Practical Access to Difluoromethyl Ketones via Straightforward Decarboxylative Difluorination of β-Ketoacids

Article abstract of DOI:10.1002/adsc.201601315

A facile synthetic approach to a series of difluoromethyl ketones from β-ketoacids has been described. This transformation is achieved through the straightforward decarboxylative difluorination of β-ketoacids in the absence of any catalyst. Furthermore, the resulted difluoromethyl ketones can be easily converted into corresponding difluoromethylated building blocks for pharmaceuticals and materials. (Figure presented.).

Full text of DOI:10.1002/adsc.201601315

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DOI: 10.1002/adsc.201601315
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Practical Access to Difluoromethyl Ketones via Straightforward
Decarboxylative Difluorination of b-Ketoacids
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Yin-Long Li,a Jian Li,a and Jun Denga, b,*
a
School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin
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University, Tianjin, 300072, People’s Republic of China
Fax: (+86)-23-65678460; e-mail: jdeng@cqu.edu.cn
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South
b
Road, Shapingba, Chongqing 401331, People’s Republic of China
Received: November 28, 2016; Revised: December 23, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601315
omethyl ketones (Scheme 1). For instance, difluoro-
Abstract: A facile synthetic approach to a series of
methylation reactions of phenylacetylene[7] or arene[8]
difluoromethyl ketones from b-ketoacids has been
by using electrophilic fluorinating reagents have been
described. This transformation is achieved through
reported (Scheme 1a). On the other hand, Piettre[9]
the straightforward decarboxylative difluorination
and Shen[10] discovered that difluoromethyl ketone
of b-ketoacids in the absence of any catalyst.
could be synthesized from aldehydes or acid chlorides
Furthermore, the resulted difluoromethyl ketones
respectively (Scheme 1b). In 2005, Shreeve[11] devel-
can be easily converted into corresponding difluor-
oped a practical method to obtain difluorinated
omethylated building blocks for pharmaceuticals
carbonyl compounds from enamines via fluorination
and materials.
reactions with Selectfluor (F-TEDA-BF4) (Sche-
me 1c). In the same year, Stavber[12] found that n-
Keywords: difluoromethyl ketone; decarboxylative
difluorination; SelectfluorTM; b-ketoacids
butylimine derivatives also could convert to a,a-
difluoro ketones by reacting with Selectfluor (Sche-
me 1c). Prakash[13] and co-worker noted the prepara-
tion difluoromethyl ketones via Mg-mediated de-
35 Fluorine-containing molecules have attracted great
36 attention from generations of chemists for their
37 unique properties.[1] Indeed, the difluoromethyl group
38 (CF2) has appeared as an intriguing structural motif in
39 drug discovery, medicinal chemistry, and life science,
40 owing to its unique role of acting as a lipophilic
41 hydrogen donor via hydrogen bonding, namely a
42 bioisostere of alcohol and thiol groups.[2] However,
43 compared to trifluoromethylation chemistry,[3] meth-
44 ods for incorporating the difluoromethyl group into
45 organic compounds are far less documented. In most
46 cases, synthetic strategies of difluoromethyl-containing
47 compounds often based on the deoxyfluorination of
48 aldehydes or ketones with DAST, Deoxofluor, Xtal-
49 Fluor and other fluorinating reagents.[4] Additionally,
50 the transition-metal-catalyzed difluoromethylation re-
51 action also could be achieved by using Me3SiCF2H as
52 the difluoromethyl source along with other related
53 reactions.[5]
54
As for the difluoromethyl ketone could be an
55 important moiety in many pharmaceuticals and mate-
56 rials,[6] over the past few decades, promising new
57 approaches have been developed to accessing difluor-
Scheme 1. Previous approaches to difluoromethyl ketone
derivatives.
