Palladium-Catalyzed Para-Selective Difluoromethylation of Arene Esters

Article abstract of DOI:10.1021/acs.joc.0c01257

Highly efficient, palladium-catalyzed, para-selective difluoromethylation of arene esters has been developed using [1,1′-biphenyl]-2-dicyclohexylphosphine as the effective ligand. A wide variety of arene esters bearing various functional groups were all compatible with the reaction conditions, leading to para-difluoromethylated products in moderate to good yields. Moreover, benzoylamide and benzenesulfonamide were also well-tolerated, suggesting that this novel catalyst system has broad applications to a variety of substrates.

Full text of DOI:10.1021/acs.joc.0c01257

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Article
Palladium-Catalyzed para-Selective Difluoromethylation of Arene Esters
Guangliang Tu, Dongjie Wang, Chunchen Yuan, Jingyu Zhang, and Yingsheng Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01257 • Publication Date (Web): 24 Jul 2020
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Palladium-Catalyzed para-Selective Difluoromethylation of
Arene Esters
Guangliang Tu,† Dongjie Wang,† Chunchen Yuan,† Jingyu Zhang, ‡* Yingsheng Zhao†*
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†
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, P. R. China
‡
College of Energy, Soochow Institute for Energy and Materials Innovations, Soochow University, Suzhou 215006, P. R.
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China
ABSTRACT: A highly efficient, palladium-catalyzed, para-selective
difluoromethylation of arene esters has been developed using [1,1'-
biphenyl]-2-dicyclohexylphosphine as the effective ligand. A wide
variety of arene esters bearing various functional groups were all
compatible with the reaction conditions, leading to para-difluoromethylated products in moderate to good yields. Moreover,
benzoylamide and benzenesulfonamide were also well-tolerated, suggesting this novel catalyst system has broad application to a
variety of substrates.
Subsequently, the directed para- difluoromethylation of various
aromatic carbonyls with ethyl bromodifluoroacetate in the
INTRODUCTION
Arene esters are key structural motifs that exist in a vast range
presence of a palladium (II) catalyst was also reported by the Xu
group.12 However, only limited examples of methyl benzoate were
of bioactive molecules and drugs such as benzyl benzoate,
cocaine, hexylcaine, flavoxate, and bopindolol (shown in Figure
reported with low yields. In 2020, the Li group developed an
1). More importantly, the ester group is not only widely available
effective
difluoroalkylation
visible-light-induced
of aromatic
iridium-catalyzed
carbonyl
para-
compounds.13
but also easily converted into other functional groups, including
amides, alcohols, or other carbonyl compounds.1 The
development of a novel method to functionalize arene esters
directly is highly important. Although ester assisted, ortho-
selective C-H reactions have been extensively explored in recent
years,2-7 para-selective C-H functionalization of arene esters
remains rare (Scheme 1). Several strategies have selectively
functionalized para C-H bonds of general aromatic compounds,8
such as the use of electronic or spatial effects of substrates and the
design of D-shaped targeting groups. However, most of these
strategies do not apply to arene esters. Only recently, the
Chattopadhyay group reported an effective strategy for the para-
selective borylation of aromatic esters.9 It has been proposed that
the noncovalent interaction between the iridium catalyst, L-
shaped ligand, and the substrate controls the selectivity. Recently,
Nakao and co-workers pioneered para-selective alkylation of
benzamide, diaryl ketones, and aryl sulfone using cooperative
nickel/aluminum catalysis.10 In 2018, our group successfully
developed a method that resulted in selective difluoromethylation
of acetophenone and benzophenone derivatives at the para
position using tetrakis(triphenylphosphine) palladium as the
catalyst.11
Unfortunately, the applicability of these substrates to aromatic
esters leads to very poor reaction results.
The difluoromethyl group is a special fluorine-containing
functional group with unique physicochemical properties and has
been incorporated in many scientific fields, from medicinal
chemistry to materials science.14 Thus, based on research into the
site-selective C-H difluoromethylation of arenes,15-17 the
development of a novel method to introduce difluoromethyl
groups to the para-position of arene esters is highly attractive and
in great demand. Herein, we report our recent results on the [1,1'-
biphenyl]-2-dicyclohexylphosphin
assisted
tetrakis(triphenylphosphine)palladium-catalyzed
para-selective
difluoromethylation of arene esters. This new approach is
compatible with a variety of arene esters, leading to highly para-
selective difluoromethylated products in moderate to good yields.
A preliminary mechanistic study revealed the reaction undergoes
a free radical pathway.
Scheme 1. C-H Functionalization of Arene Esters.
Figure 1. Examples of drugs containing the arene ester moiety
(highlighted in red).
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Table 1. Optimization of Reaction Conditions.a
trifluoromethylphenyl)phosphine have
a
promoting effect,
affording products in greater than 50 % yield (Table 1, entries 9-
10). [1,1'-biphenyl]-2-yldicyclohexylphosphine gave the para-
difluoromethylated methyl benzoate, 3a, in 74 % yield (Table 1,
entry 14), whereas a small amount of meta-difluoromethylated
product was observed (p/m = 19/1). Further studies revealed
bidentate phosphine ligands all resulted in poorer yields relative to
[1,1'-biphenyl]-2-yldicyclohexylphosphine (Table 1, entries 11-
13). As a result, we found the phosphine ligand was indispensable
for this reaction (Table 1, entry 15). When an oxygen atmosphere
was used instead of argon under the optimal conditions, a
significant decrease in yield was observed (Table 1, entry 16).
Next, using potassium fluoride and silver acetate as additives
instead of silver fluoride, it was found that the reaction yields
were greatly reduced (Table 1, entry 17-18). When silver fluoride
was not added, the yield was 63 %, and poor selectivity was
obtained (Table 1, entry 19). Although the specific role of silver
fluoride is unclear, it may be acted as a lewis acid to assist the
palladium complex, further activating the aromatic ring. Also, it
was found that the reaction can proceed smoothly with non-polar
solvents, but none of them were comparable to the effect of n-
hexane (Table 1, entry 20-22). Control experiments revealed the
palladium catalyst was essential in the reaction (Table 1, entry
23).
(3a + 4a)
yield (%)
46
3a/4a
(p/m)b
35/1
12/1
20/1
15/1
-
entry
catalyst
ligand
9
1
2
Pd(PPh3)4
Pd(dba)2
PPh3
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11
12
13
14
15
16
17
18
19
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22
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58
59
60
PPh3
26
3
Pd(PPh3)2Cl2
Pd(OAc)2
PdCl2
PPh3
41
4
PPh3
34
5
PPh3
<5
6
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
none
P(t-Bu)3
<5
-
7
P(n-Bu)3
<5
-
8
P(Cy)3
<5
-
9
P(4-OMePh)3
59
32/1
13/1
12/1
16/1
44/1
19/1
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
P(4-CF3Ph)3
53
dppf
36
dppp
40
Table 2. Various protecting groups of benzoic acid.a
DPEPhos
61
L
-
74
<5
L
L
L
L
L
L
L
L
54c
48d
57e
63f
25/1
16/1
15/1
10/1
21/1
17/1
13/1
-
46g
51h
25i
<5
aReaction performed on 0.2 mmol scale with 2 (1 mmol). The selectivity
b
1
d
ratio determined by H NMR analysis. cO2 atmosphere. KF instead of
e
f
g
h
AgF. AgOAc instead of AgF. no AgF. Cyclohexane. Petroleum ether.
iToluene. Key: 1,1'-bis(diphenylphosphino)ferrocene (dppf),
1,3-
Bis(diphenylphosphino)propane (dppp), bis[(2-diphenylphosphino)phenyl]
ether (DPEphos), L = [1,1'-biphenyl]-2-yldicyclohexylphosphine.
