Keto-difluoromethylation of aromatic alkenes by photoredox catalysis: Step-economical synthesis of α-CF2H-substituted ketones in flow

Article abstract of DOI:10.1021/acscatal.9b01312

A step-economical method for synthesis of α-CF₂H-substituted ketones from readily available alkene feedstocks has been developed. Radical difluoromethylation of aromatic alkenes combining DMSO oxidation and photoredox catalysis is a key to the successful transformation. Electrochemical analysis, laser flash photolysis (LFP), and density functional theory (DFT) calculations reveal that N-tosyl-S-difluoromethyl-S-phenylsulfoximine serves as the best CF₂H radical source among analogous sulfone-based CF₂H reagents. The present photocatalytic keto-difluoromethylation has been applied to flow synthesis and easily scaled up to gram-scale synthesis within a reasonable reaction time. Furthermore, potentials of the α-CF₂H-substituted ketones for useful synthetic intermediates are shown; e.g., synthesis of the CF₂H-containing α-hydroxyamide with the same carbon skeleton as that of the anticonvulsant active CF₃-analogue, is disclosed. Additionally, mechanistic studies are also discussed in detail.

Full text of DOI:10.1021/acscatal.9b01312

Subscriber access provided by ALBRIGHT COLLEGE
Article
Keto-Difluoromethylation of Aromatic Alkenes by Photoredox Catalysis:
2
Step-Economical Synthesis of #-CFH-Substituted Ketones in Flow
Yoshiki Nakayama, Gaku Ando, Manabu Abe, Takashi Koike, and Munetaka Akita
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01312 • Publication Date (Web): 12 Jun 2019
Downloaded from http://pubs.acs.org on June 12, 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 39
ACS Catalysis
1
2
3
4
5
6
7
8
9
Keto-Difluoromethylation of Aromatic Alkenes by
Photoredox Catalysis: Step-Economical Synthesis of
-CF2H-Substituted Ketones in Flow
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
Yoshiki Nakayama,‡ Gaku Ando,† Manabu Abe,§ Takashi Koike,*†,‡ Munetaka Akita*†,‡
†Laboratory for Chemistry and Life Science, Institute of Innovative Research, ‡School of
Materials and Chemical Technology, Tokyo Institute of Technology, R1-27, 4259
Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
§Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1
Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
ABSTRACT: A step-economical method for synthesis of -CF2H-substituted ketones from
readily available alkene feedstocks has been developed. Radical difluoromethylation of
aromatic alkenes combining DMSO oxidation and photoredox catalysis is a key to the
successful transformation. Electrochemical analysis, laser flash photolysis (LFP), and
density functional theory (DFT) calculations reveal that N-tosyl-S-difluoromethyl-S-
ACS Paragon Plus Environment
1

ACS Catalysis
Page 2 of 39
1
2
3
4
5
6
7
8
9
phenylsulfoximine serves as the best CF2H radical source among analogous sulfone-based
CF2H reagents. The present photocatalytic keto-difluoromethylation has been applied to
flow synthesis and easily scaled up to gram-scale synthesis within reasonable reaction
time. Furthermore, potentials of the -CF2H-substituted ketones for useful synthetic
intermediates are shown, e.g., synthesis of the CF2H-containing -hydroxyamide with the
same carbon skeleton as that of the anticonvulsant active CF3-analogue, is disclosed.
Additionally, mechanistic studies are also discussed in detail.
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
KEYWORDS: photoredox catalysis, difluoromethylation, alkene difunctionalization, radical
reaction, flow synthesis
1. INTRODUCTION
Organofluorine compounds are of strong interest for researchers in the fields of
pharmaceuticals, agrochemicals, and organic functional materials.1 In particular,
fluorinated ketones are regarded as notable compounds because they can be utilized
for bioactive molecules as themselves, valuable fluorine-containing building blocks, and
other materials.2 For the past several years, various strategies for catalytic synthesis of -
CF3-substituted ketones have been developed.3 Representative synthetic methods from
alkenes, alkynes, -ketoacids, and activated carbonyl compounds are shown in Scheme
1a. On the other hand, the difluoromethyl (CF2H) group has recently attracted great
ACS Paragon Plus Environment
2

