Visible-Light-Promoted Oxo-difluoroalkylation of Alkenes with DMSO as the Oxidant

Article abstract of DOI:10.1021/acs.joc.9b01077

Visible-light-promoted oxo-difluoroalkylation (acetylation and acetamidation) of alkenes with dimethyl sulfoxide as both the solvent and the oxidant was developed, affording the corresponding α,α-difluoro-?-ketoacetates and acetamides in modest yields. Both terminal and internal alkenes worked well for the reaction. This reaction features simple starting materials, a green oxidant, mild reaction conditions, and highly functional products.

Full text of DOI:10.1021/acs.joc.9b01077

Subscriber access provided by UNIV AUTONOMA DE COAHUILA UADEC
Article
Visible Light Promoted Oxo-Difluoroalkylation
of Alkenes with DMSO as the Oxidant
Zi-Hao Xia, Zhong-Hua Gao, Lei Dai, and Song Ye
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01077 • Publication Date (Web): 14 May 2019
Downloaded from http://pubs.acs.org on May 15, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Visible Light Promoted Oxo-Difluoroalkylation of Alkenes with
DMSO as the Oxidant
8
9
Zi-Hao Xia,a, b Zhong-Hua Gao,a Lei Dai,a, b and Song Yea,b*
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
(a) Beijing National Laboratory for Molecular Science, Key Laboratory of Molecular
Recognition and Functional, CAS Research/Education Center for Excellence in
Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
(b) University of Chinese Academy of Science, Beijing 100049, P.R. China
ABSTRACT
Visible light promoted oxo-difluoroalkylation (acetylation and acetamidation) of
alkenes with DMSO as both the solvent and the oxidant was developed, affording the
corresponding α, α-difluoro-γ-ketoacetates and acetamides in modest yields. Both
terminal and internal alkenes worked well for the reaction. This reaction features
simple starting materials, green oxidant, mild reaction condtions and highly functional
products.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
4
5
INTRODUCTION
6
7
8
9
Fluorinated organic compounds play an important role in pharmaceuticals,
agrochemicals and materials.1 As a bioisostere of oxygen and carbonyl group,
incorporation of difluoromethyl into molecules can modulate the physical and
chemical properties such as increasing the dipole moments and enhancing the acidity
of adjacent group.2 In particular, α,α-difluoroacetates (CF2CO2R) are of great interest
for their presence in many bioactive compounds and as building blocks for further
transformations.3
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
Alkene difunctionalization is powerful for the rapid synthesis of structurally
diverse molecules from simple starting materials.4 The metal-catalyzed
difluoroacetylation of alkenes
has been well established, including the
difluoroacetylation with arylation,5 oxylation,6 thiolation7 and halogenation reactions.8
Meanwhile, the visible light promoted difluoroacetylation of alkenes emerged as a
useful alternative for the synthesis of α, α-difluoroacetates (Scheme 1). In 2011,
Stephenson et al. reported the pioneering photocatalyzed halo-difluoroacetylation of
alkenes (reaction a).9 Lately, the photocatalyzed difuoroacetylation of alkenes along
with heteroarylation (reaction b),10 alkenylation11 and alkynylation12 (reaction c),
amination with bromodifluoroacetamide13 or trimethylsilylazide14 (reaction d), and
oxygenation with carboxylic acid15 or carbon dioxide16 (reaction e) have been
established.
Being an essential functional group, the synthesis of ketones from simple starting
2
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
materials is one of the key transformations in organic reaction. Very recently, Glorius
et al. and we independently reported a photocatalyzed synthesis of ketones from
alkenes.17 In this paper, we report the synthesis of α,α-difluoro-γ-ketoesters via the
oxo-difluoroacetylation of alkenes (Scheme 1, reaction f). Although the synthesis of
α,α-difluoro-γ-ketoesters from enol ether or acetate has been reported,18 our work
provides a highly valued method via the difunctionalization of simple alkenes using
DMSO as the oxidant.
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
Scheme 1. Photocatalyzed difunctionalization of alkenes with difluoroacetylation
RESULTS AND DISCUSSION
Initially, the model reaction of 4-methylstyrene (1a) with BrCF2CO2Et (2a) in the
presence of base was carried out under photocatalysis using DMSO as both the
oxidant and solvent (Table 1). Disappointedly, the reaction using Ir(ppy)3 as the
photocatalyst under the irradiation with blue LEDs in the presence of common
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
6
7
8
9
organic (DBU, Et3N) and inorganic bases (NaOAc and Cs2CO3) only gave trace
desired α,α-difluoro-γ-ketoester 3a (Table 1, entries 1-4). Interestingly, the reaction in
the presence of K3PO4 gave α,β-unsaturated-α-fluoro-γ-ketoester 4a in 61% yield
(entry 5). Considering the possible elimination of hydrofluoride from compound 3a to
give 4a under basic condition, we then explored weaker bases for the reaction. It was
found that the reaction using K2HPO4 and KH2PO4 afforded the desired
oxo-difluroroacetylation product 3a in good yields without the formation of
elimination product 4a (entries 6 & 7). Variation of loading of the base did not give
better results (entries 8 and 9). Screening of the photocatalysts showed that
[Ir(ppy)2(dtbbpy)](PF6) and 4CzIPN did not perform as well as Ir(ppy)3 (entries 10 &
11).
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
Table 1. Optimization of conditionsa
entry PC (2 mol%)
base
3a (%)b 4a (%)b
1
2
3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
DBU
Et3N
trace
trace
trace
0
0
0
NaOAc
4
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Cs2CO3
K3PO4
trace
trace
61
0
5
61
0
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
6
K2HPO4
KH2PO4
7
75c
66
0
d
8
KH2PO4
0
e
9
KH2PO4
70
0
10
11
[Ir(ppy)2(dtbbpy)] (PF6)
4CzIPN
KH2PO4
KH2PO4
5
0
34
0
a General conditions: 1a (0.3 mmol), 2 (0.45 mmol), PC (2.0 mol%), base (0.6 mmol),
DMSO (2 mL), irradiation by 12 W blue LEDs at room temperature for 14h under
b
19
nitrogen atmosphere. Yields based on F-NMR spectroscopy using benzotrifluoride
c
d
e
as an internal standard. 70% isolated yield. KH2PO4 (1.5 equiv) was used.