RESULTS AND DISCUSSION
Initially, ethyl benzoate (1a) was treated with ethyl
bromodifluoroacetate (2) in the presence of Pd(PPh3)4 (5 mol %),
KOAc (4 equiv), PPh3 (30 mol %), and AgF (30 mol %) at 140 °C
for 20 h in n-hexane which afforded para-difluoromethylated
methyl benzoate in 46 % yield along with a trace amount of meta-
aReaction performed on 0.2 mmol scale with 2 (1 mmol) in a sealed tube.
L= [1,1'-biphenyl]-2-yldicyclohexylphosphine. b1 mmol scale synthesis.
n-hexane (1 mL), 30 h.
difluoromethylated methyl benzoate (p/m
= 35/1). Several
palladium precursors including Pd(dba)2, Pd(PPh3)2Cl2, Pd(OAc)2,
and PdCl2 were investigated; all of these palladium precursors did
not perform as well as Pd(PPh3)4 (Table 1, entries 1-5). The ligand
normally plays an important role in palladium-catalyzed para-
selective difluoromethylation reactions, therefore, a variety of
phosphine ligands were screened. Electronic rich phosphine
ligands such as tri-tert-butylphosphine, tributylphosphine, and
tricyclohexylphosphine all yield the difluoromethylated product
3a in yields of less than 5 %, along with the recovery of methyl
benzoate (Table 1, entries 6-8). Interestingly, tris(4-
After optimizing the reaction conditions, the protecting group
tolerance of benzoic acid was investigated (Table 2). Changing
the alkoxy moiety of the benzoate, including increasing the
number of linear carbons or adjusting the steric hindrance did not
reduce the reaction efficiency but resulted in similar product
yields (3a-j). Among those, substrates 1c-e indicated that as the
number of linear carbon atoms increased, the para-selectivity of
difluoromethylation decreases slightly (p/m
Unfortunately, even though the neopentyl benzoate (1g) substrate
≈
10/1).
methoxyphenyl)phosphine
and
tris(4-
2
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provided good yields, site selectivity was relatively poor (p/m =
reacted smoothly with bromodifluoroacetate (2) to afford the
corresponding difluoromethylated products (8a–8c) in moderate
to good yields (43 %, 52 %, and 61 %, respectively); unreacted
starting materials were also recovered. Notably, trioctyl 1,2,4-
benzenetricarboxylate (7d), a commonly used plasticizer for
polyvinyl chloride, reacted well and selectively afforded 8c in 54
% yield.
6/1). The reaction of the substrate methyl benzoate was scaled up
to 1 mmol, providing product 3a with a yield of 53%. When
1,1,2,2-tetrafluoroethanol and p-cresol were employed as the
protecting groups, the 1,1,2,2-tetrafluoroethyl benzoate (3k) and
p-tolyl benzoate (3l) substrates afforded the corresponding
products in only moderate yields. Also, when using pyridin-2-
ylmethylbenzoate as
a substrate, only a trace amount of
Table 4. Examples of other aromatic substrates.a
difluoromethylated product was obtained. It is believed that the
nitrogen atom in the pyridine can interact with the palladium
catalyst, which reduced the effect of carbonyl oxygen, making the
yield drop sharply (3m). Finally, when there is an olefin or alkyne
in the benzoic acid protecting group, the corresponding
difluoromethylated product cannot be obtained (3n-3o). It might
be the unsaturated group can direct trap difluoromethyl radical,
which can shut down the para-selective C-H difluoromethylation.
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Table 3. Functional group tolerance on methyl benzoate.a
aReaction performed on 0.2 mmol scale with 2 (1 mmol) in a sealed tube.
L= [1,1'-biphenyl]-2-yldicyclohexylphosphine.
To understand the reaction pathway, a series of control
experiments were performed (Scheme 2). For example, the radical
scavenger TEMPO completely shut down the reaction.
Meanwhile, when 1,1-diphenylethylene was treated with
BrCF2CO2Et under standard reaction conditions, product 10 was
obtained in 73 % yield. These results strongly supported the idea
that this difluoromethylation reaction involved a free-radical
pathway. The palladium complex can release a ·CF2CO2Et radical
through a single-electron transfer process. Finally, compound 11
reacts in moderate yield with high selectivity at the benzoyl ring
to give a single para-difluoromethylated result, which indicates
that the interaction of the arene-bound ester carbonyl group and
the palladium catalyst is a key factor for realizing the para-
difluoromethylation reaction.
Scheme 2. Reaction Pathway Control Experiments.
aReaction performed on 0.2 mmol scale with 2 (1 mmol) in a sealed tube.
L= [1,1'-biphenyl]-2-yldicyclohexylphosphine.
The substrate range applicability using benzoate compounds
was also examined (Table 3). Ortho-substituted benzoates with
various functional groups such as Me, Et, OMe, OCF3, OPh, and
CF3 were all well-tolerated and yielded the para-
difluoromethylated products (6a-f) in moderate to good yields
(47–72 %). All reactions with meta-substituted substrates
proceeded smoothly under this condition as well (6g-j; 37–70 %).
Further study indicated that the disubstituted arene esters all
performed well and yielded corresponding products in acceptable
yields. (6k-t; 38–73 %). Impressively, the substrate 5r was also
tolerated, yielding the corresponding product in 73 % yield with
high para-selectivity.
Based on these results and previous reports11,18, a plausible
reaction pathway was proposed and is shown in Scheme 3. First,
palladium(0) interacts with ethyl bromodifluoroacetate in the form
of a single-electron transfer (SET) to generate BrPd(I)PPh3 and
releases a portion of ethyl difluoroacetate free radicals. Next, a
palladium(II) complex was derived from the combination of
palladium(I) and ethyl bromodifluoroacetate. Under the action of
the large hindered phosphine ligand L and silver fluoride, ligand
exchange occurs to regenerate palladium(II), which further plays
an important role in coordination with the carbonyl oxygen to
improve the reactivity of the aromatic ring of the arene ester. The
difluoromethyl radical can be trapped by the active aromatic ring
at the less hindered para position to produce the complex II.
Subsequent potassium acetate takes away the proton hydrogen to
Subsequently, the diversity of aryl carbonyl substrates was
explored under the optimized reaction conditions (Table 4). All
reactions, including methyl thiophene-2-carboxylate (7a), N-(tert-
butyl)benzamide (7b) and N,N-diethylbenzenesulfonamide (7c),
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get complex III, followed by a SET process by the palladium(II)
complex and aromatization to release 3a.