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fluorination of CF3-ketones in 2001 (Scheme 1d). tion, no desired difluoromethylated product 2a was
Nevertheless, Pohmakotr[14] disclosed PhSCF2SiMe3 observed (Table 1, entries 6 to 8). Gratifyingly, the
could be a difluoromethyl building block and provided desired difluoromethyl ketone 2a was furnished in
a
general strategy to difluoromethyl ketones 29% yield when DMF (N, N-dimethyl formamide)
(Scheme 1d). Recently, Pattison[15] described one-pot was employed as the solvent (Table 1, entry 9).
synthesis of difluoromethyl ketones by a difluorina- Further solvent screening showed the use of CH3CN
tion/fragmentation process (Scheme 1e). Despite these could give the product 2a in 34% yield (Table 1,
excellent achievements, most of the strategies have entry 10). Finally, CH3NO2 was selected as the optimal
fundamental drawbacks such as harsh conditions, solvent and the yield of 2a increased to 43% (Table 1,
10 therefore designing more practical methods to syn- entry 11).
11 thesis of difluoromethyl ketones from easily available,
12 convenient and inexpensive precursor are still highly
Table 1. Screening of the solvent and concentration.[a]
13 desirable.
14
In the case of cleaving a CÀC bond, one of the
15 most useful methods is decarboxylation reaction,[16]
16 because it is a powerful, yet mild process for
17 generating a reactive intermediate. The carboxylic
18 acids,[17] which are commercially available, inexpen-
Entry
Solvent
Con. (M)
Yield (%)[b]
19 sive, simple handle and diversiform, are widely used in
20 decarboxylative reactions. We developed a practical
21 and novel process for the synthesis of a-fluoroketones
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toluene
CH2Cl2
CHCl3
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.3
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0
0
0
0
0
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22 via decarboxylative fluorination of b-ketoacids (Sche-
THF
23 me 2a).[18] On the basis of this discovery and mecha-
1,4-dioxane
MeOH
acetone
DMSO
DMF
CH3CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
24 nism study, we wish to demonstrate herein that the
25 decarboxylative difluorination reaction of b-ketoacids
26 towards a series of difluoromethyl ketones (Sche-
27 me 2b).
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0.1
0.075
0.06
[a] Reaction conditions: b-ketoacids 1 (0.30 mmol), Select-
fluor (2.4 equiv.), rt for 72 h.
[b] Isolated yield.
Additionally, the choice of the concentration is
crucial for the conversion. When the concentration of
the reaction was increased to 3.0 M, the yield of 2a
markedly decreased to 21% (Table 1, entry 12). For-
tunately, the yield of the reaction could be improved
to 51% when the concentration was diminished to
0.1 M (Table 1, entry 13). The desired product 2a was
afforded in 53% yield when the concentration was
0.075 M and lower yield was detected when the
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Scheme 2. Decarboxylative fluorination reactions of b-ketoa-
cids.
Based on our previous studies, b-ketoacid 1a was concentration was reduced to 0.06 M (Table 1, en-
49 chosen as the model substrate to test the feasibility of tries14 and 15).
50 difluorination reaction. Our initial efforts were fo-
Next, several bases were applied to the decarbox-
51 cused on solvent screening and we were surprised to ylative difluorination reaction. Disappointedly, we
52 find that the reaction showed dramatic solvent effects found that in the presence of inorganic bases such as
53 (Table 1). When the reaction was conducted in Na2CO3, t-BuOK and CH3ONa, failed to enhance the
54 toluene, CH2Cl2, CHCl3, THF and 1,4-dioxane, no yield of 2a (Table 2, entries 2 to 4). The addition of K2
55 desired product 2a was obtained (Table 1, entries 1 to CO3 only had a slightly effect on the reaction and
56 5). Other solvents such as MeOH, acetone and DMSO gave the product 2a in 56% yield (Table 2, entry 5).