KH2PO4 (3 equiv) was used. PC = photocatalyst.
With the optimized reaction conditions in hand (Table 1, entry 7), a variety of
alkenes were investigated for the reaction with ethyl bromodifluoroacetate (2a)
(Scheme 2). It was found that styrenes with electron-donating groups (Ar = p-MeC6H4,
p-t-BuC6H4, p-AcOC6H4) performed better than those with electron-withdrawing
groups (Ar = p-FC6H4, p-ClC6H4, p-BrC6H4), giving the α,α-difluoro-γ-ketoacetates
(3a-3g) in moderate to good yields. Both meta- and ortho-substituents are tolerated to
give the corresponding products (3h-3j) in moderate yields. It should be noted that
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
5
6
7
8
9
some unidentified byproducts were formed along with the desired products for the
reaction with moderate yields. In addition, both 4-vinyl-1,1’-biphenyl and
2-vinylnaphthalene worked well for the reaction (3k-3l). More importantly, the
reaction of the internal alkenes went smoothly under the same conditions to give the
β-substituted-α,α-difluoro-γ-ketoacetates (3m-3p) in good to high yields. Furthermore,
the reaction of indene and estrone-derived alkenes afforded the corresponding
oxo-difluoroacetylation products 3q and 3r in 49% and 54% yield, respectively. It
should be noted that the reaction of styrenes with strong electron-withdrawing group
such as 4-trifluoromethyl gave α,β-unsaturated-α-fluoro-γ-ketoester 4 via the
elimination of hydrofluoride from the oxo-difluoroalkylaiton product, and the reaction
of aliphatic alkenes failed under current reaction conditions.
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
6
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 2. Reaction with ethyl bromodifluoroacetate
6
7
8
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
The reactions with difluoroacetamides were also investigated (Scheme 3). It was
found that both aniline and indole-derived difluoroacetamides 2b and 2c worked well
under the previous standard photocatalysis conditions, resulting in the desired
oxo-difluoroacetamidation products 3s and 3t in moderate to good yields.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
5
Scheme 3. Reaction with bromodifluoroacetamides
6
7
8
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
Scheme 4. Gram-scale reaction.
The reaction could be easily scaled up with 5 mmol of 4-methylstyrene under
standard conditions, giving 0.95 g of the α,α-difluoro-γ-ketoacetate 3a in 74% yield
(Scheme 4).
The multi-functional product affords many possible further chemical
transformations (Scheme 5). For example, reduction of the α,α-difluoro-γ-ketoacetate
3a by LiAlH4 gave the corresponding 2,2-difluro-1,4-diol 5 in 68% yield. The
8
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
difluorodiol could be cyclized via ZnCl2 mediated dehydration to afford
4,4-difluoro-2-(p-tolyl)tetrahydrofuran 6 in high yield.
8
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
Scheme 5. Chemical transformations of 3a.
Scheme 6. Control experiments.
The radical trapping experiment was conducted (Scheme 6, reaction a). When the
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
5
6
7
8
9
reaction was carried out under the standard condition but with addition of 5.0 equiv of
TEMPO as the radical scavenger, the formation of oxo-difluoroacetylation product 3a
was completely prohibited, while adduct 7 between TEMPO and difluoroacetate
radical from 2a was detected by HRMS (ESI). The experiment suggests a radical
mechanism for the photocatalyzed reaction. To classify the oxidation of DMSO, the
control experiment using tetrahydrothiophene 1-oxide instead of DMSO was
conducted (Scheme 6, reaction b), which gave the desired oxo-difluoroalkylation
prouduct 3a in 33% and tetrahydrothiophene was detected by HRMS.
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
A plausible mechanism for the reaction is depicted in Scheme 7. Under the
visible-light irradiation, the catalyst fac-Ir(ppy)3 is excited and then reduces
BrCF2CO2Et (
bromide.9a The addition of radical
, which is oxidized by IrIV to form the key carbocation intermediate
C
2) to produce radical intermediate A via the elimination of
A
to alkenes gives difluoroacetate radical
species
B
and regenerates the photocatalyst. The combination of carbocation intermediate
and DMSO affords the alkoxysulfonium intermediate , which is fragmented
C
D
in the presence of base via [2,3]-δ rearrangement to give the ketone 3, a process
similar to Kornblum oxidation.19
10
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 7. Proposed mechanism.
6
7
8
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
CONCLUSION
In summary, the visible light mediated oxo-difluoroalkylation of alkenes is
developed, with ethyl 2-bromo-2,2-difluoroacetate and
2-bromo-2,2-difluoroacetamides as the difluoroalkyl radical source and DMSO as the
oxidant. The corresponding α,α-difuoro-γ-ketoesters and amides were obtained in
good yields. This reaction features simple starting materials, green oxidant, mild
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
5
6
7
reaction condtion and highly functional products. Other related visible light mediated
difunctionalization reactions of alkenes are underway in our laboratory.
8
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
EXPERIMENTAL SECTION
General Remarks. Unless otherwise indicated, all reactions were carried out under
N2 protection at room temperature with magnetic stirring in a Schlenk tube of normal
borosilicate glass. Photocatalysts fac-Ir(ppy)3,20 [Ir(ppy)2(dtbbpy)](PF6)4h and
4-CzIPN21 were prepared according to literatures. All H NMR (400 and 500 MHz),
1
13C NMR (100 and 125 MHz), and F NMR (376 MHz) spectra were recorded on a
19
Bruker Avance 400 and Bruker Avance 500 spectrometer in CDCl3, with
tetramethylsilane as an internal standard and reported in parts per million (ppm, δ).