(PE/EA = 30/1) on silica gel to give the product. These compound
1f20, 1g21, 1h22, 1k23, 5b24 and 5j25 were known.
3,3,3-trifluoropropyl benzoate (1i). Colorless oil, 80%. 1H
NMR (400 MHz, CDCl3) δ 8.07 – 8.02 (m, 2H), 7.61 – 7.55 (m,
1H), 7.49 – 7.43 (m, 2H), 4.55 (t, J = 6.3 Hz, 2H), 2.67 – 2.55 (m,
2H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.23, 133.40, 129.79,
129.7, 26.0 (q, JC-F = 276.7 Hz), 128.6, 57.8 (q, JC-F = 3.7 Hz),
33.6 (q, JC-F = 29.3 Hz). 19F NMR (376 MHz, CDCl3) δ -65.0 (t,
JC-F = 10.4 Hz). HRMS (ESI) m/z: [M + Na]+ Calcd for
C10H9F3O2Na 241.0447; Found: 241.0441.
Scheme 3. Plausible Mechanism.
9
General Procedure for p-tolyl benzoate (1l).26 To a solution of
p-cresol (1.08 g, 10 mmol, 1 equiv) in pyridine (10 mL) cooled in
an ice bath was added benzoyl chloride (1.38 mL, 12 mmol, 1.2
equiv) dropwise over 10 min with stirring. After stirring for 60
minutes, the ice bath was removed, and then quenched with 1 N
HCl. The resulting mixture was extracted with CH2Cl2 (3 × 10
mL), and the mixed organic layer was washed with water, and
finally dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The resulting residue was purifified by column
chromatography (PE/EA = 10/1) on silica gel to give the product.
10
11
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1
p-tolyl benzoate (1l). White solid, 95%, mp 63-64 °C. H NMR
(400 MHz, CDCl3) δ 8.17 (d, J = 7.8 Hz, 2H), 7.63 – 7.54 (m, 1H),
7.52 – 7.40 (m, 2H), 7.23 – 7.13 (m, 2H), 7.07 (dd, J = 8.5, 2.3 Hz,
2H), 2.34 (d, J = 2.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.5, 148.8, 135.6, 133.6, 130.3, 130.1, 129.8, 128.6, 121.5, 21.0.
General Procedure for n-(Tert-butyl)benzamide (7a). To a
solution of Tert-butylamine (1.6 mL, 15 mmol, 1.5 equiv) and
Et3N (2.0 ml, 15 mmol) in CH2Cl2 (25 ml) cooled in an ice bath
was added benzoyl chloride (1.16 mL, 10 mmol, 1 equiv)
dropwise over 2 min with stirring. After stirring for 20 minutes,
the ice bath was removed, stirring was continued for 12 hours at
room temperature, and then quenched with saturated NaHCO3.
The resulting mixture was extracted with CH2Cl2 (3 × 10 mL),
and dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The resulting residue was purifified by column
chromatography (PE/EA = 5/1) on silica gel to give the product.
N-(tert-butyl)benzamide (7a).27 White solid, 92%, mp 130-131
CONCLUSIONS
In summary, we have developed an efficient method for the
para-selective difluoromethylation of arene esters based on
tetrakis(triphenylphosphine)palladium as the catalyst and [1,1'-
biphenyl]-2-dicyclohexylphosphine as the ligand. Diverse arene
esters bearing various functional groups were well tolerated under
the optimized conditions, providing the para-difluoromethylated
products in moderate to good yields. Moreover, benzoylamide and
benzenesulfonamide are also suitable for this reaction strategy,
which provides the possibility for the synthesis of biologically
active molecules and drugs.
1
oC. H NMR (400 MHz, CDCl3) δ 7.73 – 7.68 (m, 2H), 7.48 –
7.42 (m, 1H), 7.42 – 7.35 (m, 2H), 1.46 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3) δ 167.0, 136.0, 131.1, 128.5, 126.8, 51.7, 29.0.
General procedures for 1 mmol-Scale Synthesis. A mixture of
1a (136 mg, 1 mmol, 1.0 equiv), BrCF2CO2Et (650 μL, 5 mmol,
5.0 equiv), Pd(PPh3)4 (57.8 mg, 0.05 mmol, 0.05 equiv), KOAc
(392.5 mg, 4 mmol, 4.0 equiv), L (105.1 mg, 0.3 mmol, 0.3 equiv),
AgF (38.1 mg, 0.3 mmol, 0.3 equiv) and n-hexane (1 mL) in a 15
mL glass vial sealed under argon atmosphere was heated at 140
oC oil bath for 30 hours. The reaction mixture cooled to room
temperature and concentrated in vacuo. The resulting residue was
purified by column chromatography (PE / EA = 50 / 1) on silica
gel to give the product 3a (Colorless oil, 136.8 mg, 53% yield).
General procedures for para-Difluoromethylation of Benzoate.
A mixture of 1 or 5 (0.2 mmol, 1.0 equiv), BrCF2CO2Et (130 μL,
1 mmol), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 0.05 equiv), KOAc
(78.5 mg, 0.8 mmol, 4 equiv), L (21.0 mg, 0.06 mmol, 0.3 equiv),
AgF (7.6 mg, 0.06 mmol, 0.3 equiv) and n-hexane (0.25 mL) in a
15 mL glass vial sealed under argon atmosphere was heated at
EXPERIMENTAL SECTION
General. Unless otherwise noted, all reagents were purchased
from commercial suppliers and used without further purification.
Column chromatography purifications were performed using 200–
300 mesh silica gel. NMR spectra were recorded on Varian
Inova–400 MHz, Inova–300 MHz, Bruker DRX–400 or Bruker
DRX–500 instruments and calibrated using residual solvent peaks
as internal reference. Multiplicities are recorded as: s = singlet, d
= doublet, t = triplet, q = quartet, dd = doublet of doublets, td =
triplet of doublets, m = multiplet. HRMS analysis were carried out
using
a Bruker micrOTOF–Q instrument or a TOF–MS
instrument.
General Procedure for the Benzoate Derivatives.19 To a
solution of alcohols (12 mmol, 1.2 equiv) and Et3N (1.75 ml, 12.5
mmol) in CH2Cl2 (25 ml) cooled in an ice bath was added benzoyl
chloride (1.16 ml, 10 mmol, 1 equiv) dropwise over 2 min with
stirring. After stirring for 20 minutes, the ice bath was removed,
stirring was continued for 12 hours at room temperature, and then
quenched with 1 N HCl. The resulting mixture was extracted with
CH2Cl2 (3 × 5 mL), and the mixed organic layer was washed with
saturated NaHCO3 and brine successively, and finally dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
resulting residue was purifified by column chromatography
o
140 C oil bath for 20 hours. The reaction mixture cooled to
room temperature and concentrated in vacuo. The resulting
residue was purified by column chromatography (PE / EA = 50 /
1 – 10 / 1) on silica gel to give the product 3 or 6.
methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (3a).