57 also proved to be inappropriate for this transforma- Subsequently, some organic bases were subjected to
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the reaction conditions, the results indicated that Et3
With the optimized conditions in hand, further
N, pyridine and DMAP showed inferior reactivity investigation of substrate scope was focused on
toward the conversion of 1a (Table 2, entries 6 to 8). various b-ketoacids. As depicted in Table 3, the
Then we evaluated the amount of Selectfluor. It was substrates with different substituents on the aromatic
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observed that 3.6 equiv. of
ring were investigated. The results revealed that
electron-donating groups (i.e., Me, OMe) at different
positions on the aromatic ring could provide the
difluoromethylated products 2b–e in moderate to
good yields within 24 h. The reactions of the substrates
with electron-withdrawing groups (i.e., F, Cl and Br)
were also successful, the corresponding products 2f–h
could be obtained in 38–66% yields. However, when
the substrate was appended with a strong electron-
withdrawing group (i.e., CF3), no desired product was
isolated under the optimized conditions (not shown).
Notably, 1- and 2-naphthyl b-ketoacids also tolerated
in this protocol, products 2i and 2j were observed in
74% and 68% yields, respectively. Moreover, the
heterocyclic substrate 1k could generate the desired
product 2k in 56% yield. It is noted that the substrates
carrying a substituent in the a-position of the b-
ketoacids uneventfully produced the difluoromethyl
ketones 2l and 2m in 88% and 45% yields. Compara-
bly, the conditions were not effective for the reactions
of the substrates with two substituents (1n and 1o),
products 2n and 2o were afforded in relatively low
yields.
A plausible mechanistic pathway for the straight-
forward decarboxylative difluorination of b-ketoacids
is outlined in Scheme 3. In the polar aprotic solvent,
the enolate I (the enolization form of b-ketoacid)
occurred nucleophilic fluorination with Selectfluor via
the intermediate II, which could give the a-fluoroke-
toacid III. Subsequently, the a-fluoroketoacid III
underwent a decarboxylation reaction to generate the
high reactive species IV. Finally, the nucleophilic
fluorination of species IV with another Selectfluor
Table 2. Further optimization of reaction conditions.[a]
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Entry Flourine
source
Base
(1.2 equiv.)
Temp.
(oC)
Yield
(%)[b]
1
2
3
4
5
6
7
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
–
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25
25
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40
60
80
60
60
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68
83
73
0
Na2CO3
t-BuOK
CH3ONa
K2CO3
Et3N
pyridine
DMAP
–
–
–
–
–
–
–
8
9[c]
10[d] Selectfluor
11[c] Selectfluor
26 12[c] Selectfluor
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13[c] Selectfluor
14[c] NFSI
15[c] NFPT
0
[a] Reaction conditions: b-ketoacid 1 (0.30 mmol), CH3NO2
(4.0 mL), 72 h. NFSI= N-fluorobenzenesulfonimide;
NFPT= N-fluoropentachloropyridinium triflate.
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33 [b] Isolated yield.
[c] 3.6 equiv. of fluorine reagent was used.
[d] 5.0 equiv. of fluorine reagent was used.
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Selectfluor could promote the yield of 2a to 64% could furnish the difluoromethyl ketone 2, otherwise
39 and the yield was improved to 69% when 5.0 equiv. of nucleophilic trapping by H2O would lead to the
40 Selectfluor was employed (Table 2, entries 9 and 10). formation of a-fluoroketone V.
41 In consideration of economy, we used 3.6 equiv. of
In summary, we have developed a novel and
42 Selectfluor for additional investigation on the influ- convenient protocol for the synthesis of difluorometh-
43 ence of the reaction temperature. To our delight, yl ketones via the straightforward decarboxylative
44 relatively good yield of 2a was afforded when the difluorination reactions of b-ketoacids. Compared
45 reaction performed at 408C (Table 2, entry 11). Fur- with traditional difluoromethylation methods, the
46 ther elevated the reaction temperature to 608C, the obvious advantages of good substrate scopes, mild
47 corresponding difluoromethyl ketone was furnished reaction conditions, and practical procedure make this
48 with a satisfying yield (83%, Table 2, entry 12). system highly appealing for introduction of the
49 However, switching the reaction temperature to 808C difluoromethyl group to pharmaceuticals and materi-
50 led to lower yield, provided product 2a in 73% yield als. Further investigations on the decarboxylative
51 (Table 2, entry 13). Other flourine sources were also fluorination reactions are currently underway in our
52 examined, unfortunately, NFSI and NFPT were slug- laboratory.
