade, and obtained from commer-
cial suppliers and used without further purification. All NMR spectra
2H), 7.00–6.99 (m, 2H), 3.93(s, 3H); 19F NMR (470 MHz, CDCl3): δ
−53.27 (s, 2F); 13C NMR (125 MHz, CDCl3):
F = 22.5 Hz), 165.0, 133.4, 120.9, 114.3, 95.5 (t, JC-F = 306.3 Hz),
55.7 ppm. HRMS (EI): calcd for C9H7F2IO2 [M]+: 311.9459, found:
311.9460.
δ
181.1 (t, JC-
2
were recorded on
a Bruker Avance 500 (resonance frequencies
500 MHz for 1H and 125 MHz for 13C) equipped with a 5 mm inverse
broadband probe head with z-gradients at 295.8 K with standard Bruker
pulse programs. The samples were dissolved in 0.6 mL CDCl3 (99.8%
D.TMS). Chemical shifts were given in values of δH and δC referenced to
residual solvent signals (δH 7.26 for 1H, δC 77.0 for 13C in CDCl3). The
19F NMR spectra were obtained using a 500 spectrometer (470 MHz)
using trifluorotoluene as external standard. High resolution mass
spectra (HRMS) were recorded on a Bruker solan X 70 FT-MS (samples
was dissolved in CH3OH and the ion source was ESI), and the energy
was 22.5 eV at MS/MS. High resolution mass spectra (HRMS)
(Compounds 1c-f, 1i, 5o and 5p) were recorded under electron impact
conditions using a MicroMass GCT CA 055 instrument and recorded on
a MicroMass LCTTM spectrometer. Melting points are uncorrected.
1
4.2.5. 2,2-Difluoro-2-iodo-1-(thiophen-2-yl)ethanone (1i)
Light yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.06–7.87 (m,
2H), 7.26–7.24 (m, 1H); 19F NMR (470 MHz, CDCl3): δ-54.5 (s, 2F); 13
C
2
NMR (125 MHz, CDCl3): δ 176.6 (t, JC-F = 25.0 Hz), 137.7, 136.7,
1
133.7, 129.1, 29.7 (t, JC-F = 300.0 Hz) ppm. HRMS (EI): calcd for
C6H3F2IOS [M]+: 287.8917, found: 287.8918.
4.3. The synthesis of α,α-difluorobenzoyl latones 3a-l
The synthetic method and spectral data of α,α-difluorobenzoyl la-
tones 3a-l see reference 9.
4.2. Preparation of 2-iodo-2,2-difluoroacetophenone 1a-i
The 2-iodo-2,2-difluoroacetophenone 1a-i were prepared according
to the reported procedure [11]. As shown in Scheme 2, the inter-
mediates enols were obtained from the reaction of ethyl 2,2,2-tri-
fluoroacetate and ketones. The enols reacted with Selectfluor® to form
fluorinated gem-diols, which then reacted with I2 to afford 2-iodo-2,2-
difluoroacetophenone 1a-i using the trifluoroacetate release conditions
(Scheme 2). The data of NMR and HRMS of new compounds 1c-f and 1i
were as follows.
4.4. General procedure for the synthesis of compounds 5a-p
To a solution of 2-iodo-2,2-difluoroacetophenones 1a-i (1.5 mmol)
was added unsaturated alcohol 4 (1 mmol), AIBN (50 mg, 30 mol%)
and 2,6-lutidine (160 mg, 1.5 mmol) at room temperature, the mixture
was then heated to 80 °C and stirred for 20 h (TLC). After the com-
pletion of reaction, the reaction was quenched with H2O. The aqueous
phase was extracted with ethyl acetate (3 × 10 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was purified by
flash column chromatography using petroleum ether/ethyl acetate
(20:1) as eluent to afford the corresponding compounds 5.