1H NMR spectroscopy splitting patterns were designated as singlet (s), doublet (d),
triplet (t), quartet (q). Splitting patterns that could not be interpreted or easily
visualized were designated as multiplet (m) or broad (br). Infrared spectra were
recorded on a JASCO FT/IR-480 spectrophotometer and reported as wave number
(cm-1). Column chromatography was carried out on silica gel (200-300 mesh). HRMS
were obtained on an ESI- Orbitrap mass analyzer，EI-TOF mass analyzer and
ESI-ICR mass analyzer. Experiments upon visible-light irradiation were carried out
using household blue LED lamps (JDY-THDGY, λmax = 455 nm, 18 × 1W).
Irradiation occurred from the bottom of each vial at a distance of 3 cm.
12
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
Typical procedure for the oxo-difluoroalkylation (Schemes 2 and 3). To a 10 mL
Schlenk-tube equipped with a rubber septum and magnetic stir bar was charged with
styrene 1a (35.4 mg, 0.3 mmol), ethyl 2-bromo-2,2-difluoroacetate 2a (90.9 mg, 0.45
mmol), KH2PO4 (81.6 mg, 0.6 mmol) and Ir(ppy)3 (3.9 mg, 2.0 mol%). The tube was
evacuated and backfilled with N2 for three times. DMSO (2.0 mL) was added with a
syringe under nitrogen. The mixture was then irradiated by 12 W blue LEDs. After
14h, the reaction mixture was poured into a separatory funnel containing 20 mL of
H2O and 20 mL of DCM. The organic layer was collected and washed with H2O
(2×20 mL) and brine, successively, dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash chromatography on silica
gel (200-300 mesh) to afford the desired product 3a.
ethyl 2,2-difluoro-4-oxo-4-(p-tolyl)butanoate (3a).
1
54 mg. 70% yield. Colorless oil. Rf = 0.35 (petroleum ether/ethyl acetate 10:1); H
NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.37 (q,
J = 7.2 Hz, 2H), 3.88 (t, J = 13.5 Hz, 2H), 2.42 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H);
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
3
4
5
6
7
8
9
13C{1H} NMR (125 MHz, CDCl3) δ 192.5 (t, J = 5.6 Hz), 163.3 (t, J = 31.3 Hz),
145.3, 133.2, 129.6, 128.3, 114.5 (t, J = 247.5 Hz), 63.0, 43.7 (t, J = 25 Hz), 21.7,
13.9; 19F NMR (376 MHz, CDCl3) δ -104.4 (s, 2F); IR (KBr) 1778, 1687, 1607, 1091.
Orbitrap-HRMS (ESI) calcd for C13H15F2O3 [M+H]+ 257.0983, found 257.0985.
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
ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-oxobutanoate (3b).
1
68 mg. 76% yield. Oil. Rf = 0.45 (petroleum ether/ethyl acetate 10:1); H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.37 (q, J = 7.2 Hz,
2H), 3.89 (t, J = 13.6 Hz, 2H), 1.36 -1.34 (m, 12H); 13C{1H} NMR (100 MHz, CDCl3)
δ 192.5 (t, J = 6.0 Hz), 163.3 (t, J = 31.0 Hz), 158.1, 133.1, 128.2, 125.9, 114.5 (t, J =
19
248.0 Hz), 63.0, 43.8 (t, J = 25 Hz), 35.3, 31.0, 13.9; F NMR (376 MHz, CDCl3) δ
-104.4 (s, 2F); IR (KBr) 1778, 1686, 1190, 1091. Orbitrap-HRMS (ESI) calcd for
C16H21F2O3 [M+H]+ 299.1453, found 299.1454.
ethyl 4-(4-acetoxyphenyl)-2,2-difluoro-4-oxobutanoate (3c).
59 mg. 66% yield. Colorless oil. Rf = 0.15 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz,
2H), 4.37 (q, J = 7.1 Hz, 2H), 3.89 (t, J = 13.0 Hz, 2H), 2.33 (s), 1.36 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 191.7 (t, J = 6.3 Hz), 168.7, 163.2
(t, J = 31.3 Hz), 155.2, 133.1, 129.9, 122.2, 114.3 (t, J = 248.8 Hz), 63.1, 43.8
19
(t, J = 25.0 Hz), 21.3, 13.9; F NMR (376 MHz, CDCl3) δ -104.3 (s, 2F); IR
(KBr) 1760, 1688, 1600, 1190. Orbitrap-HRMS (APCI) calcd for C14H15F2O5
14
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
4
5
[M+H]+ 301.0882, found 301.0884.
6
7
8
ethyl 2,2-difluoro-4-oxo-4-phenylbutanoate (3d).
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
1
46 mg. 63% yield. Colorless oil. Rf = 0.69 (petroleum ether/ethyl acetate 10:1); H
NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.50 (t, J
= 7.8 Hz, 2H), 4.38 (q, J = 7.0 Hz, 2H), 3.91 (t, J = 13.2 Hz, 2H), 1.36 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.9 , 163.3 (t, J = 32.0 Hz), 135.6, 134.2,
19
128.9, 128.2, 114.4 (t, J = 248.0 Hz), 63.1, 43.8 (t, J = 25 Hz), 13.9; F NMR (376
MHz, CDCl3) δ -104.4 (s, 2F); IR (KBr) 1776, 1689, 1192, 1092. Orbitrap-HRMS
(ESI) calcd for C12H13F2O3 [M+H]+ 243.0827, found 243.0829.
ethyl 2,2-difluoro-4-(4-fluorophenyl)-4-oxobutanoate (3e).