Page 3 of 39
ACS Catalysis
1
2
3
4
5
6
7
8
9
interest as a useful structural motif because it serves as a bioisostere of alcohol and
thiol.4 However, synthesis of -CF2H-substituted ketones through catalytic
difluoromethylation5 has not been reported yet. In 2012, Mikami and co-workers
reported on difluoromethylation of lithium enolate through substitution of fluoroform,
which focused on synthesis of -CF2H-substituted amides and esters. Only one example
of -CF2H-substituted ketone that bears a quaternary carbon atom was reported
(Scheme 1b).6 In 2017, the group of Paquin developed multi-step synthesis of -CF2H-
substituted ketones from alkynes (Scheme 1c).7 Development of novel operationally
simple and step-economical synthetic methods is associated with exploration of CF2H-
containing drugs.
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
ACS Paragon Plus Environment
3

ACS Catalysis
Page 4 of 39
1
2
3
4
5
6
7
8
(a) selected examples of catalytic synthesis of -CF3-substituted ketones
OAc
Cu cat.
photocat.
R2
R1
R1
CF3SO2Na
tBuOOH
Togni II
DMSO
R2
organocat. with
photocat. or Cu cat.
9
Ag cat. or
photocat.
O
O
OSO2CF3
R2
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
CF3
R1
R1
R1
R1
w/ or w/o
oxidant
CF3I or Togni I
R2
R2
O
O
Ag cat.
Cu cat.
Togni II
R1
OH
R2
CF3SO2Na, O2
oxidant
R2
(b) previous work reported by the group of Mikami
O
O
1) LHMDS (2 equiv.)
Bn
Bn
CF2H
2) CF3H (ca. 5 equiv.)
MeO
MeO
(c) previous work reported by the group of Paquin
R1
O
R1
Au cat.
MeOH
nBuLi
Me-DAST
DDQ
CF2H
R1
HCHO
CF2H
H
(d) this work: photocatalytic synthesis of -CF2H ketones from alkenes in flow
photocat.
O
radical
R2
R1
CF2H
difluoromethylation
&
+
1a
R1
R3
R3 R2
DMSO oxidation
DMSO, rt
visible light
CF3 & CF2H reagents
CF3
I
O
O
NTs
CF3
I
O
S
Me
Me
O
Ph
CF2H
1a
Togni I reagent
Togni II reagent
Hu reagent
Scheme 1. Strategies for Synthesis of -Fluoromethylated Ketones
Herein, we report on the first example of photoredox-catalyzed keto-
difluoromethylation, i.e., a single-step synthesis of -CF2H-substituted ketones from
ACS Paragon Plus Environment
4

Page 5 of 39
ACS Catalysis
1
2
3
4
5
6
7
8
9
alkenes (Scheme 1d). Previously, we reported on efficient generation of -CF2H-
substituted carbocationic species A by the Ir photocatalytic reaction of aromatic alkenes
2 with N-tosyl-S-difluoromethyl-S- phenylsulfoximine (1a). 8,9,10 The in-situ DMSO-
trapping reaction of A involved in so-called Kornblum oxidation11 is expected to lead to
synthetically useful -CF2H-substituted ketones 3 in one-pot operation (Scheme 2).
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
previous
works
IrIV
IrIII
*IrIII
IrIV
O
NTs
+ 1e
– 1e
CF2H
R1 R2
S
Ar
·CF2H
R1
Ph
CF2H
visible light
Ar
1a
A
R2
2
DMSO
fragmentation
+ 1e
oxidation
O
O
X
this
work
CF2H
CF2H-containing
molecules
S
Ar
Ar
CF2H
R1 R2
anionic radicals
3
IrIII = fac-[Ir(ppy)3]
Scheme 2. Contents Highlighted in this Article
In addition to the synthetic studies, laser flash photolysis (LFP) and density functional
theory (DFT) calculations are performed to gain new mechanistic insights into the CF2H
radical generation process promoted by electron transfer from the excited Ir species
(*IrIII) to the reagent 1a. Furthermore, photocatalytic flow synthesis, synthetic
applications of the obtained CF2H-ketone, and basic mechanistic studies are also
discussed in detail.
2. RESULTS AND DISCUSSION
ACS Paragon Plus Environment
5