53 gish to this reaction and no products were formed. At
54 last, the use of 1a (1.0 equiv.) and Selectfluor
55 (3.6 equiv.) in CH3NO2 (0.075 M ) at 608C for 72 h
56 was established as the optimal reaction conditions for
57 the decarboxylative difluorination reaction.
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Table 3. Scope of b-ketoacids.[a]
relative to solvent residual peak. The H NMR spectra were
recorded at 600 MHz, 13C NMR spectra were recorded at
150 MHz, and 19F NMR spectra were recorded at 564 MHz.
Melting points were determined using a micromelting point
apparatus and were uncorrected/calibrated. TLC analysis
was performed over glass-backed plates (60 ꢁ, 250 mm) and
visualized using UV. High-resolution mass spectra were
obtained using a Q-TOF micro spectrometer.
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General Procedure for Synthesis of Difluoroketones
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To a solution of b-ketoacid 1 (0.30 mmol) in CH3NO2
(4.0 mL) was added selectfluor (1.08 mmol, 382 mg,
3.6 equiv.). The resulting solution was stirred at 608C, after
the TLC showed that the starting material was exhausted,
the reaction was quenched by water (5.0 mL), extracted with
CH2Cl2 (33 20 mL), then dried by Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by
flash column chromatography (silica gel, gradient eluent: 0%
to 5% EtOAc in petroleum ether) to provide the correspond-
ing difluoromethyl ketones 2.
2,2-Difluoro-1-phenylethanone (2a).[15] Reaction time: 72 h.
Yield: 39.0 mg, 83%, colorless oil. Rf =0.30 (Petroleum
1
Ether); H NMR (600 MHz, CDCl3) d 6.30 (t, J=53.5 Hz,
1H), 7.54 (t, J=7.4 Hz, 2H), 7.68 (t, J=7.3 Hz, 1H), 8.08 (d,
J=7.6 Hz, 2H); 19F NMR (564 MHz, CDCl3) d À121.9 (s,
2F); 13C NMR (150 MHz, CDCl3) d 111.2 (t, J=252.0 Hz),
129.0, 129.7, 131.5, 134.9, 187.6 (t, J=25.2 Hz). HRMS (ESI):
m/z calcd for C8H7OF2 (M+H)+ 157.0465, found 157.0461.
2,2-Difluoro-1-(p–tolyl)ethanone (2b).[15] Reaction time:
16 h. Yield: 26.0 mg, 51%, white solid, mp: 45–48 oC. Rf =
1
0.10 (Petroleum Ether); H NMR (600 MHz, CDCl3) d 2.43
(s, 3H), 6.27 (t, J=53.6 Hz, 1H), 7.30 (d, J=7.7 Hz, 2H), 7.96
(d, J=7.7 Hz, 2H); 19F NMR (564 MHz, CDCl3) d À121.9 (d,
J=56.4 Hz, 2F); 13C NMR (150 MHz, CDCl3) d 21.9, 111.2
(t, J=251.9 Hz), 129.0, 129.7, 129.8, 146.2, 187.2 (t, J=
25.1 Hz).
[a] Reaction conditions: b-ketoacids 1 (0.30 mmol), Select-
fluor (3.6 equiv.) in CH3NO2 (4.0 mL) at 608C, isolated
yields.