4.2.1. 2,2-Difluoro-1-(4-fluorophenyl)-2-iodoethanone (1c)
Light yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.24–8.22 (m,
2H), 7.24–7.20 (m, 2H); 19F NMR (470 MHz, CDCl3): δ −54.4 (s, 2F),
2
−110.5 (s, 1F); 13C NMR (125 MHz, CDCl3),
δ
180.9 (t, JC-
1′
4′
F = 22.5 Hz), 166.7 (d,
J
= 257.5 Hz), 133.8 (d,
J
= 8.8 Hz),
C-F
C-F
4.4.1. 2,2-Difluoro-1-phenyl-3-(tetrahydrofuran-2-yl)propan-1-one (5a)
Yellow oily liquid, yield: 86%. 1H NMR (500 MHz, CDCl3): δ
8.11–7.49 (m, 5H), 4.23–4.18 (m, 1H), 3.79 (dd, J = 14.7, 7.5 Hz, 1H),
3.71 (dd, J = 14.2, 8.0 Hz, 1H), 2.67–2.53 (m, 1H), 2.45–2.35 (m, 1H),
2.17–2.10 (m, 1H), 1.98–1.84 (m, 2H), 1.65–1.58 (m, 1H); 19F NMR
3′
2′
1
130.3 (d,
J
= 10.0 Hz), 116.4 (d,
J
= 22.5 Hz), 29.7 (t, JC-
C-F
C-F
F = 43.8 Hz) ppm. HRMS (EI): calcd for C8H4F3IO [M]+: 299.9259,
found: 299.9257.
(470 MHz, CDCl3):
δ
−99.05 (AB, J = 282.0 Hz, 2F); 13C NMR
4.2.2. 2,2-Difluoro-1-(3-fluorophenyl)-2-iodoethanone (1d)
Light yellow liquid. 1H NMR (500 MHz, CDCl3): δ 7.99–7.85 (m,
2H), 7.54–7.53 (m, 1H), 7.43–7.37 (m, 1H); 19F NMR (470 MHz,
CDCl3): δ-54.9 (s, 2F), −110.3 (s, 1F); 13C NMR (125 MHz, CDCl3), δ
2
(125 MHz, CDCl3): δ 189.4 (t, JC-F = 30.0 Hz), 134.0, 132.4, 130.0 (t,
3JC-F = 3.1 Hz), 128.6, 119.0 (t, JC-F = 251.9 Hz), 73.1 (t,
J
C-
1
3′
2′
F = 4.4 Hz), 67.6, 40.0 (t,
J
C-F
= 21.9 Hz), 32.0, 25.4 ppm. IR (KBr)
2
1′
3′
181.2 (t, JC-F = 22.5 Hz), 162.5 (d,
J
= 247.5 Hz), 130.7 (d,
= 21.2 Hz), 117.6 (d,
J
J
νmax: 2977, 2871, 1703, 1598, 1450, 1275, 1176, 1104, 1039, 1027,
C-F
C-
2′
2′’
917, 714, 687, 612, 423 cm−1. HRMS calcd for C13H14F2O2 (M+Na)+
263.0859, found: 263.0854.
:
F = 7.5 Hz), 126.6, 122.3 (d,
F = 23.8 Hz), 95.0 (t, JC-F = 323.8 Hz) ppm. HRMS (EI): calcd for
J
C-F
C-
1
C8H4F3IO [M]+: 299.9259, found: 299.9261.
4.4.2. 3-(4,4-Dimethyltetrahydrofuran-2-yl)-2,2-difluoro-1-phenylpropan-
1-one (5b)
4.2.3. 1-(4-Bromophenyl)-2,2-difluoro-2-iodoethanone (1e)
Light yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.04–8.03 (m,
Yellow oily liquid, yield: 84%. 1H NMR (500 MHz, CDCl3): δ
8.08–7.47 (m, 5H), 3.80–3.74 (m, 2H), 3.72 (dd, J = 10.0, 2.0 Hz, 1H),
2.44–2.24 (m, 2H), 1.78–1.69 (m, 2H), 1.07 (s, 3H), 0.95 (s, 3H); 19F
2H), 7.70–7.68 (m, 2H); 19F NMR (470 MHz, CDCl3): δ-54.7 (s, 2F); 13
C
2
NMR (125 MHz, CDCl3): δ 181.5 (t, JC-F = 23.8 Hz), 132.4, 132.2,
Scheme 2. Synthesis of 2-iodo-2,2-difluoroacetophenone 1a-i.