1
Colorless oil, 38.2mg, 74%. H NMR (400 MHz, CDCl3) δ 8.12
(d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 4.30 (q, J = 7.1 Hz,
2H), 3.94 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 166.3, 163.8 (t, JC-F = 34.8 Hz), 137.1 (t, JC-F
=
25.5 Hz), 132.8 (t, JC-F = 1.5 Hz), 130.0, 125.8 (t, JC-F = 6.1 Hz),
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113.1 (t, JC-F = 252.8 Hz), 63.5, 52.6, 14.0. 19F NMR (376 MHz,
130.0, 125.8 (t, J = 6.1 Hz), 113.2 (t, JC-F = 252.7 Hz), 75.9, 63.5,
34.0, 27.7, 22.8, 14.1, 14.0. 19F NMR (376 MHz, CDCl3) δ -104.4.
HRMS (ESI) m/z: [M + Na]+ Calcd for C20H28F2O4Na 393.1848;
Found: 393.1848.
1
2
3
4
5
6
7
8
CDCl3) δ -104.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C12H12F2O4Na 281.0596; Found: 281.0588.
ethyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate
(3b).
1
Colorless oil, 36.5mg, 67%. H NMR (400 MHz, CDCl3) δ 8.12
(d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 4.40 (q, J = 7.1 Hz,
2H), 4.30 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.29 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 163.8 (t,
JC-F = 34.8 Hz), 137.0 (t, JC-F = 25.5 Hz), 133.1, 130.0, 125.7 (t,
JC-F = 6.1 Hz), 113.1 (t, JC-F = 252.8 Hz), 63.5, 61.5, 14.4, 14.0.
19F NMR (376 MHz, CDCl3) δ -104.5. HRMS (ESI) m/z: [M +
Na]+ Calcd for C13H14F2O4Na 295.0752; Found: 295.0751.
3,3,3-trifluoropropyl
4-(2-ethoxy-1,1-difluoro-2-
oxoethyl)benzoate (3i). Colorless oil, 35.4mg, 52%. 1H NMR (400
MHz, CDCl3) δ 8.12 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H),
4.57 (t, J = 6.2 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.68 – 2.55 (m,
2H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.3, 163.8 (t, JC-F = 34.6 Hz), 137.6 (t, JC-F = 25.7 Hz), 132.2,
130.1, 125.9 (t, JC-F = 6.0 Hz), 125.9 (q, JC-F = 278.0 Hz ), 113.1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(t, JC-F = 252.9 Hz), 63.6, 58.2 (q, JC-F = 3.6 Hz), 33.6 (q, JC-F
=
propyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate
(3c).
29.3 Hz), 14.0. 19F NMR (376 MHz, CDCl3) δ -64.9 (t, JC-F = 10.9
Hz), -104.5. HRMS (ESI) m/z: [M + H]+ Calcd for C14H14F5O4
341.0807; Found: 341.0811.
1
Colorless oil, 32.0mg, 56%. H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 4.33 – 4.27 (m, 4H),
1.87 – 1.73 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.4 Hz,
cyclohexyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (3j).
1
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 163.8 (t, JC-F
34.8 Hz), 137.0 (t, JC-F = 25.6 Hz), 133.1, 130.0, 125.8 (t, JC-F
6.1 Hz), 113.1 (t, JC-F = 252.8 Hz), 67.1, 63.5, 22.2, 14.0, 10.6. 19
=
=
F
Colorless oil, 35.9mg, 55%. H NMR (400 MHz, CDCl3) δ 8.12
(d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 5.09 – 4.99 (m, 1H),
4.30 (q, J = 7.1 Hz, 2H), 1.99 – 1.90 (m, 2H), 1.85 – 1.74 (m, 2H),
1.64 – 1.54 (m, 4H), 1.51 – 1.40 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 136.9 (t, JC-F = 25.5 Hz),
133.6, 130.0, 125.7 (t, JC-F = 6.1 Hz), 113.1 (t, JC-F = 252.7 Hz),
73.8, 63.5, 31.7, 25.6, 23.8, 14.0. 19F NMR (376 MHz, CDCl3) δ -
104.5. HRMS (ESI) m/z: [M + Na]+ Calcd for C17H20F2O4Na
349.1222; Found: 349.1223.
NMR (376 MHz, CDCl3) δ -104.5. HRMS (ESI) m/z: [M + H]+
Calcd for C14H17F2O4 287.1089; Found: 287.1094.
butyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate
(3d).
1
Colorless oil, 37.8mg, 63%. H NMR (400 MHz, CDCl3) δ 8.12
(d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 4.37 – 4.27 (m, 4H),
1.81 – 1.71 (m, 2H), 1.53 – 1.42 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H),
0.98 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.8, 163.8 (t, JC-F = 34.8 Hz), 137.0 (t, JC-F = 25.5 Hz), 133.1,
130.0, 125.8 (t, JC-F = 6.1 Hz), 113.1 (t, JC-F = 252.8 Hz), 65.4,
63.5, 30.8, 19.4, 14.0, 13.9. 19F NMR (376 MHz, CDCl3) δ -104.5.
HRMS (ESI) m/z: [M + H]+ Calcd for C15H19F2O4 301.1246;
Found: 301.1245.
2,2,3,3-tetrafluoropropyl
4-(2-ethoxy-1,1-difluoro-2-
oxoethyl)benzoate (3k). Colorless oil, 30.8mg, 43%. 1H NMR
(400 MHz, CDCl3) δ 8.14 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.6 Hz,
2H), 5.94 (tt, J = 53.1, 3.3 Hz, 1H), 4.75 (tt, J = 12.8, 1.2 Hz, 2H),
4.31 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.3, 163.7 (t, JC-F = 34.7 Hz), 138.1 (t, JC-F
pentyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate
(3e).
= 25.7 Hz), 131.2, 130.4, 126.1 (t, JC-F = 6.1 Hz), 114.3 (t, JC-F =
1
Colorless oil, 37.7mg, 60%. H NMR (400 MHz, CDCl3) δ 8.12
(d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 4.36 – 4.26 (m, 4H),
1.82 – 1.73 (m, 2H), 1.45 – 1.35 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H),
0.93 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.8, 163.8 (t, JC-F = 34.9 Hz), 137.0 (t, JC-F = 25.6 Hz), 133.2,
130.0, 125.8 (t, JC-F = 6.1 Hz), 113.1 (t, JC-F = 252.7 Hz), 65.7,
63.5, 28.5, 28.3, 22.5, 14.1, 14.0. 19F NMR (376 MHz, CDCl3) δ -
104.5. HRMS (ESI) m/z: [M + H]+ Calcd for C16H21F2O4
315.1402; Found: 315.1405.
253.6 Hz), 112.9 (t, JC-F = 255.1 Hz), 109.6 (t, JC-F = 37.6 Hz),
63.6, 60.3 (t, JC-F = 29.0 Hz), 14.0. 19F NMR (376 MHz, CDCl3) δ
-104.7, -122.7 (t, JC-F = 1.9 Hz), -136.6 (t, JC-F = 1.9 Hz). HRMS
(ESI) m/z: [M + Na]+ Calcd for C14H12F6O4Na 381.0532; Found:
381.0537.
p-tolyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate
(3l).