2,2-Difluoro-1-(2-methoxyphenyl)ethanone (2c). Reaction
time: 24 h. Yield: 42.0 mg, 75%, colorless oil. Rf =0.20
Experimental Section
General Information
1
(Petroleum Ether); H NMR (600 MHz, CDCl3) d 3.94 (s,
3H), 6.60 (t, J=53.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 7.06 (t,
J=7.4 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.6 Hz,
1H); 19F NMR (564 MHz, CDCl3) d À128.6 (d, J=50.8 Hz,
2F); 13C NMR (150 MHz, CDCl3) d 55.9, 109.7 (t, J=
246.0 Hz), 111.9, 121.3, 123.6, 131.5, 135.9, 159.5, 189.2 (t, J=
All purchased chemicals were used as received without
further purification. Solvents were distilled prior to use.
Chromatographic separations were performed using silica gel
200À300 mesh. The chemical shifts are reported in ppm
Scheme 3. Proposed mechanistic pathway.
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24.4 Hz). HRMS (ESI): m/z calcd for C9H9O2F2 (M+H)+
187.0571, found 187.0565.
134.0, 135.5, 189.7 (t, J=24.0 Hz). HRMS (ESI): m/z calcd
for C12H9OF2 (M+H)+ 207.0621, found 207.0616.
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2,2-Difluoro-1-(3-methoxyphenyl)ethanone (2d).[19] Reaction
time: 24 h. Yield: 27.0 mg, 48%, colorless oil. Rf =0.40 (5%
EtOAc/Petroleum Ether); 1H NMR (600 MHz, CDCl3) d
3.87 (s, 3H), 6.30 (t, J=53.5 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H),
7.43 (t, J=8.1 Hz, 1H), 7.56 (s, 1H), 7.66 (d, J=7.6 Hz, 1H);
19F NMR (564 MHz, CDCl3) d À122.1 (d, J=50.8 Hz, 2F);
13C NMR (150 MHz, CDCl3) d 55.5, 111.0 (t, J=252.1 Hz),
113.4, 121.7, 122.3, 130.0, 132.7, 160.0, 187.4 (t, J=25.2 Hz).
HRMS (ESI): m/z calcd for C9H8O2NaF2 (M+Na)+
209.0390, found 209.0383.
2,2-Difluoro-1-(naphthalen-2-yl)ethanone (2j).[15] Reaction
time: 28 h. Yield: 42.0 mg, 68%, colorless oil. Rf =0.45 (5%
EtOAc/Petroleum Ether); 1H NMR (600 MHz, CDCl3) d
6.41 (t, J=53.5 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.65 (t, J=
7.5 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H),
7.98 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.6 Hz, 1H), 8.62 (s, 1H);
19F NMR (564 MHz, CDCl3) d À121.3 (d, J=50.8 Hz, 2F);
13C NMR (150 MHz, CDCl3) d 111.4 (t, J=252.1 Hz), 124.1,
127.2, 127.9, 128.8, 129.0, 129.7, 130.1, 132.3, 132.5, 136.3,
187.5 (t, J=24.5 Hz). HRMS (ESI): m/z calcd for C12H8OF2
Na (M+Na)+ 229.0441, found 229.0430.
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2,2-Difluoro-1-(4-methoxyphenyl)ethanone (2e).[15] Reaction
14 time: 24 h. Yield: 38.0 mg, 68%, white solid, mp: 38–408C.
2,2-Difluoro-1-(thiophen-2-yl)ethanone (2k).[15] Reaction
time: 24 h. Yield: 27.0 mg, 56%, colorless oil. Rf =0.10
(Petroleum Ether); 1H NMR (600 MHz, CDCl3) d 6.19 (t, J=
53.4 Hz, 1H), 7.24 (s, 1H), 7.85 (d, J=4.5 Hz, 1H), 8.02 (s,
1H); 19F NMR (564 MHz, CDCl3) d À121.6 (d, J=50.8 Hz,
2F); 13C NMR (150 MHz, CDCl3) d 110.5 (t, J=252.4 Hz),
128.9, 135.6 (t, J=3.7 Hz), 136.8, 137.7, 181.1 (t, J=26.4 Hz).