44

H. Chen et al.
JournalofFluorineChemistry200(2017)41–46
NMR (470 MHz, CDCl3): δ −98.91 (AB, J = 282.0 Hz, 2F); 13C NMR
2.40–2.29 (m, 1H), 2.11–2.04 (m, 1H), 1.90–1.80 (m, 2H), 1.59–1.53
2
(125 MHz, CDCl3): δ 189.8 (t, JC-F = 42.5 Hz), 133.8, 132.6, 130.0 (t,
(m, 1H); 19F NMR (470 MHz, CDCl3): δ −98.51 (AB, J = 282.0 Hz, 2F);
3JC-F = 3.1 Hz), 128.5, 119.5 (t, JC-F = 251.9 Hz), 80.3 (t,
J
13C NMR (125 MHz, CDCl3): δ 187.7 (t, JC-F = 30.0 Hz), 164.3, 132.6
1
3′
2
C-
F = 3.8 Hz), 65.7, 41.0, 40.3, 35.4 (t, 2′JC-F = 21.9 Hz), 25.0, 21.5 ppm.
(t, JC-F = 3.8 Hz), 119.1 (t, JC-F = 251.3 Hz), 113.9, 73.1 (t,
J
C-
3
1
3′
HRMS calcd for C15H18F2O2 (M+Na)+: 291.1173, found: 291.1179.
F = 3.8 Hz), 67.6, 55.5, 40.0 (t,
J
= 21.3 Hz), 39.3, 32.1, 25.4,
2′
C-F
23.2 ppm. IR (KBr) νmax: 2846, 1698, 1601, 1573, 1515, 1463, 1427,
1317, 1266, 1251, 1179, 1137, 1059, 975, 872, 833, 554 cm−1. HRMS
calcd for C14H16F2O3 (M+Na)+: 293.0965, found: 293.0933.
4.4.3. 2,2-Difluoro-1-phenyl-3-(tetrahydro-2H-pyran-2-yl)propan-1-one
(5c)
Yellow oily liquid, yield: 82%. 1H NMR (500 MHz, CDCl3): δ
8.07–7.47 (m, 5H), 3.78–3.76 (m, 1H), 3.66–3.62 (m, 1H), 3.31–3.26
(m, 1H), 2.59–2.47 (m, 1H), 2.34–2.28 (m, 1H), 1.84–1.81 (m, 1H),
1.68–1.65 (m, 1H), 1.54–1.48 (m, 2H), 1.46–1.44 (m, 1H), 1.38–1.34
(m, 1H); 19F NMR (470 MHz, CDCl3): δ −98.95 (AB, J = 272.6 Hz, 2F);
13C NMR (125 MHz, CDCl3): δ 189.8 (t, 2JC-F = 30.6 Hz), 133.7, 132.9,
4.4.8. 3-(4,4-Dimethyltetrahydrofuran-2-yl)-2,2-difluoro-1-(4-
methoxyphenyl)propan-1-one (5 h)
Yellow oily liquid, yield: 87%. 1H NMR (500 MHz, CDCl3): δ
8.13–6.97 (m, 4H), 3.91 (s, 3H), 3.85–3.78 (m, 2H), 3.73 (dd, J = 7.6,
3.9 Hz, 1H), 2.36–2.27 (m, 2H), 1.79–1.73 (m, 2H), 1.09 (s, 3H), 0.96
(s, 3H); 19F NMR (470 MHz, CDCl3): δ −98.46(AB, J = 282.0 Hz, 2F);
13C NMR (125 MHz, CDCl3): δ 188.1 (t, 2JC-F = 32.5 Hz), 164.1, 132.6,
3
1
129.9 (t, JC-F = 2.5 Hz), 128.5, 119.0 (t, JC-F = 251.3 Hz), 72.2 (t,
3′
2′
J
= 5.0 Hz), 68.1, 41.6 (t,
J
C-F
= 22.5 Hz), 32.0, 25.4, 23.2 ppm.