1
Colorless oil, 27.4mg, 41%. H NMR (400 MHz, CDCl3) δ 8.29
(d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.1 Hz,
2H), 7.09 (d, J = 8.5 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.38 (s,
3H), 1.32 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
164.6, 163.8 (t, JC-F = 34.7 Hz), 148.7, 137.7, 136.0, 132.4, 130.6,
130.2, 126.0 (t, JC-F = 6.1 Hz), 121.4, 113.1 (t, JC-F = 253.1 Hz),
63.6, 21.1, 14.0. 19F NMR (376 MHz, CDCl3) δ -104.5. HRMS
(ESI) m/z: [M + H]+ Calcd for C18H17F2O4 335.1089; Found:
335.1095.
2,2,2-trifluoroethyl
4-(2-ethoxy-1,1-difluoro-2-
oxoethyl)benzoate (3f). Colorless oil, 39.8mg, 61%. 1H NMR (400
MHz, CDCl3) δ 8.17 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H),
4.72 (q, J = 8.3 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.2, 163.7 (t, JC-F
= 34.7 Hz), 138.2 (t, JC-F = 25.6 Hz), 131.0, 130.5, 126.1 (t, JC-F
=
6.1 Hz), 124.5 (t, JC-F = 277.1 Hz), 113.0 (t, JC-F = 253.0 Hz), 63.6,
61.2 (q, JC-F = 36.9 Hz), 14.0. 19F NMR (376 MHz, CDCl3) δ -
64.9, -104.6. HRMS (ESI) m/z: [M + H]+ Calcd for C13H12F5O4
327.0650; Found: 327.0648.
methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methylbenzoate
1
(6a). Colorless oil, 38.6mg, 71%. H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 8.7 Hz, 1H), 7.48 – 7.47 (m, 2H), 4.30 (q, J = 7.1 Hz,
2H), 3.91 (s, 3H), 2.63 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 167.4, 163.9 (t, JC-F = 34.9 Hz), 140.8,
136.0 (t, JC-F = 25.5 Hz), 132.3, 131.0, 128.7 (t, JC-F = 6.0 Hz),
123.0 (t, JC-F = 6.1 Hz), 113.0 (t, JC-F = 252.7 Hz), 63.5, 52.3, 21.8,
14.0. 19F NMR (376 MHz, CDCl3) δ -104.7. HRMS (ESI) m/z:
[M + Na]+ Calcd for C13H14F2O4Na 295.0752; Found: 295.0752.
neopentyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (3g).
1
Colorless oil, 39.6mg, 63%. H NMR (400 MHz, CDCl3) δ 8.14
(d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 4.30 (q, J = 7.1 Hz,
2H), 4.04 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 165.8, 163.9 (t, JC-F = 34.9 Hz), 137.1
(t, JC-F = 25.5 Hz), 133.2, 130.0, 125.8 (t, JC-F = 6.1 Hz), 113.1 (t,
JC-F = 252.7 Hz), 74.8, 63.5, 31.8, 26.7, 14.0. 19F NMR (376 MHz,
CDCl3) δ -104.5. HRMS (ESI) m/z: [M + H]+ Calcd for
C16H21F2O4 315.1402; Found: 315.1401.
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-ethylbenzoate
1
(6b). Colorless oil, 40.1mg, 70%. H NMR (400 MHz, CDCl3) δ
7.90 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.48 (dd, J = 8.2, 1.5 Hz,
1H), 4.30 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.00 (q, J = 7.5 Hz,
2H), 1.30 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 167.6, 164.0 (t, JC-F = 34.9 Hz), 146.6,
136.1 (t, JC-F = 25.5 Hz), 132.2, 130.9, 127.3 (t, JC-F = 6.0 Hz),
123.0 (t, JC-F = 6.1 Hz), 113.1 (t, JC-F = 252.6 Hz), 63.5, 52.4, 27.6,
15.8, 14.0. 19F NMR (376 MHz, CDCl3) δ -104.6. HRMS (ESI)
nonan-5-yl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (3h).
1
Colorless oil, 45.2mg, 61%. H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 5.20 – 5.09 (m, 1H),
4.30 (q, J = 7.1 Hz, 2H), 1.76 – 1.60 (m, 4H), 1.38 – 1.27 (m,
11H), 0.92 – 0.85 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.5, 163.9 (t, JC-F = 34.9 Hz), 136.9 (t, JC-F = 25.6 Hz), 133.5,
5
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The Journal of Organic Chemistry
Page 6 of 9
m/z: [M + Na]+ Calcd for C14H16F2O4Na 309.0908; Found:
309.0908.
(d, J = 8.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 1.30 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.1, 162.7
1
2
3
4
5
6
7
8
methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methoxybenzoate
(t, JC-F = 33.5 Hz), 135.4 (t, JC-F = 24.4 Hz), 134.0, 132.5 (t, JC-F
4.2 Hz), 131.7, 128.1, 127.7 (t, JC-F = 8.5 Hz), 112.0 (t, JC-F
=
=
1
(6c). Colorless oil, 41.5mg, 72%. H NMR (400 MHz, CDCl3) δ
7.83 (d, J = 8.0 Hz, 1H), 7.24 – 7.18 (m, 2H), 4.30 (q, J = 7.1 Hz,
2H), 3.94 (s, 3H), 3.90 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 166.1, 163.8 (t, JC-F = 34.8 Hz), 159.1,
137.6 (t, JC-F = 25.6 Hz), 132.0, 122.8, 117.3 (t, JC-F = 6.1 Hz),
112.9 (t, JC-F = 253.2 Hz), 109.2 (t, JC-F = 6.3 Hz), 63.6, 56.4, 52.5,
14.0. 19F NMR (376 MHz, CDCl3) δ -104.7. HRMS (ESI) m/z:
[M + Na]+ Calcd for C13H14F2O5Na 311.0701; Found: 311.0692.
251.7 Hz), 63.7, 52.9, 13.9. 19F NMR (376 MHz, CDCl3) δ -102.9.
HRMS (ESI) m/z: [M + Na]+ Calcd for C12H11ClF2O4Na
315.0206; Found: 315.0203.