1
44 mg. 56% yield. Colorless oil. Rf = 0.39 (petroleum ether/ethyl acetate 10:1); H
NMR (500 MHz, CDCl3) δ 7.96 – 7.93 (m, 2H), 7.16 (t, J = 8.8 Hz, 2H), 4.37 (q, J =
7.1 Hz, 2H), 3.87 (t, J = 13.5 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); C{1H} NMR (125
13
MHz, CDCl3) δ 191.4 (t, J = 6.3 Hz), 166.3 (d, J = 256.3 Hz), 163.2 (t, J = 31.3 Hz),
132.1, 130.9 (d, J = 10.0 Hz), 116.1 (d, J = 22.5 Hz), 114.3 (t, J = 248.8 Hz), 63.1,
19
43.7 (t, J = 25.0 Hz), 13.8; F NMR (376 MHz, CDCl3) δ -103.0 (s, 1F), -104.4 (s,
2F); IR (KBr) 1176, 1691, 1600, 1234. Orbitrap-HRMS (ESI) calcd for C12H12F3O3
[M+H]+ 261.0733, found 261.0735.
ethyl 4-(4-chlorophenyl)-2,2-difluoro-4-oxobutanoate (3f).
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
4
5
6
7
8
9
38 mg. 46% yield. Colorless oil. Rf = 0.39 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz,
2H), 4.37 (q, J = 7.2 Hz, 2H), 3.87 (t, J = 13.0 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 191.8 (t, J = 6.3 Hz), 163.2 (t, J = 31.3 Hz),
140.8, 133.9, 129.6, 129.3, 114.2 (t, J = 248.8 Hz), 63.1, 43.8 (t, J = 23.8 Hz),
13.9; 19F NMR (376 MHz, CDCl3) δ -104.3 (s, 2F); IR (KBr) 1773, 1690, 1590,
1092. Orbitrap-HRMS (ESI) calcd for C12H12F2O3Cl [M+H]+ 277.0438, found
277.0439.
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
ethyl 4-(4-bromophenyl)-2,2-difluoro-4-oxobutanoate (3g).
1
44 mg. 46% yield. Colorless oil. Rf = 0.38 (petroleum ether/ethyl acetate 10:1); H
NMR (500 MHz, CDCl3) δ 7.78(d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 4.38 (q,
13
J = 7.1 Hz, 2H), 3.86 (t, J = 13.0 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H); C{1H} NMR
(125 MHz, CDCl3) δ 192.0 (t, J = 6.3 Hz), 163.2 (t, J = 31.3 Hz), 134.3, 132.3, 129.63,
129.59, 114.2 (t, J = 250.0 Hz), 63.2, 43.7 (t, J = 25.0 Hz), 13.9; 19F NMR (376 MHz,
CDCl3) δ -104.3 (s, 2F); IR (KBr) 1774, 1691, 1586, 1091. ICR-HRMS (ESI) calcd
for C12H11BrF2O3Na [M+Na]+ 342.9752, found 342.9755.
ethyl 2,2-difluoro-4-(3-methoxyphenyl)-4-oxobutanoate (3h).
1
35 mg. 43% yield. Colorless oil. Rf = 0.29 (petroleum ether/ethyl acetate 10:1); H
NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.40 (t, J
= 8 Hz, 1H), 7.17 – 7.15 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.88 (t, J = 13.5 Hz, 2H),
16
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1.37 (t, J = 7.2 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 192.8 (t, J = 6.3 Hz),
163.3 (t, J = 31.3 Hz), 160.2, 136.9, 129.9, 120.84, 120.81,114.4 (t, J = 247.5 Hz),
112.1, 63.1, 55.5, 44.0 (t, J = 25.0 Hz), 13.9; 19F NMR (376 MHz, CDCl3) δ -104.5 (s,
2F); IR (KBr) 1776, 1689, 1266, 1092. Orbitrap-HRMS (ESI) calcd for C13H15F2O4
[M+H]+ 273.0933, found 273.0934.
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
ethyl 4-(3-bromophenyl)-2,2-difluoro-4-oxobutanoate (3i).
41 mg. 43% yield. Colorless oil. Rf = 0.48 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 8.05 – 8.04 (m, 1H), 7.84 – 7.83 (m, 1H), 7.76 –
7.74 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 4.38 (q, J = 7.5 Hz, 2H), 3.87 (t, J = 13.0
Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 191.7 (t,
J = 5.0 Hz), 163.1 (t, J = 31.2 Hz), 137.2, 137.0, 131.2, 130.5, 126.7, 123.3,
19
114.1 (t, J = 250.0 Hz), 63.2, 43.9 (t, J = 25.0 Hz), 13.9; F NMR (376 MHz,
CDCl3) δ -104.3 (s, 2F); IR (KBr) 1776, 1693, 1191, 1092. ICR-HRMS (ESI)
calcd for C12H11BrF2O3Na [M+Na]+ 342.9752, found 342.9753.
ethyl 4-(2-chlorophenyl)-2,2-difluoro-4-oxobutanoate (3j).
48 mg. 58% yield. Colorless oil. Rf = 0.48 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 7.0 Hz, 1H), 7.45 – 7.43 (m, 1H),
7.37 – 7.34 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.95 (t, J = 13.5 Hz, 2H), 1.37 (t,
J = 7.1 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 195.0 (t, J = 6.3 Hz),
13
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
4
5
163.1 (t, J = 31.3 Hz), 137.0, 133.1, 131.7, 130.9, 130.0, 127.2, 113.9 (t, J =
6
7
19
250.0 Hz), 63.1, 47.8 (t, J = 23.8 Hz), 13.9; F NMR (376 MHz, CDCl3) δ
8
9
-104.3 (s, 2F); IR (KBr) 1776, 1703, 1374, 1198. ICR-HRMS (ESI) calcd for
C12H11ClF2O3Na [M+Na]+ 299.0257, found 299.0258.
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
4-([1,1'-biphenyl]-4-yl)-2,2-difluoro-4-oxobutanoate (3k).