C-F
119.6 (t, 1JC-F = 250.6 Hz), 117.2, 80.3 (t, 3′JC-F = 3.1 Hz), 65.8, 55.5,
IR (KBr) νmax: 2938, 2856, 1703, 1599, 1450, 1263, 1092, 806, 721,
701 cm−1. HRMS calcd for C14H16F2O2 (M+Na)+: 277.1016, found:
277.1018.
2′
41.1, 40.5, 35.2 (t,
J
= 22.5 Hz), 24.9, 23.5, 21.5 ppm. IR (KBr)
C-F
νmax: 2962, 1693, 1602, 1513, 1465, 1316, 1264, 1173, 1027, 845,
770 cm−1. HRMS calcd for C16H20F2O3 (M+H)+: 299.1459, found:
299.1469.
4.4.4. 2,2-Difluoro-3-(tetrahydrofuran-2-yl)-1-(p-tolyl)propan-1-one (5d)
Yellow oily liquid, yield: 87%.1H NMR (500 MHz, CDCl3):
δ
8.00–7.27 (m, 4H), 4.20–4.14 (m, 1H), 3.78 (dd, J = 14.7, 7.4 Hz, 1H),
3.68 (dd, J = 14.3, 7.8 Hz, 1H), 2.64–2.52 (m, 1H), 2.41 (s, 3H),
2.38–2.27 (m, 1H), 2.14–2.07 (m, 1H), 1.95–1.81 (m,2H), 1.62–1.55
(m, 1H); 19F NMR (470 MHz, CDCl3): δ −98.94 (AB, J = 282.00 Hz,
4.4.9. 2,2-Difluoro-1-(4-fluorophenyl)-3-(tetrahydrofuran-2-yl)propan-1-
one (5i)
Yellow oily liquid, yield: 82%. 1H NMR (500 MHz, CDCl3): δ
8.15–7.15 (m, 4H), 4.20–4.17 (m, 1H), 3.78 (dd, J = 14.7, 7.5 Hz, 1H),
3.69 (dd, J = 14.3, 7.9 Hz, 1H), 2.64–2.52 (m, 1H), 2.44–2.33 (m, 1H),
2.15–2.09 (m, 1H), 1.94–1.83 (m, 2H), 1.64–1.57 (m, 1H); 19F NMR
(470 MHz, CDCl3): δ −98.80 (AB, J = 282.0 Hz, 2F), −102.92 (s, 1F);
13C NMR (125 MHz, CDCl3): δ 188.0 (t, 2JC-F = 30.0 Hz), 166.2 (d, 1′JC-
F = 255.0 Hz), 132.9 (dt, 3′JC-F = 2.5 Hz, 3JC-F = 8.8 Hz), 128.7, 119.0
2
2F); 13C NMR (125 MHz, CDCl3): δ 189.0 (t, JC-F = 30.0 Hz), 145.2,
3
1
130.2 (t, JC-F = 3.1 Hz), 129.3, 119.0 (t, JC-F = 251.3 Hz), 73.1 (t,
3′
2′
J
= 4.4 Hz), 67.7, 40.1 (t,
J
= 21.9 Hz), 32.1, 25.5, 23.3,
C-F
C-F
21.7 ppm. IR (KBr) νmax: 2978, 2871, 1748, 1698, 1608, 1275, 1197,
1177, 1036, 824, 756, 742, 594, 482 cm−1
HRMS calcd for
14H16F2O2 (M+Na)+: 277.1016, found: 277.1017.
.