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-3-
1
(methylthio)benzoate (6j). Colorless oil, 22.5mg, 37%. H NMR
(400 MHz, CDCl3) δ 8.10 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.76
(d, J = 8.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 2.48 (s,
3H), 1.31 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
166.0, 163.5 (t, JC-F = 33.5 Hz), 137.9 (t, JC-F = 3.7 Hz), 137.0 (t,
JC-F = 23.3 Hz), 133.0, 131.1, 127.2, 126.7 (t, JC-F = 8.8 Hz),
112.8 (t, JC-F = 251.3 Hz), 63.4, 52.7, 18.2, 14.0. 19F NMR (376
MHz, CDCl3) δ -99.9. HRMS (ESI) m/z: [M + Na]+ Calcd for
C13H14F2O4SNa 327.0472; Found: 327.0475.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-
1
(trifluoromethoxy)benzoate (6d). Colorless oil, 39.7mg, 58%. H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.2 Hz, 1H), 7.63 (dd, J =
8.2, 1.5 Hz, 1H), 7.58 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.95 (s,
3H), 1.31 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
164.2, 163.0 (t, JC-F = 34.4 Hz), 147.6, 138.1 (t, JC-F = 26.4 Hz),
132.5, 127.5, 124.2 (t, JC-F = 6.1 Hz), 120.3 (t, JC-F = 6.2 Hz),
120.2 (q, JC-F = 259.1 Hz), 112.0 (t, JC-F = 253.9 Hz), 63.7, 52.8,
13.8. 19F NMR (376 MHz, CDCl3) δ -57.6, -104.6. HRMS (ESI)
m/z: [M + Na]+ Calcd for C13H11F5O5Na 365.0419; Found:
365.0417.
methyl
2,3-dichloro-4-(2-ethoxy-1,1-difluoro-2-
oxoethyl)benzoate (6k). Colorless oil, 26.7mg, 41%. 1H NMR
(400 MHz, CDCl3) δ 7.71 – 7.77 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H),
3.97 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 165.3, 162.5 (t, JC-F = 33.2 Hz), 135.8 (t, JC-F = 24.8 Hz),
135.2, 133.4, 132.6 (t, JC-F = 3.7 Hz), 128.7, 125.2 (t, JC-F = 8.9
Hz), 111.6 (t, JC-F = 252.3 Hz), 63.9, 53.2, 13.9. 19F NMR (376
MHz, CDCl3) δ -102.7. HRMS (ESI) m/z: [M + Na]+ Calcd for
C12H10Cl2F2O4Na 348.9816; Found: 348.9821.
methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-phenoxybenzoate
1
(6e). Colorless oil, 34.3mg, 49%. H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 8.2, 1.6 Hz, 1H), 7.37 –
7.33 (m, 2H), 7.20 (d, J = 1.4 Hz, 1H), 7.17 – 7.11 (m, 1H),
6.99 – 6.96 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.26 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.7, 163.5
(t, JC-F = 34.6 Hz), 156.8, 156.6, 137.9 (t, JC-F = 25.9 Hz), 132.4,
methyl
3-chloro-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-
1
methylbenzoate (6l). Colorless oil, 31.8mg, 52%. H NMR (400
MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H),
4.35 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 2.61 (s, 3H), 1.31 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.38, 163.1 (t, JC-
F = 33.4 Hz), 138.6, 135.0, 134.6 (t, JC-F = 24.1 Hz), 133.7, 128.3,
124.5 (t, JC-F = 9.0 Hz), 112.1 (t, JC-F = 251.1 Hz), 63.6, 52.7, 17.5,
14.0. 19F NMR (376 MHz, CDCl3) δ -102.7. HRMS (ESI) m/z:
[M + Na]+ Calcd for C13H13ClF2O4Na 329.0362; Found: 329.0370.
130.1, 125.6, 124.1, 120.2 (t, JC-F = 6.0 Hz), 118.7, 117.6 (t, JC-F
=
6.2 Hz), 112.5 (t, JC-F = 253.2 Hz), 63.6, 52.6, 13.9. 19F NMR
(376 MHz, CDCl3) δ -104.4. HRMS (ESI) m/z: [M + Na]+ Calcd
for C18H16F2O5Na 373.0857; Found: 373.0853.
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-
(trifluoromethyl)benzoate (6f). Colorless oil, 30.6mg, 47%. 1H
NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.87 – 7.86 (m, 2H), 4.32
(q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 166.3, 163.1 (t, JC-F = 34.4 Hz), 135.9
methyl
8-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2,3-
dihydrobenzo[b][1,4]dioxine-5-carboxylate (6m). Colorless oil,
1
27.2mg, 43%. H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz,
(t, JC-F = 26.4 Hz), 133.3 (q, JC-F = 1.7 Hz), 130.7, 129.5 (q, JC-F
=
1H), 7.22 (d, J = 8.3 Hz, 1H), 4.41 – 4.26 (m, 6H), 3.90 (s, 3H),
1.30 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.5, 163.5 (t, JC-F = 33.8 Hz), 144.0, 141.9 (t, JC-F = 4.8 Hz),
125.4 (t, JC-F = 24.9 Hz), 123.1, 122.5, 117.5 (t, JC-F = 7.6 Hz),
111.6 (t, JC-F = 249.9 Hz), 64.5, 64.1, 63.1, 52.5, 14.1. 19F NMR
(376 MHz, CDCl3) δ -103.1. HRMS (ESI) m/z: [M + Na]+ Calcd
for C14H16F2O6Na 341.0807; Found: 341.0815.
33.3 Hz), 129.1 (t, JC-F = 6.1 Hz), 124.2 (q, JC-F = 5.8 Hz), 122.7
(q, JC-F = 273.7 Hz), 112.2 (t, JC-F = 253.7 Hz), 63.8, 53.2, 13.8.
19F NMR (376 MHz, CDCl3) δ -60.0, -104.6. HRMS (ESI) m/z:
[M + Na]+ Calcd for C13H11F5O4Na 349.0470; Found: 349.0472.
methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-3-methylbenzoate
1
(6g). Colorless oil, 27.8mg, 51%. H NMR (400 MHz, CDCl3) δ
7.95 – 7.88 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 4.31 (q, J = 7.1 Hz,
2H), 3.93 (s, 3H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 166.4, 163.8 (t, JC-F = 34.7 Hz), 137.0
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2,5-
dimethoxybenzoate (6n). Colorless oil, 43.3mg, 68%. 1H NMR
(400 MHz, CDCl3) δ 7.35 (s, 1H), 7.28 (s, 1H), 4.33 (q, J = 7.1
Hz, 2H), 3.91 (s, 6H), 3.80 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 163.5 (t, JC-F = 33.5
Hz), 153.2, 150.1 (t, JC-F = 4.8 Hz), 126.5 (t, JC-F = 23.9 Hz),
123.0, 114.8, 111.7 (t, JC-F = 250.7 Hz), 111.2 (t, JC-F = 7.8 Hz),
63.1, 57.0, 56.6, 52.6, 14.1. 19F NMR (376 MHz, CDCl3) δ -103.1.
HRMS (ESI) m/z: [M + Na]+ Calcd for C14H16F2O6Na 341.0807;
Found: 341.0802.
(t, JC-F = 3.0 Hz), 135.5 (t, JC-F = 23.3 Hz), 133.0, 132.4 (t, JC-F
=
1.3 Hz), 127.2, 126.5 (t, JC-F = 8.9 Hz), 113.9 (t, JC-F = 252.4 Hz),
63.5, 52.5, 19.8 (t, JC-F = 2.7 Hz), 14.0. 19F NMR (376 MHz,
CDCl3) δ -102.0. HRMS (ESI) m/z: [M + Na]+ Calcd for
C13H14F2O4Na 295.0752; Found: 295.0747.
methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-3-methoxybenzoate
1
(6h). Colorless oil, 40.3mg, 70%. H NMR (400 MHz, CDCl3) δ
7.74 (dd, J = 8.1, 1.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (s,
1H), 4.33 (q, J = 7.1 Hz, 1H), 3.94 (s, 1H), 3.88 (s, 1H), 1.29 (t, J
= 7.1 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 163.7 (t,
JC-F = 33.5 Hz), 156.8 (t, JC-F = 4.8 Hz), 134.1 (t, JC-F = 1.5 Hz),
126.7 (t, JC-F = 7.5 Hz), 126.4 (t, JC-F = 24.1 Hz), 122.0, 112.2,
63.0, 56.1, 52.7, 14.1. 19F NMR (376 MHz, CDCl3) δ -103.5.