51 mg. 53% yield. Colorless oil. Rf = 0.33 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz,
2H), 7.64 – 7.62 (m, 2H), 7.50 – 7.47 (m, 2H), 7.44 – 7.41 (m, 1H), 4.40 (q, J =
13
7.1 Hz, 2H), 3.95 (t, J = 13.5 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 192.5 (t, J = 6.3 Hz), 163.3 (t, J = 31.2 Hz), 146.9, 139.5,
134.3,129.0, 128.8, 128.6, 127.5, 127.3, 114.4 (t, J = 248.8 Hz), 63.1, 43.9 (t, J
= 23.8 Hz), 13.9; 19F NMR (376 MHz, CDCl3) δ -104.3 (s, 2F); IR (KBr) 1775,
1685, 1604, 1190. Orbitrap-HRMS (ESI) calcd for C18H17F2O3 [M+H]+
319.1140, found 319.1140.
ethyl 2,2-difluoro-4-(naphthalen-2-yl)-4-oxobutanoate (3l).
50 mg. 57% yield. Solid. m.p.= 43 - 44
℃. Rf = 0.33 (petroleum ether/ethyl
acetate 10:1); 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 7.98 – 7.92 (m, 2H),
7.90 – 7.88 (m, 2H), 7.65 – 7.62 (m, 1H), 7.60 – 7.57 (m, 1H), 4.40 (q, J = 7.0
Hz, 2H), 4.05 (t, J = 13.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 192.9 (t, J = 6.3 Hz), 163.4 (t, J = 31.3Hz), 136.0, 133.0, 132.4,
18
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
3
4
5
130.4, 129.7, 129.1, 128.9, 127.9, 127.2, 123.3, 114.5 (t, J = 248.8 Hz), 63.1,
6
7
19
43.9 (t, J = 23.8 Hz), 13.9; F NMR (376 MHz, CDCl3) δ -104.3 (s, 2F); IR
8
9
(KBr) 1773, 1685, 1188, 1090. Orbitrap-HRMS (ESI) calcd for C16H15F2O3
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
[M+H]+ 293.0983, found 293.0985.
ethyl 2,2-difluoro-3-methyl-4-oxo-4-(p-tolyl)butanoate (3m).
56 mg. 69% yield. Colorless oil. Rf = 0.35 (petroleum ether/ethyl acetate 10:1)
;
1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz,
2H), 4.32 – 4.26 (m, 3H), 2.42 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0
Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.2 (d, J = 6.3 Hz), 163.5 (t, J =
32.5 Hz), 144.8, 132.8, 129.5, 128.7, 115.1 (dd, J = 247.5 Hz, 257.5 Hz ), 62.9,
19
46.1 (dd, J = 21.3 Hz, 23.8 Hz), 21.7, 13.8, 11.5 (dd, J = 3.8 Hz, 5.0Hz); F
NMR (376 MHz, CDCl3) δ -105.6 (d, J = 270.7 Hz, 1F), -112.3 (d, J = 270.7
Hz, 1F); IR (KBr) 1774, 1683, 1235, 1120. Orbitrap-HRMS (ESI) calcd for
C14H17F2O3 [M+H]+ 271.1140, found 271.1142.
ethyl 2,2-difluoro-3-methyl-4-oxo-4-phenylbutanoate (3n).
42 mg. 55% yield. Colorless oil. Rf = 0.57 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H),
7.50 (t, J = 7.5 Hz, 2H), 4.33 – 4.28 (m, 3H), 1.47 (d, J = 7.5 Hz, 3H), 1.30 (t, J
= 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.7 (d, J = 6.3 Hz), 163.5
(t, J = 31.3 Hz), 135.4, 133.8, 128.9, 128.6, 115.1 (dd, J = 247.5 Hz, 258.8 Hz ),
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
4
5
6
7
8
9
19
63.0, 46.2 (dd, J = 22.5 Hz, 25.0 Hz), 13.8, 11.4 (dd, J = 3.8 Hz, 5.0Hz); F
NMR (376 MHz, CDCl3) δ -105.7 (d, J = 267.0 Hz, 1F), -112.4 (d, J = 270.7
Hz, 1F); IR (KBr) 1774, 1686, 1219, 1121. Orbitrap-HRMS (ESI) calcd for
C13H15F2O3 [M+H]+ 257.0983, found 257.0984.
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
ethyl 4-(4-chlorophenyl)-2,2-difluoro-3-methyl-4-oxobutanoate (3o).
51 mg. 59% yield. Colorless oil. Rf = 0.35 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz,
2H), 4.32 – 4.22 (m, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 196.4 (d, J = 6.3 Hz), 163.4 (t, J = 31.3 Hz),
140.4, 130.0, 129.2, 115.0 (dd, J = 248.8 Hz, 258.8 Hz ), 63.1, 46.0 (dd, J =
19
21.3 Hz, 23.8 Hz), 13.8, 11.3 (dd, J = 3.8 Hz, 5.0Hz); F NMR (376 MHz,
CDCl3) δ -105.8 (d, J = 270.7 Hz, 1F), -111.9 (d, J = 270.7 Hz, 1F); IR (KBr)
1774, 1687, 1589, 1093. Orbitrap-HRMS (ESI) calcd for C13H14F2O3Cl [M+H]+
291.0594, found 291.0596.
ethyl 4-(4-bromophenyl)-2,2-difluoro-3-methyl-4-oxobutanoate (3p).
58 mg. 58% yield. Colorless oil. Rf = 0.45 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz,
2H), 4.33 – 4.21 (m, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.30 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 196.6 (d, J = 5.0 Hz), 163.4 (t, J = 32.5 Hz),
134.1, 132.2, 130.1, 129.2, 115.0 (dd, J = 248.8 Hz, 258.8 Hz ), 63.1, 46.0 (dd,
20
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J = 22.5 Hz, 25.0 Hz), 13.8, 11.3 (dd, J = 3.8 Hz, 5.0 Hz); 19F NMR (376 MHz,
CDCl3) δ -105.8 (d, J = 270.7 Hz, 1F), -111.9 (d, J = 270.7 Hz, 1F); IR (KBr)
1774, 1687, 1585, 1072. ICR-HRMS (ESI) calcd for C13H13BrF2O3Na [M+Na]+
356.9908, found 356.9912.