C
1
2′’
3′’
(t, JC-F = 251.9 Hz), 115.9 (d,
J
= 21.9 Hz), 73.0 (t,
J
C-F
C-
2′
F = 4.4 Hz), 67.7, 39.9 (t,
J
C-F
= 22.5 Hz), 32.1, 25.4 ppm. IR (KBr)
4.4.5. 3-(4,4-Dimethyltetrahydrofuran-2-yl)-2,2-difluoro-1-(p-tolyl)
propan-1-one (5e)
νmax: 2977, 2872, 1705, 1600, 1508, 1239, 850, 815, 768, 618,
593 cm−1. HRMS calcd for C13H13F3O2 (M+Na)+: 281.0765, found:
281.0765.
Yellow oily liquid, yield: 85%.1H NMR (500 MHz, CDCl3):
δ
8.02–7.28 (m, 4H), 3.83–3.71 (m, 2H), 3.72 (d, J = 9.5 Hz, 1H), 2.43
(s, 3H), 2.37–2.24 (m, 2H), 1.80–1.70 (m, 2H), 1.08 (s, 3H), 0.95 (s,
3H); 19F NMR (470 MHz, CDCl3): δ −98.85 (AB, J = 282.0 Hz, 2F); 13
C
4.4.10. 3-(4,4-Dimethyltetrahydrofuran-2-yl)-2,2-difluoro-1-(4-
fluorophenyl)propan-1-one (5j)
2
NMR (125 MHz, CDCl3): δ 189.3 (t, JC-F = 30.0 Hz), 145.0, 130.2 (t,
Yellow oily liquid, yield: 79%. 1H NMR (500 MHz, CDCl3): δ
8.14–7.14 (m, 4H), 3.80–3.72 (m, 2H), 3.69 (dd, J = 9.9, 1.6 Hz, 1H),
2.41–2.22 (m, 2H), 1.78–1.69 (m, 2H), 1.07 (s, 3H), 0.94 (s, 3H); 19F
NMR (470 MHz, CDCl3): δ −98.69 (AB, J = 282.0 Hz, 2F), −103.13 (s,
1F); 13C NMR (125 MHz, CDCl3): δ 188.3 (t, 2JC-F = 30.6 Hz), 166.1 (d,
1
3JC-F = 2.5 Hz), 128.6, 128.6, 119.5 (t, JC-F = 252.5 Hz), 80.3 (3′JC-
2′
F = 2.5 Hz), 65.7, 41.0, 40.4, 35.3 (t,
J
= 22.5 Hz), 25.0, 21.8,
C-F
21.5 ppm. IR (KBr) νmax: 2965, 2874, 1698, 1608, 1467, 1178, 1121,
1107, 918, 753 cm−1 HRMS calcd for C16H20F2O2 (M+Na)+
.
:
305.1392, found: 305.1326.
1′
3′
3
J
= 255.0 Hz), 132.9 (dt,
J
= 2.5 Hz, JC-F = 8.8 Hz), 128.9,
C-F
C-F
1
2′’
3′’
119.5 (t, JC-F = 251.9 Hz), 115.8 (d,
F = 2.5 Hz), 65.7, 41.0, 40.3, 35.3 (t,
J
= 22.5 Hz), 80.3 (t,
J
C-F
C-
4.4.6. 2,2-Difluoro-3-(tetrahydro-2H-pyran-2-yl)-1-(p-tolyl)propan-1-one
(5f)
2′
J
= 21.88 Hz), 25.0,
C-F
Yellow oily liquid, yield: 83%. 1H NMR (500 MHz, CDCl3): δ
7.98–7.28 (m, 4H), 3.81–3.79 (m, 1H), 3.66–3.62 (m, 1H), 3.33–3.28
(m, 1H), 2.57–2.47 (m, 1H), 2.44 (s, 3H), 2.34–2.24 (m, 1H), 1.84–1.82
(m,1H), 1.67 (d, J = 12.80 Hz, 1H), 1.56–1.49 (m, 2H), 1.47–1.44 (m,
1H), 1.41–1.33 (m, 1H); 19F NMR (470 MHz, CDCl3): δ −98.79 (AB,
21.5 ppm. IR (KBr) νmax: 2925, 2853, 1717, 1604, 1510, 1275,
1231 cm−1. HRMS calcd for C15H17F3O2 (M+Na)+: 309.1078, found:
309.1075.