HRMS (ESI) m/z: [M + Na]+ Calcd for C13H14F2O5Na [M+Na+]:
311.0701, Found: 311.0697.
methyl
2,5-dichloro-4-(2-ethoxy-1,1-difluoro-2-
oxoethyl)benzoate (6o). Colorless oil, 45.6mg, 70%. 1H NMR
(400 MHz, CDCl3) δ 7.89 (s, 1H), 7.82 (s, 1H), 4.36 (q, J = 7.1
Hz, 2H), 3.96 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.3, 162.2 (t, JC-F = 33.3 Hz), 135.2 (t, JC-F
= 24.8 Hz), 133.3, 132.8, 130.4 (t, JC-F = 4.2 Hz), 130.3 (t, JC-F
=
8.9 Hz), 111.2 (t, JC-F = 252.8 Hz), 63.9, 53.2, 13.9. 19F NMR
(376 MHz, CDCl3) δ -103.2. HRMS (ESI) m/z: [M + Na]+ Calcd
for C12H10Cl2F2O4Na 348.9816, Found: 348.9821.
methyl
3-chloro-4-(2-ethoxy-1,1-difluoro-2-
1
oxoethyl)benzoate(6i). Colorless oil, 35.0mg, 60%. H NMR (400
MHz, CDCl3) δ 8.10 (s, 1H), 8.04 (dd, J = 8.2, 1.2 Hz, 1H), 7.82
methyl
5-chloro-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-
1
methylbenzoate (6p). Colorless oil, 32.4mg, 53%. H NMR (400
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MHz, CDCl3) δ 7.96 (s, 1H), 7.62 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H),
7.90 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 4.31 (q, J = 7.1
Hz, 2H), 3.26 (q, J = 7.2 Hz, 4H), 1.31 (t, J = 7.1 Hz, 3H), 1.15 (t,
J = 7.1 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, JC-F
3.92 (s, 3H), 2.62 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 166.2, 162.9 (t, JC-F = 33.5 Hz), 139.3, 134.0
(t, JC-F = 24.1 Hz), 133.1, 132.6, 130.7 (t, JC-F = 8.4 Hz), 129.1 (t,
JC-F = 4.1 Hz), 111.9 (t, JC-F = 251.6 Hz), 63.7, 52.5, 21.4, 13.9.
19F NMR (376 MHz, CDCl3) δ -103.0. HRMS (ESI) m/z: [M +
Na]+ Calcd for C13H13ClF2O4Na 329.0363; Found: 329.0373.
= 34.7 Hz), 143.5, 136.7 (t, JC-F = 25.7 Hz), 127.4, 126.6 (t, JC-F
=
6.1 Hz), 112.8 (t, JC-F = 253.7 Hz), 63.7, 42.3, 14.3, 14.0. 19F
NMR (376 MHz, CDCl3) δ -104.3. HRMS (ESI) m/z: [M + H]+
Calcd for C14H20F2NO4S 336.1076; Found: 336.1080.
methyl
2-chloro-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-5-
trioctyl
5-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzene-1,2,4-
1
1
methylbenzoate (6q). Colorless oil, 25.1mg, 41%. H NMR (400
MHz, CDCl3) δ 7.67 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H),
2.39 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 165.6, 163.3 (t, JC-F = 34.3 Hz), 135.4 (t, JC-F = 23.9 Hz),
135.2 (t, JC-F = 3.1 Hz), 134.6, 132.1, 131.3, 129.0 (t, JC-F = 9.4
Hz), 113.0 (t, JC-F = 253.3 Hz), 63.7, 52.8, 19.2, 14.0. 19F NMR
(376 MHz, CDCl3) δ -102.5. HRMS (ESI) m/z: [M + Na]+ Calcd
for C13H13ClF2O4Na 329.0363, Found: 329.0374.
tricarboxylate (8d). Colorless viscous oil, 72.2mg, 54%. H NMR
(400 MHz, CDCl3) δ 8.30 (s, 1H), 8.16 (s, 1H), 4.34 (q, J = 7.1
Hz, 2H), 4.32 – 4.19 (m, 6H), 1.76 – 1.64 (m, 3H), 1.48 – 1.22 (m,
27H), 0.97 – 0.84 (m, 18H). 13C{1H} NMR (100 MHz, CDCl3) δ
166.4, 166.1, 164.8, 162.7 (t, JC-F = 30.5 Hz), 136.6, 135.9, 134.4,
131.5 (t, JC-F = 3.3 Hz), 131.4, 127.7 (t, JC-F = 10.3 Hz), 112.5 (t,
JC-F = 249.4 Hz), 69.1, 68.8, 68.8, 63.2, 38.9, 38.9, 38.8, 30.5,
30.5, 29.1, 29.0, 23.9, 23.9, 23.1, 23.1, 14.2, 14.2, 14.0, 11.1, 11.1.
19F NMR (376 MHz, CDCl3) δ -99.6. HRMS (ESI) m/z: [M + H]+
Calcd for C37H59F2O8 669.4173; Found: 669.4178.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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45
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47
48
49
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51
52
53
54
55
56
57
58
59
60
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2,5-bis(2,2,2-
trifluoroethoxy)benzoate (6r). Colorless oil, 66.3mg, 73%. 1H
NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.36 (s, 1H), 4.44 (q, J =
8.1 Hz, 2H), 4.38 (q, J = 7.9 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H),
3.94 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
General procedures for TEMPO inhibition experiments. A
mixture of 1a (0.2 mmol, 1.0 equiv), BrCF2CO2Et (130 μL, 1
mmol), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 0.05 equiv), KOAc
(78.5 mg, 0.8 mmol, 4 equiv), L (15.7 mg, 0.06 mmol, 0.3
equiv), AgF (7.6 mg, 0.06 mmol, 0.3 equiv), TEMPO (5 equiv)
and n-hexane (0.25 mL) in a 15 mL glass vial sealed under
CDCl3) δ 164.9, 162.9 (t, JC-F = 32.9 Hz), 152.2, 149.6 (t, JC-F
=
4.5 Hz), 128.0 (t, JC-F = 24.7 Hz), 125.6, 123.1 (q, JC-F = 278.2
Hz), 122.8 (q, JC-F = 277.8 Hz), 116.5 (t, JC-F = 7.8 Hz), 116.2,
o
111.2 (t, JC-F = 252.0 Hz), 69.0 (q, JC-F = 35.8 Hz), 66.9 (q, JC-F
=
argon atmosphere was heated at 140 C for 20 hours. Totally
36.6 Hz), 63.5, 52.9, 13.8. 19F NMR (376 MHz, CDCl3) δ -73.9 (t,
JC-F = 7.7 Hz), -74.1 (t, JC-F = 8.1 Hz), -103.2. HRMS (ESI) m/z:
[M + Na]+ Calcd for C16H14F8O6Na 477.0554; Found: 477.0559.