ACS Catalysis
Page 6 of 39
1
2
3
4
5
6
2.1. Optimization of Photocatalytic Keto-Difluoromethylation of Alkenes: NMR-
scale Experiment.
7
8
9
We commenced the reaction of 4-methylstyrene (2a) with the CF2H reagent 1a in
DMSO-d6 in the presence of fac-[Ir(ppy)3] (5 mol%) under visible light irradiation (425 nm).
To our delight, the desired -CF2H-ketone product, 3,3-difluoro-1-(4-
methylphenyl)propanone (3a), was obtained in an 87% NMR yield together with a small
amount of CF2H-alkene 4a (4% NMR yield) (entry 1 in Table 1). Examination of other
sulfone-based CF2H reagents (1b12a, 1c12b, and 1d12d)12 and commonly used
photocatalysts ([Ru(bpy)3](PF6)2 and [Ir(ppy)2(dtbbpy)](PF6) (bpy: 2,2’-bipyridine, dtbbpy:
4,4’-di-tert-butyl-2,2’-bipyridine)) revealed that the combination of fac-[Ir(ppy)3] and the
phenylsulfoximine reagent 1a was the best for the present transformation (entries 2–6).
Next, the reaction was applied to 4-methoxystyrene (2b). Unfortunately, the desired
ketone 3b was obtained only in a 41% NMR yield and a considerable amount of the
corresponding CF2H-alkene 4b was formed (39% NMR yield). Usually DMSO oxidation
proceeds via the reactive ylide species, which is formed from deprotonation of an
alkoxysulfonium intermediate, to afford the carbonyl product. Then, we explored addition
of a base to promote the deprotonation (entries 10–12). As a result, sodium benzoate
suppressed the formation of by-product 4b to give keto-difluoromethylated product 3b
in a 75% NMR yield. The reaction did not proceed at all either in the dark or in the absence
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
ACS Paragon Plus Environment
6

Page 7 of 39
ACS Catalysis
1
2
3
4
of the photocatalyst (entries 7, 8, 13, and 14). These results suggest that the photoexcited
5
6
7
fac-[Ir(ppy)3] is involved in the reaction.
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
ACS Paragon Plus Environment
7

ACS Catalysis
Page 8 of 39
1
2
3
4
Table 1. Optimization of Photocatalytic Keto-Difluoromethylation of Alkenes on NMR
5
6
7
Scalea
8
9
O
5 mol % photocat.
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
CF2H
CF2H reagent
+
+
CF2H
Ar
DMSO-d6, base, rt, 2 h
425 nm blue LEDs
Ar
R
4
1
3
R = Me: 2a
= OMe: 2b
1:1.2
CF2H reagent
photocatalyst
O
NTs
O
O
S
CF2H
1b
(PF6)2
PF6
S
tBu
tBu
N
Ph
CF2H
Ph
N
N
N
N
N
N
1a
N
N
RuII
N
IrIII
IrIII
N
O
O
O
O
N
N
S
S
N
CF2H
CF2H
S
N
[Ru(bpy)3](PF6)2
fac-[Ir(ppy)3]
[Ir(ppy)2(dtbbpy)](PF6)
1c
1d
Entry Alkene Photocatalyst (E*ox)b
CF2H
reagent 1
Base
NMR yield NMR yield
2
of
of
CF2H-
CF2H-
ketone 3c alkene 4d
—
1
2a
fac-[Ir(ppy)3]
(–2.14 V)
1a
87
4
—
—
—
—
2
3
4
5
2a
2a
2a
2a
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
[Ru(bpy)3](PF6)2
(–1.22 V)
1b
1c
1d
1a
0
0
trace
19
0
0
trace
0
—
—
6
7
2a
2a
[Ir(ppy)2(dtbbpy)](PF6) 1a
0
0
0
0
(–1.37 V)
none
1a
ACS Paragon Plus Environment
8

Page 9 of 39
ACS Catalysis
1
2
3
4
5
6
7
8
9
8e
2a
2b
2b
2b
2b
2b
2b
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
none
1a
1a
1a
1a
1a
1a
1a
0
0
—
—
9
41
39
4
10
11
12
13
14e
PhCO2Na 75
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
NEt3
13
17
f
f
K2CO3
–
–
PhCO2Na 0
PhCO2Na 0
0
0
fac-[Ir(ppy)3]
aReaction conditions: A mixture of photocatalyst (0.75 mol, 5 mol%), 1 (15 mol, 1
equiv.), 2 (18 mol, 1.2 equiv.), and additional base (15 mol, 1 equiv.) in DMSO-d6 (0.46
mL) was irradiated by 3 W blue LEDs ( = 425 ± 15 nm) at room temperature. bReported
reducing power (E*ox V vs. Cp2Fe) in the parenthesis. [E*ox vs. Cp2Fe] = [E*ox vs. SCE] –
0.41.13 cYields were determined by 1H NMR spectroscopy. dYields were determined by 19F
NMR spectroscopy. eIn the dark. fComplicated mixture.
2.2. Evaluation of CF2H-Sulfone Derivatives 1 as CF2H Radical Precursors.
As mentioned above, 1a turned out to be the best difluoromethylating reagent for the
present keto-difluoromethylation. On the other hand, the group of Hu reported that 1d
also serves as a CF2H radical precursor by the action of photoredox catalysis.12c Thus, we
examined properties and reaction of the related CF2H reagents 1 by means of cyclic
voltammetry (CV), LFP and DFT calculations.
2.2.1. Cyclic voltammetry of the CF2H reagents 1.
Irreversible broad reduction waves were observed in the CV traces for the CF2H reagents
(1a: –2.26 V, 1b: –2.50 V, 1c: –2.31 V, 1d: –1.79 V vs. Cp2Fe in DMSO) as shown in Figure
ACS Paragon Plus Environment
9