4.4.11. 2,2-Difluoro-1-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-2-yl)
propan-1-one (5k)
2
J = 277.3 Hz, 2F); 13C NMR (125 MHz, CDCl3): δ 189.3 (t, JC-
3
F = 30.0 Hz), 144.8, 130.2, 130.1 (t, JC-F = 2.5 Hz), 129.3, 119.1 (t,
Yellow oily liquid, yield: 76%. 1H NMR (500 MHz, CDCl3): δ
8.10–7.13 (m, 4H), 3.74–3.72 (m, 1H), 3.63–3.59 (m, 1H), 3.25 (t,
J = 9.6 Hz,1H), 2.56–2.44 (m, 1H), 2.33–2.23 (m, 1H), 1.82–1.81 (m,
1H), 1.64 (d, J = 12.9 Hz, 1H), 1.52–1.47 (m, 1H), 1.45–1.44 (m, 1H),
1.44–1.38 (m, 1H), 1.35 (s, 1H); 19F NMR (470 MHz, CDCl3): δ −98.82
(AB, J = 277.3 Hz, 2F), −103.49 (s, 1F); 13C NMR (125 MHz, CDCl3): δ
3′
2′
1JC-F = 251.3 Hz), 72.2 (t,
J
C-F
= 5.0 Hz), 68.2, 41.6 (t,
J
C-
F = 22.5 Hz), 32.0, 25.5, 23.3, 21.8 ppm. IR (KBr) νmax: 2959, 2922,
2851, 1716, 1464, 1457, 1317, 1247, 1195, 1178, 1133, 1082, 1048,
1013, 966, 816 cm−1
. :
HRMS calcd for C15H18F2O2 (M+Na)+
291.1173, found: 291.1173.
2
1′
3′
188.2 (t, JC-F = 29.4 Hz), 166.0 (d,
J
= 255.0 Hz), 132.7 (dt, J
C-F C-
3
1
4.4.7. 2,2-Difluoro-1-(4-methoxyphenyl)-3-(tetrahydrofuran-2-yl)propan-
1-one (5 g)
F = 2.5 Hz, JC-F = 8.8 Hz), 129.3, 119.0 (t, JC-F = 250.6 Hz), 115.7
2′’
3′2
2′
(d,
F = 22.5 Hz), 31.9, 25.4, 23.2 ppm. IR (KBr) νmax: 2943, 2859, 1705,
1600, 1581, 1509, 1239, 850, 840, 768 cm−1
HRMS calcd for
14H15F3O2 (M+Na)+: 295.0922, found: 295.0918.
J
= 21.3 Hz), 72.1 (t,
J
= 2.5 Hz), 68.1, 41.6 (t,
J
C-F
C-F
C-
Yellow oily liquid, yield: 90%. 1H NMR (500 MHz, CDCl3): δ
8.07–6.91 (m, 4H), 4.16–4.11 (m, 1H), 3.83 (s, 3H), 3.76 (q,
J = 7.3 Hz, 1H), 3.66 (dd, J = 14.2, 8.0 Hz, 1H), 2.60–2.48 (m, 1H),
.
C
45