no reaction.
ethyl 2,2-difluoro-4,4-diphenylbut-3-enoate (10). Yellow oil,
44.1mg, 73%. 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.29 (m, 6H),
7.29 – 7.24 (m, 2H), 7.24 – 7.17 (m, 2H), 6.28 (t, J = 11.8 Hz,
1H), 3.92 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H). 19F NMR
(376 MHz, cdcl3) δ -91.1 (d, JC-F = 11.9 Hz). HRMS (ESI) m/z:
[M + Na]+ Calcd for C18H16F2O2Na 325.1011; Found: 325.1010.
phenethyl benzoate (11). Colorless oil. 1H NMR (400 MHz,
CDCl3) δ 8.11 – 7.90 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J =
7.7 Hz, 2H), 7.37 – 7.17 (m, 5H), 4.53 (t, J = 7.0 Hz, 2H), 3.08 (t,
J = 7.0 Hz, 2H).
methyl
3,5-dichloro-4-(2-ethoxy-1,1-difluoro-2-
oxoethyl)benzoate (6s). Colorless oil, 33.3mg, 51%. 1H NMR
(400 MHz, CDCl3) δ 8.01 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.96
(s, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 164.1, 162.5 (t, JC-F = 32.5 Hz), 135.2 (t, JC-F = 2.7 Hz), 133.4,
132.2 (t, JC-F = 22.9 Hz), 131.3, 112.9 (t, JC-F = 256.1 Hz), 63.9,
53.2, 13.9. 19F NMR (376 MHz, CDCl3) δ -97.6. HRMS (ESI)
m/z: [M + Na]+ Calcd for C12H10Cl2F2O4Na 348.9819; Found:
348.9822.
phenethyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (12).
1
methyl
4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-3,5-
Colorless oil, 32.7mg, 47%. H NMR (400 MHz, CDCl3) δ 8.09
dimethoxybenzoate (6t). Colorless oil, 24.2mg, 38%. 1H NMR
(400 MHz, CDCl3) δ 7.20 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3.87
(s, 3H), 3.81 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
(d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.38 – 7.22 (m, 5H),
4.56 (t, J = 7.0 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.09 (t, J = 6.9
Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
MHz, CDCl3) δ 166.1, 164.3 (t, JC-F = 32.7 Hz), 159.16 (t, JC-F
=
CDCl3) δ 165.7, 163.8 (t, JC-F = 34.7 Hz), 137.8, 137.2 (t, JC-F =
2.6 Hz), 134.0, 113.8 (t, JC-F = 23.5 Hz), 112.9 (t, JC-F = 250.4 Hz),
106.0, 62.8, 56.6, 52.7, 14.2. 19F NMR (376 MHz, CDCl3) δ -99.0.
HRMS (ESI) m/z: [M + Na]+ Calcd for C14H16F2O6Na 341.0807;
Found: 341.0814.
25.5 Hz), 132.9, 130.0, 129.1, 128.8, 126.9, 125.8 (t, JC-F = 6.0
Hz), 113.1 (t, JC-F = 252.9 Hz), 66.0, 63.5, 35.3, 14.0. 19F NMR
(376 MHz, CDCl3) δ -104.5. HRMS (ESI) m/z: [M + Na]+ Calcd
for C19H18F2O4Na 371.1065; Found: 371.1068.
methyl
5-(2-ethoxy-1,1-difluoro-2-oxoethyl)thiophene-2-
carboxylate (8a). Colorless oil, 22.7mg, 43%. 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 3.9 Hz, 1H), 7.37 (d, J = 3.9 Hz, 1H), 4.37
(q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 162.8 (t, JC-F = 34.5 Hz), 162.0, 140.1
(t, JC-F = 30.0 Hz), 136.9, 133.0, 128.7 (t, JC-F = 5.5 Hz), 111.2 (t,
JC-F = 252.0 Hz), 63.9, 52.7, 14.0. 19F NMR (376 MHz, CDCl3) δ
-94.5. HRMS (ESI) m/z: [M + H]+ Calcd for C10H11F2O4S
265.0346; Found: 265.0343.
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the internet at
http://pubs.acs.joc.
1H, 13C and 19F NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
ethyl
2-(4-(tert-butylcarbamoyl)phenyl)-2,2-difluoroacetate
1
(8b). Colorless oil, 31.1mg, 52%. H NMR (400 MHz, CDCl3) δ
7.79 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 5.94 (br, 1H),
4.29 (q, J = 7.1 Hz, 2H), 1.47 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 163.9 (t, JC-F = 35.0 Hz),
138.6, 135.5 (t, JC-F = 25.6 Hz), 127.2, 125.9 (t, JC-F = 6.1 Hz),
113.1 (t, JC-F = 252.6 Hz), 63.5, 52.1, 29.0, 14.0. 19F NMR (376
MHz, CDCl3) δ -104.4. HRMS (ESI) m/z: [M + H]+ Calcd for
C15H20F2NO3 300.1406; Found: 300.1408.
*E-mail: jyzhang@suda.edu.cn;
yszhao@suda.edu.cn
Notes
The authors declare no competing financial interest.
ethyl
2-(4-(N,N-diethylsulfamoyl)phenyl)-2,2-difluoroacetate
1
(8c). Yellow oil, 40.9mg, 61%. H NMR (400 MHz, CDCl3) δ
ACKNOWLEDGMENT
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This work was supported by the Natural Science Foundation of
selective ketonisation using soft electrophilic vinyl ethers.
Nat. Commun. 2018, 9, 3582. (h) Maji, A.; Guin, S.; Feng,
S.; Dahiya, A.; Singh, V. K.; Liu, P.; Maiti, D. Experimental
and Computational Exploration of para ‐Selective
Silylation with a Hydrogen‐Bonded Template. Angew.
Chem. Int. Ed. 2017, 56, 14903-14907. (i) Dutta, U.; Maiti,
S.; Pimparkar, S.; Maiti, S.; Gahan, L. R.; Krenske, E.
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assisted distal para-C–H olefination. Chem. Sci. 2019, 10,
7426-7432. (j) Dey, A.; Sinha, S. K.; Achar, T. K.; Maiti, D.
Accessing Remote meta-and para-C(sp2)−H Bonds with
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Ed. 2019, 58, 10820-10843. (k) Dey, A.; Maitya, S.; Maiti,
D. Reaching the south: metal-catalyzed transformation of
the aromatic para-position. Chem. Commun. 2016, 52,
12398-12414.
China (Nos. 21772139, 21572149), the Jiangsu Province Natural
Science Found for Distinguished Young Scholars (BK20180041),
Project of Scientific and Technologic Infrastructure of Suzhou
(SZS20170), and the PAPD Project.
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