Rf =0.40 (5% EtOAc/Petroleum Ether); 1H NMR (600 MHz,
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CDCl3) d 3.90 (s, 3H), 6.26 (t, J=53.7 Hz, 1H), 6.99 (d, J=
8.5 Hz, 2H), 8.06 (d, J=8.3 Hz, 2H); 19F NMR (564 MHz,
CDCl3) d À121.4 (d, J=50.8 Hz, 2F); 13C NMR (150 MHz,
CDCl3) d 55.6, 111.5 (t, J=252.2 Hz), 114.3, 124.5, 132.2,
164.9, 186.1 (t, J=24.7 Hz). HRMS (ESI): m/z calcd for C9H9
O2F2 (M+H)+ 187.0571, found 187.0568.
2,2-Difluoro-3,4-dihydronaphthalen-1(2H)-one (2l).[12] Reac-
tion time: 16 h. Yield: 48.0 mg, 88%, white solid, mp: 43–
458C. Rf =0.15 (Petroleum Ether); 1H NMR (600 MHz,
CDCl3) d 2.55-2.62 (m, 2H), 3.19 (t, J=6.6 Hz, 2H), 7.31 (d,
J=7.8 Hz, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.59 (t, J=7.8 Hz,
1H), 8.12 (d, J=7.8 Hz, 1H); 19F NMR (564 MHz, CDCl3) d
À111.2 (s, 2F); 13C NMR (150 MHz, CDCl3) d 25.6 (t, J=
5.6 Hz), 32.4 (t, J=22.8 Hz), 113.7 (t, J=246.8 Hz), 127.5,
128.7, 128.9, 130.1, 135.1, 142.8, 185.2 (t, J=26.3 Hz). HRMS
(ESI): m/z calcd for C10H9OF2 (M+H)+ 183.0621, found
183.0625.
2,2-Difluoro-1-(4-fluorophenyl)ethanone (2f).[20] Reaction
time: 24 h. Yield: 34.5 mg, 66%, colorless oil. Rf =0.50 (5%
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EtOAc/Petroleum Ether); 1H NMR (600 MHz, CDCl3) d
6.25 (t, J=53.5 Hz, 1H), 7.21 (t, J=8.3 Hz, 2H), 8.13 (t, J=
6.8 Hz, 2H); 19F NMR (564 MHz, CDCl3) d À101.0 (q, J=
5.64 Hz, F), À121.4 (d, J=50.8 Hz, 2F); 13C NMR (150 MHz,
CDCl3) d 111.5 (t, J=252.7 Hz), 116.4 (d, J=22.0 Hz),
132.58 (d, J=1.8 Hz), 132.65 (d, J=1.9 Hz), 166.8 (d, J=
256.9 Hz), 186.2 (t, J=25.8 Hz).
1-(4-Chlorophenyl)-2,2-difluoroethanone (2g).[15] Reaction
time: 36 h. Yield: 26.4 mg, 46%, colorless oil. Rf =0.55 (5%
2,2-Difluoro-1-phenylpropan-1-one (2m).[21] Reaction time:
24 h. Yield: 23.0 mg, 45%, colorless oil, Rf =0.65 (5%
EtOAc/Petroleum Ether); 1H NMR (600 MHz, CDCl3) d
1.90 (t, J=19.8 Hz, 3H), 7.50 (t, J=7.6 Hz, 2H), 7.64 (t, J=
7.5 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H); 19F NMR (564 MHz,
CDCl3) d À92.7 (d, J=22.6 Hz, 2F); 13C NMR (150 MHz,
CDCl3) d 20.8 (t, J=24.9 Hz), 119.4 (t, J=248.7 Hz), 128.7,
130.3, 131.6, 134.3, 189.2 (t, J=32.0 Hz). HRMS (ESI): m/z
calcd for C9H8OF2Na (M+Na)+ 193.0441, found 183.0447.