H. Chen et al.
JournalofFluorineChemistry200(2017)41–46
4.4.12. 2,2-Difluoro-1-(3-fluorophenyl)-3-(tetrahydrofuran-2-yl)propan-
1-one (5l)
1.99–1.85 (m, 1H), 1.67–1.58 (m, 1H); 19F NMR (470 MHz, CDCl3): δ
−101.1(AB, J = 277.3 Hz, 2F); 13C NMR (125 MHz, CDCl3), δ 182.8 (t,
2JC-F = 28.8 Hz), 138.4, 136.1, 135.6, 128.7, 121.6 (d, 3JC-F = 6.3 Hz),
Light yellow oily liquid, yield: 79%. 1H NMR (500 MHz, CDCl3): δ
7.87–7.30 (m, 4H), 4.20–4.15 (m, 1H), 3.74 (dd, J = 15.0, 7.5 Hz, 1H),
3.67 (dd, J = 14.0, 7.5 Hz, 1H), 2.64–2.52 (m, 1H), 2.43–2.33 (m, 1H),
2.14–2.07 (m, 1H), 1.92–1.83 (m, 2H), 1.63–1.56 (m, 1H); 19F NMR
(470 MHz, CDCl3): δ −99.22 (AB, J = 286.7 Hz, 2F), −111.47(s, 1F);
119.6 (t, JC-F = 252.5 Hz), 73.0 (t, 3′JC-F = 3.8 Hz), 67.7, 39.9 (t, 2′JC-
F = 21.3 Hz), 32.0, 25.4 ppm. IR (KBr) νmax: 2978, 2869, 2852, 1678,
1598, 1515, 1462, 1412, 1357, 1185, 1132, 839, 727 cm−1. HRMS (EI):
calcd for C11H12F2O2S [M]+: 246.0526, found: 246.0525.
1
13C NMR (125 MHz, CDCl3): δ 188.4 (t, JC-F = 31.6 Hz), 162.5 (d,
2
1′J = 246.3 Hz), 137.8, 134.3 (d, JC-F = 2.5 Hz), 130.3 (d, JC-
Acknowledgments
3
F = 3.8 Hz), 125.8 (d, JC-F = 1.9 Hz), 121.0 (d, JC-F = 10.6 Hz), 119.0
1
3′
2′
(t, JC-F = 251.9 Hz), 73.0 (t,
J
C-F
= 4.4 Hz), 67.7, 39.9 (t,
J
We are grateful for financial supports from the National Natural
Science Foundation of China (Grant No. 21672151, 21472126,
21302128), and the Science Foundation of Shanghai Institute of
Technology (YJ2013-45).
C-
F = 21.9 Hz), 32.0, 25.4 ppm. IR (KBr) νmax: 2876, 1711,1588, 1486,
1443, 1251, 1132, 1057, 831, 758 cm−1. HRMS calcd for C13H13F3O2
(M+Na)+: 281.0765, found: 281.0779.
4.4.13. 1-(4-Bromophenyl)-2,2-difluoro-3-(tetrahydro-2H-pyran-2-yl)
propan-1-one (5m)
References
Yellow oily liquid, yield: 78%. 1H NMR (500 MHz, CDCl3): δ
7.90–7.60 (m, 4H), 3.70 (dd, J = 10.80, 3.00 Hz, 1H), 3.61–3.57 (m,
1H), 3.27–3.19 (m, 1H), 2.56–2.43 (m, 1H), 2.32–2.22 (m, 1H),
1.81–1.80 (m, 1H), 1.63 (d, J = 12.9 Hz, 1H), 1.50–1.45 (m, 2H),
1.44–1.41 (m, 1H), 1.38–1.32 (m, 1H); 19F NMR (470 MHz, CDCl3): δ
−99.10 (AB, J = 272.6 Hz, 2F); 13C NMR (125 MHz, CDCl3): δ 189.0
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(t, JC-F = 29.4 Hz), 131.9, 131.8, 131.3 (t, JC-F = 3.8 Hz), 129.0,
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3′
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121.0, 119.0 (t, JC-F = 251.3 Hz), 72.1 (t,
J
= 3.8 Hz), 68.0, 41.7
C-F
2′
(t,
J
= 22.5 Hz), 31.8, 25.4, 23.2 ppm. IR (KBr) νmax: 2977, 2871,
C-F
1705, 1586, 1566, 1397, 1315, 824, 759, 473, 421 cm−1. HRMS calcd
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4.4.14. 1-(4-Chlorophenyl)-2,2-difluoro-3-(tetrahydrofuran-2-yl)propan-
1-one (5n)
Yellow oily liquid, yield: 78%. 1H NMR (500 MHz, CDCl3): δ
8.03–7.45 (m, 4H), 4.20–4.14 (m, 1H), 3.75 (dd, J = 15.0, 8.0 Hz, 1H),
3.67 (dd, J = 14.0, 8.0 Hz, 1H), 2.63–2.51 (m, 1H), 2.43–2.33 (m, 1H),
2.14–2.08 (m, 1H), 1.94–1.82 (m, 2H), 1.63–1.56 (m, 1H); 19F NMR
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99–122;
(470 MHz, CDCl3):
δ
−99.04 (AB, J = 282.0 Hz, 2F); 13C NMR
2
3
(125 MHz, CDCl3): δ 188.4 (t, JC-F = 30.6 Hz), 140.6, 131.4 (t, JC-
1
F = 3.1 Hz), 130.7, 129.4, 129.0, 118.9 (t, JC-F = 251.9 Hz), 73.0 (t,
3′
2′
J
= 4.4 Hz), 67.7, 39.9 (t,
J
C-F
= 21.9 Hz), 32.0, 25.4 ppm. IR
C-F
(KBr) νmax: 2978, 2873, 1706, 1589, 1489, 1403, 1192, 1177, 1093,
1015, 917, 844, 825, 761 cm−1. HRMS calcd for C13H13ClF2O2 (M
+Na)+: 297.0470, found: 297.0471.