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
ethyl 2,2-difluoro-2-(1-oxo-2,3-dihydro-1H-inden-2-yl)acetate (3q).
37 mg. 49% yield. Yellow oil. Rf = 0.29 (petroleum ether/ethyl acetate 10:1);
1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.5 Hz, 1H), 7.66 – 7.63 (m, 1H),
7.52 (d, J = 7.5 Hz, 1H), 7.42 – 7.27 (m, 1H), 4.42 (q, J = 7.0 Hz, 2H), 3.72 –
3.63 (m, 1H), 3.39 (d, J = 6.5 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 199.4 (d, J = 7.5 Hz), 163.0 (t, J = 32.5 Hz), 152.9, 136.0
(d, J = 3.8 Hz), 135.6, 128.0, 126.6, 124.4, 115.0 (dd, J = 250.0 Hz, 253.8 Hz ),
19
63.3, 51.0 (t, J = 22.5 Hz), 26.8 (d, J = 2.5 Hz), 13.9; F NMR (376 MHz,
CDCl3) δ -103.9 (d, J = 267.0 Hz, 1F), -115.2 (d, J = 267.0 Hz, 1F); IR (KBr)
1774, 1723, 1294, 1067. Orbitrap-HRMS (ESI) calcd for C13H13F2O3 [M+H]+
255.0827, found 255.0828.
ethyl-2,2-difluoro-4-((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,1
5,16,17-
(3r).
decahydro-6H-cyclopenta[a]phenanthren-3-yl)-4-oxobutanoate
68 mg. 54% yield. Colorless oil. Rf = 0.55 (petroleum ether/ethyl acetate 1:1);
1H NMR (500 MHz, CDCl3) δ 7.69 – 7.66 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H),
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
5
6
7
8
9
4.38 (q, J = 7.1 Hz 2H), 3.88 (t, J = 13.5 Hz, 2H), 2.98 – 2.97 (m, 2H), 2.51 –
2.49 (m, 1H), 2.37 – 2.33 (m, 1H), 2.20 – 2.11 (m, 1 H), 2.08 – 2.04 (m, 2H),
2.01 – 1.99 (m, 1H), 1.67 – 1.58 (m, 3H), 1.56 – 1.43 (m 4H), 1.36 (t, J = 7.2
Hz, 3H), 0.92 (s, 3H), 0.89 – 0.83 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
220.4, 192.7 (t, J = 6.3 Hz), 163.3 (t, J = 31.3 Hz, ), 146.8, 137.4, 133.3, 128.8,
125.9, 125.6, 114.5 (t, J = 247.5 Hz), 63.0, 50.5, 47.9, 44.8, 43.8 (t, J = 23.8
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
19
Hz), 37.7, 35.8, 31.5, 29.3, 26.2, 25.5, 21.6, 13.9, 13.8; F NMR (376 MHz,
CDCl3) δ -104.4 (s, 2F); IR (KBr) 1738, 1684, 1195, 1091. Orbitrap-HRMS
(ESI) calcd for C24H29F2O4 [M+H]+ 419.2028, found 419.2029.
2,2-difluoro-4-oxo-N-phenyl-4-(p-tolyl)butanamide (3s).
o
40 mg. 44% yield. Solid. m.p.= 144 – 145 C. Rf = 0.14 (petroleum ether/ethyl
acetate 10:1); 1H NMR (400 MHz, CDCl3) δ 8.21 (brs, 1H), 7.82 (d, J = 8.0 Hz,
2H), 7.61 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.29 – 7.24 (m, 2H),
13
7.19 (t, J = 7.2 Hz 1H), 4.00 (t, J = 14.0 Hz, 2H), 2.42 (s, 3H); C{1H} NMR
(125 MHz, CDCl3) δ 192.6 (t, J = 5.0 Hz), 161.7 (t, J = 26.3 Hz), 145.2, 136.3,
133.2, 129.6, 129.2, 128.3, 125.5, 120.4, 116.4 (t, J = 252.5 Hz), 42.9 (t, J =
19
25.0 Hz), 21.8; F NMR (376 MHz, CDCl3) δ -103.7 (s, 2F); IR (KBr) 1686,
1606, 1544, 1230. Orbitrap-HRMS (ESI) calcd for C17H16NF2O2 [M+H]+
304.1144, found 304.1144.
2,2-difluoro-1-(indolin-1-yl)-4-(p-tolyl)butane-1,4-dione (3t).
22
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
5
51 mg. 52% yield. Solid. m.p.= 66 - 67
℃. Rf = 0.71 (petroleum ether/ethyl
6
7
8
9
acetate 10:1); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, 1H), 7.86 (d, J
= 8.4 Hz, 2H), 7.29 – 7.18 (m, 4H), 7.09 (t, J = 7.2 Hz, 1H), 4.46 (t, J = 8.0 Hz,
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
13
2H), 3.96 (t, J = 14.4 Hz, 2H), 3.24 (t, J = 8.0 Hz, 2H), 2.42 (s, 3H); C{1H}
NMR (125 MHz, CDCl3) δ 192.8 (t, J = 5 Hz), 160.9 (t, J = 28.8 Hz), 144.7,
142.7, 133.8, 131.7, 129.4, 128.4, 127.5, 125.1, 124.6, 118.4 (t, J = 255 Hz),
19
118.0, 47.9 (t, J = 8.8 Hz), 43.3 (t, J = 22.5 Hz), 28.7, 21.7; F NMR (376
MHz, CDCl3) δ -100.0 (s, 2F); IR (KBr) 1670, 1483, 1430, 1230.
Orbitrap-HRMS (ESI) calcd for C19H18NF2O2 [M+H]+ 330.1300, found
330.1299.