EtOAc/Petroleum Ether); 1H NMR (600 MHz, CDCl3) d
6.25 (t, J=53.5 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 8.03 (d, J=
8.0 Hz, 2H); 19F NMR (564 MHz, CDCl3) d À121.6 (d, J=
56.4 Hz, 2F); 13C NMR (150 MHz, CDCl3) d 111.3 (t, J=
252.6 Hz), 129.4, 129.7, 131.0, 141.7, 186.6 ( t, J=25.9 Hz).
HRMS (ESI): m/z calcd for C8H6OF2Cl (M+H)+ 191.0075,
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found 191.0073.
1-(4-Bromophenyl)-2,2-difluoroethanone (2h).[15] Reaction
time: 36 h. Yield: 27.0 mg, 38%, colorless oil. Rf =0.35
(Petroleum Ether); 1H NMR (600 MHz, CDCl3) d 6.25 (t, J=
53.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.1 Hz,
2H); 19F NMR (564 MHz, CDCl3) d À121.6 (d, J=50.8 Hz,
2F); 13C NMR (150 MHz, CDCl3) d 111.3 (t, J=252.6 Hz),
130.1, 130.6, 131.0, 132.4, 186.8 (t, J=25.5 Hz). HRMS (ESI):
m/z calcd for C8H6OF2Br (M+H)+ 234.9570, found
2,2-Difluoro-1-(4-methoxyphenyl)propan-1-one (2n).[21] Re-
action time: 18 h. Yield: 12.0 mg, 20%. colorless oil, Rf =0.35
1
(5% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3)
d 1.88 (t, J=19.5 Hz, 3H), 3.90 (s, 3H), 6.97 (d, J=8.9 Hz,
2H), 8.12 (d, J=8.8 Hz, 2H); 19F NMR (564 MHz, CDCl3) d
À92.2; 13C NMR (150 MHz, CDCl3) d 20.9 (t, J=20.0 Hz),
55.5, 114.0, 119.7 (t, J=248.6 Hz), 124.5, 132.8 (t, J=3.1 Hz),
164.4, 187.6 (t, J=30.9 Hz). HRMS (ESI): m/z calcd for C10
H11O2F2 (M+H)+ 201.0727, found 201.0727.
47 234.9579.
48
2,2-Difluoro-1-(naphthalen-1-yl)ethanone (2i).[20] Reaction
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time: 28 h. Yield: 46.0 mg, 74%, colorless oil. Rf =0.50 (5%
EtOAc/Petroleum Ether); 1H NMR (600 MHz, CDCl3) d
6.42 (t, J=53.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.58 (t, J=
7.5 Hz, 1H), 7.66 (t, J=7.3 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H),
8.10 (d, J=8.2 Hz, 1H), 8.17 (d, J=7.2 Hz, 1H), 8.86 (d, J=
1-(4-Bromophenyl)-2,2-difluoropropan-1-one (2o).[21] Reac-
tion time: 12 h. Yield: 22.0 mg, 30%. colorless oil, Rf =0.55
(Petroleum Ether); 1H NMR (600 MHz, CDCl3) d 1.89 (t, J=
19.5 Hz, 3H), 7.65 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.4 Hz,
2H); 19F NMR (564 MHz, CDCl3) d À92.7 (q, J=16.9 Hz);
13C NMR (150 MHz, CDCl3) d 20.6 (t, J=24.6 Hz), 119.4 (t,
J=248.4 Hz), 129.9, 130.3, 131.7, 132.1, 188.2 (t, J=30.0 Hz).
HRMS (ESI): m/z calcd for C9H7OF2BrNa (M+Na)+
270.9546, found 270.9553.
54 8.6 Hz, 1H); 19F NMR (564 MHz, CDCl3) d À120.4 (d, J=
56.4 Hz, 2F); 13C NMR (150 MHz, CDCl3) d 110.9 (t, J=
55
252.9 Hz), 124.2, 125.4, 127.0, 128.1, 128.9, 129.2, 131.1, 131.2,
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Acknowledgements
This work is founded by the Scientific Research Foundation
for the Returned Overseas Chinese Scholars, State Education
Ministry, the National Basic Research Project (grant no.
2014CB932201) and the National Natural Science Foundation
of China (grant no. 21572154).
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