4.4.15. 2,2-Difluoro-1-(naphthalen-2-yl)-3-(tetrahydrofuran-2-yl)propan-
1-one (5o)
Yellow oily liquid, yield: 65%. 1H NMR (500 MHz, CDCl3) δ 8.71 (s,
1H), 8.11-7.80 (m, 3H), 7.67–7.58 (m, 2H), 4.26–4.23 (m, 1H), 3.81
(dd, J = 15.0, 10.0 Hz, 1H), 3.72 (dd, J = 15.0, 10.0 Hz, 1H),
2.78–2.60 (m, 1H), 2.54–2.40 (m, 1H), 2.20–2.10 (m, 1H), 1.99–1.85
(m, 1H), 1.70–1.56 (m, 1H); 19F NMR (470 MHz, CDCl3): δ −98.4 (AB,
(e) C. Wang, G.A. Russell, J. Org. Chem. 64 (1999) 2066–2069;
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977–977;
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42 (1999) 1615–1624.
2
J = 282.0 Hz, 2F); 13C NMR (125 MHz, CDCl3): δ 189.4 (t, JC-
3
F = 30.0 Hz), 135.9, 132.5 (t, JC-F = 3.8 Hz), 132.3, 130.0, 129.7,
[8] (a) X.W. Zou, F.H. Wu, Chin. Chem. Lett. 13 (2002) 410–411;
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4′
1
128.5, 127.8, 126.9, 124.7 (d,
J
= 1.3 Hz), 119.2 (t, JC-
C-F
F = 252.5 Hz), 73.2 (t, 3′JC-F = 5.0 Hz), 67.7, 40.1 (t, 2′JC-F = 21.3 Hz),
32.1, 25.5 ppm. IR (KBr) νmax: 3715, 3649, 2959, 2917, 1698, 1627,
(c) X.Y. Yang, Z.H. Wang, Y.P. Zhu, X. Fang, X.J. Yang, F.H. Wu, Y.J. Shen, J. Fluor.
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1170, 778, 473 cm−1
. :
HRMS (EI): calcd for C17H16F2O2 [M]+
290.1118, found: 290.1119.
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4.4.16. 2,2-Difluoro-3-(tetrahydrofuran-2-yl)-1-(thiophen-2-yl)propan-1-
one (5p)
Yellow oily liquid, yield: 77%. 1H NMR (500 MHz, CDCl3) δ
8.04–8.03 (m, 1H), 7.80–7.79 (m, 1H), 7.22–7.20 (m, 1H), 4.23–4.10
(m, 1H), 3.82 (dd, J = 10.0, 5.0 Hz, 1H), 3.71(dd, J = 10.0, 5.0 Hz,
1H), 2.66–2.55 (m, 1H), 2.45–2.32 (m, 1H), 2.17–2.09 (m, 1H),
(c) J.P. John, D.A. Colby, J. Org. Chem. 76 (2011) 9163–9168.
46