Gram-scale reaction (Scheme 4). To a 100 mL Schlenk-tube equipped with a
rubber septum and magnetic stir bar was charged with styrene 1a (0.59 g, 5
mmol), ethyl 2-bromo-2,2-difluoroacetate 2a (1.52 g, 7.5 mmol), KH2PO4 (1.36
g, 10 mmol) and Ir(ppy)3 (66 mg, 2.0 mol%). The tube was evacuated and
backfilled with N2 for three times. DMSO (25mL) was added with a syringe
under nitrogen. The mixture was then irradiated by 12 W blue LEDs. After 14 h,
the reaction mixture was poured into a separatory funnel containing 50 mL of
H2O and 50 mL of DCM. The organic layer was collected and washed with
H2O (2×50 mL) and brine, successively, dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel (200-300 mesh) to afford 0.95 g (74%) of the
desired product 3a.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
5
6
7
8
9
Chemical transformations of 3a (Scheme 5). To a solution of 3a (0.128 g, 0.5
mmol) in THF (2 mL) was slowly added 1.5 mmol of LiAlH4 in THF (1M, 1.5
mL) in 5 min at 0 °C. The reaction mixture was further stirred for 1 h. The
reaction mixture was quenched at 0 °C with several drops of H2O and dried
over anhydrous MgSO4, filtered and concentrated under reduced pressure. The
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
resulting residue was purified by flash column chromatography to give diol
5
(73.0 mg, 68%) as white solid. m.p.= 66 – 67 oC. 1H NMR (500 MHz, CDCl3) δ
7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.96 (d, J = 10.5 Hz, 1H),
3.91 – 3.79 (m, 2H), 3.32 (s, 1H), 2.70 (s, 1H), 2.54 – 2.42 (m, 1H), 2.35 (s,
13
3H), 2.21 (q, J = 13.5 Hz, 1H); C{1H} NMR (125 MHz, CDCl3) δ 140.1,
138.1, 129.5, 125.6, 122.5 (t, J = 242.5 Hz), 69.3 (dd, J = 10.6, 2.2 Hz), 64.3 (t,
19
J = 33.8 Hz), 43.4 (t, J = 25.0 Hz), 21.1; F NMR (376 MHz, CDCl3) δ -98.9
(d, J = 255.7 Hz, 1F), -107.2 (d, J = 255.7 Hz, 1F); IR (KBr) 3432, 1637, 1070,
553. TOF-HRMS (EI) calcd for C11H14F2O2 [M]+ 216.0962, found 216.0965.
To a stirred solution of 3,3-difluoro-1-(p-tolyl)butane-1,4-diol
5 (43.2 mg, 0.2
mmol) in 1,2-dichloroethane (2 mL) at room temperature was added anhydrous
zinc chloride (27.2 mg, 0.2 mmol) and the reaction mixture was stirred at 80 °C
for 2.5 h. Then the reaction mixture was diluted with dichloromethane (5 mL),
and washed with water and brine. The organic layer was dried over anhydrous
MgSO4. The resulting residue was purified by silica gel flash column
chromatography to give difluorotetrahedronfuran
6 (32 mg, 81%) as colorless
oil. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz,
24
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2H), 4.97 (dd, J = 9.6, 6.0 Hz, 1H), 4.16 (q, J = 11.2 Hz, 1H), 3.95 –3.85 (m,
1H), 2.69 – 2.58 (m, 1H), 2.35 – 2.21 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3) δ 137.1, 135.5, 129.1 (t, J = 249.0 Hz), 128.3, 124.9, 79.1 (t, J = 5.0
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
19
Hz), 72.6 (t, J = 31.0 Hz), 43.0 (t, J = 23.0 Hz), 20.1. F NMR (376 MHz,
CDCl3) δ -98.9 (d, J = 233.1 Hz, 1F), -99.9 (d, J = 233.1 Hz, 1F). IR (KBr)
2926, 1370, 1066, 808. TOF-HRMS (EI) calcd for C11H12F2O [M]+ 198.0856,
found 198.0859.
Control experiments (Scheme 6). (Reaction a) To a 10 mL Schlenk-tube
equipped with a rubber septum and magnetic stir bar was charged with styrene
1a (35.4 mg, 0.3 mmol), ethyl 2-bromo-2,2-difluoroacetate 2a (90.9 mg, 0.6
mmol), KH2PO4 (81.6 mg, 0.6 mmol), TEMPO (234 mg, 1.5 mmol) and
Ir(ppy)3 (3.9 mg, 2.0 mol%). The tube was evacuated and backfilled with N2 for
three times. DMSO (2.0 mL) was added with a syringe under nitrogen. The
mixture was then irradiated by 12 W blue LEDs. After 12h, a drop of the
reaction mixture (about 50 μL) was collected for Orbitrap-HRMS (ESI) analysis
without further work-up. The adduct of TEMPO and difluoroacetate radical (7)
was detected by HR-MS (ESI): calcd for C17H28NO+ [M+H]+ 280.17188, found
280.17188 (Figure S1), while the corresponding oxo-difluoroacetylation
product 3a was not detected.
(Reaction b) To a 10 mL Schlenk-tube equipped with a rubber septum and
magnetic stir bar was charged with styrene 1a (35.4 mg, 0.3 mmol), ethyl
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
6
7
8
9
2-bromo-2,2-difluoroacetate 2a (90.9 mg, 0.45 mmol), KH2PO4 (81.6 mg, 0.6
mmol) and Ir(ppy)3 (3.9 mg, 2.0 mol%). The tube was evacuated and backfilled
with N2 for three times. Tetrahydrothiophene 1-oxide (2.0 mL) was added with
a syringe under nitrogen. The mixture was then irradiated by 12 W blue LEDs.
After 12h, a drop of the reaction mixture (about 50 μL) was collected for
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
Orbitrap-HRMS
(ESI)
analysis
without
further
work-up.
The
tetrahydrothiophene was detected by HR-MS (APCI): calcd for C4H9S+ [M+H]+
89.04195, found 89.04200. (Figure S2).
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.XXX.
HRMS spectra, copies of 1H, 13C and 19F NMR spectra (PDF)
Corresponding Author
songye@iccas.ac.cn (S. Ye)
ORCID
Song Ye: 0000-0002-3962-7738
Notes
26
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
5
The authors declare no competing financial interest.
6
7
8
ACKNOWLEDGMENT
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
Financial support from the National Natural Science Foundation of China (Nos
21425207 and 21672216), and the Chinese Academy of Sciences is greatly
acknowledged.
REFERENCES
(1) (a) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking
Beyond Intuition. Science 2007, 317, 1881; (b) O'Hagan, D. Understanding
Organofluorine Chemistry. An Introduction to the C–F Bond. Chem. Soc. Rev. 2008,
37, 308.
(2) (a) Erickson, J. A.; McLoughlin, J. I. Hydrogen Bond Donor Properties of the
Difluoromethyl Group. J. Org. Chem. 1995, 60, 1626; (b) Yudin, A. K.; Prakash, G.
K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. Preparation of and
Fluoroalkylation
with
(Chlorodifluoromethyl)trimethylsilane,
and
Difluorobis(trimethylsilyl)methane,
1,1,2,2-Tetrafluoro-1,2-bis(trimethylsilyl)ethane. J. Am. Chem. Soc. 1997, 119,
1572; (c) Bégué, J.-P.; Bonnet-Delpon, D. Recent Advances (1995–2005) in
Fluorinated Pharmaceuticals Based on Natural Products. J. Fluorine Chem. 2006,
127, 992; (d) Knust, H.; Achermann, G.; Ballard, T.; Buettelmann, B.; Gasser, R.;
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
3
4
5
6
7
8
9
Fischer, H.; Hernandez, M.-C.; Knoflach, F.; Koblet, A.; Stadler, H.; Thomas, A. W.;
Trube, G.; Waldmeier, P. The Discovery and Unique Pharmacological Profile of
RO4938581 and RO4882224 as Potent and Selective GABAA α5 Inverse Agonists
for the Treatment of Cognitive Dysfunction. Bioorg. Med. Chem. Lett. 2009, 19,
5940; (e) Meanwell, N. A. Synopsis of Some Recent Tactical Application of
Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529; (f) Feng, Z.; Chen, F.;
Zhang, X. Copper Catalyzed Cross-Coupling of Iodobenzoates with
Bromozinc-difluorophosphonate. Org. Lett. 2012, 14, 1938; (g) Feng, Z.; Min,
Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Palladium-Catalyzed Difluoroalkylation of
Aryl Boronic Acids: A New Method for the Synthesis of Aryldifluoromethylated
Phosphonates and Carboxylic Acid Derivatives. Angew. Chem., Int. Ed. 2014, 53,
1669; (h) Feng, Z.; Xiao, Y.-L.; Zhang, X. Transition-Metal (Cu, Pd, Ni)-Catalyzed
Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides. Acc. Chem. Res.
2018, 51, 2264.
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
(3) (a) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood, K.;
Swabeck, J. K.; Olah, G. A. Copper-Mediated Difluoromethylation of (Hetero)aryl
Iodides and β-Styryl Halides with Tributyl(difluoromethyl)stannane. Angew. Chem.,
Int. Ed. 2012, 51, 12090; (b) Otsuka, T.; Ishii, A.; Dub, P. A.; Ikariya, T. Practical
Selective Hydrogenation of α-Fluorinated Esters with Bifunctional Pincer-Type
Ruthenium(II) Catalysts Leading to Fluorinated Alcohols or Fluoral Hemiacetals. J.
Am. Chem. Soc. 2013, 135, 9600; (c) Sun, X.; Yu, S. Visible-Light-Mediated
Fluoroalkylation of Isocyanides with Ethyl Bromofluoroacetates: Unified Synthesis
28
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
of Mono- and Difluoromethylated Phenanthridine Derivatives. Org. Lett. 2014, 16,
2938; (d) Yu, J.-S.; Liao, F.-M.; Gao, W.-M.; Liao, K.; Zuo, R.-L.; Zhou, J. Michael
Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated
Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters. Angew. Chem.,
Int. Ed. 2015, 54, 7381; (e) Wan, W.; Ma, G.; Li, J.; Chen, Y.; Hu, Q.; Li, M.; Jiang,
H.; Deng, H.; Hao, J. Silver-Catalyzed Oxidative Decarboxylation of
Difluoroacetates: Efficient Access to C–CF2 Bond Formation. Chem. Commun.
2016, 52, 1598; (f) Yu, W.; Xu, X.-H.; Qing, F.-L. Photoredox Catalysis Mediated
Application of Methyl Fluorosulfonyldifluoroacetate as the CF2CO2R Radical
Source. Org. Lett. 2016, 18, 5130.
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
(4) (a) Muñiz, K. Imido-Osmium(viii) Compounds in Organic Synthesis:
Aminohydroxylation and Diamination Reactions. Chem. Soc. Rev. 2004, 33, 166; (b)
Chemler, S. R.; Fuller, P. H. Heterocycle Synthesis by Copper Facilitated Addition
of Heteroatoms to Alkenes, Alkynes and Arenes. Chem. Soc. Rev. 2007, 36, 1153; (c)
Wolfe, J. P. Intramolecular Alkoxycyanation and Alkoxyacylation Reactions: New
Types of Alkene Difunctionalizations for the Construction of Oxygen Heterocycles.
Angew. Chem., Int. Ed. 2012, 51, 10224; (d) Wu, W.; Jiang, H. Palladium-Catalyzed
Oxidation of Unsaturated Hydrocarbons Using Molecular Oxygen. Acc. Chem. Res.
2012, 45, 1736; (e) Romero, R. M.; Wöste, T. H.; Muñiz, K. Vicinal
Difunctionalization of Alkenes with Iodine(III) Reagents and Catalysts. Chem.
Asian J. 2014, 9, 972; (f) Cao, M.-Y.; Ren, X.; Lu, Z. Olefin Difunctionalizations via
Visible Light Photocatalysis. Tetrahedron Lett. 2015, 56, 3732; (g) Courant, T.;
29
ACS Paragon Plus Environment