ACS Catalysis
Page 10 of 39
1
2
3
4
5
6
7
8
9
1. According to the literature,13 the reduction power (E*ox) of fac-[Ir(ppy)3] in the photo-
excited state is –2.14 V, indicating that CF2H reagents except 1b could be smoothly
reduced by the excited Ir photocatalyst.
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
O
S
O
S
N
CF2H
– 1.79 V
1d
O
NTs
S
Ph
CF2H
1a
– 2.26 V
O
O
S
CF2H
N
7.6 A
1c
– 2.31 V
O
O
S
Ph
CF2H
1b
E*ox of fac-[Ir(ppy)3]* (– 2.14 V)
– 2.50 V
– 3
– 2
potentials vs. Cp2Fe (V)
– 1
– 0.5
Figure 1. Cyclic voltammograms of the CF2H reagents (1a–d). Measurements were
performed for DMSO solutions ([sample] = 2.0 mM, [(NBu4)PF6] = 0.10 M) with a platinum
disk (working electrode), a platinum wire electrode (counter electrode), and a Ag/AgNO3
ACS Paragon Plus Environment
10

Page 11 of 39
ACS Catalysis
1
2
3
4
5
6
reference electrode under N2 at room temperature. The scan rate was 100 mV/s. Ferrocene
(Cp2Fe) was used as a reference.
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
2.2.2. Laser flash photolysis.
To gain mechanistic insights into the variable yields of 3 dependent on 1, firstly, the
quenching rate constants (kq) of the electronically excited state fac-[Ir(ppy)3]* by the CF2H
reagents (1a–d) were evaluated. The observed decay rates (kobs) of phosphorescence from
fac-[Ir(ppy)3]* in the presence of different concentrations of each reagent 1 are
determined by the LFP method. The phosphorescence decay (excited at 355 nm and
monitored at 780 nm in DMSO at 295 K) of fac-[Ir(ppy)3]* in the presence of 1a is shown
as an example (Figure 2a, for data on the other reagents, see the Supporting Information).
The CF2H reagents except 1b significantly shortened the lifetime. The obtained kobs values
are plotted against concentrations of each reagent 1 and compiled into Figure 2b. Their
quenching rate constants (kq) were determined from the slopes in Figure 2b to be 6.7 x
107 M–1s–1 (1a), 1.7 x 105 M–1s–1 (1b), 1.3 x 108 M–1s–1 (1c), and 2.0 x 109 M–1s–1 (1d). In
addition, transient absorption spectroscopic analyses with 1a suggest that the present
phosphorescence decay was not caused by an energy transfer process but by a SET
process from fac-[Ir(ppy)3]* (see the Supporting Information).14
ACS Paragon Plus Environment
11

ACS Catalysis
Page 12 of 39
1
2
3
4
5
6
7
8
9
(a)
1.75
1.25
0.75
0.25
O
NTs
S
CF2H
Ph
1a
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
0 mM
7.1 mM
14 mM
-1
0
1
2
3
4
5
6
time (s)
(b)
O
O
14
S
N
CF2H
S
12
10
1d (kq = 2.0 x 109 M– 1s– 1
)
O
O
S
CF2H
8
6
N
1c (kq = 1.3 x 108 M– 1s– 1
)
O
NTs
k
S
Ph
CF2H
1a (kq = 6.7 x 107 M– 1s– 1
)
4
2
O
O
S
Ph
CF2H
1b (kq = 1.7 x 105 M– 1s– 1
)
0
0
0.01
0.02
0.03
0.04
0.05
concentration of CF2H reagent (M)
Figure 2. (a) Measurements of phosphorescence decay (excited at 355 nm and monitored
at 780 nm in DMSO at 295 K) of fac-[Ir(ppy)3]* in the presence of the CF2H reagent 1a. (b)
Evaluation of the quenching rate constants (kq) of fac-[Ir(ppy)3]* by each of 1a–d.
ACS Paragon Plus Environment
12

Page 13 of 39
ACS Catalysis
1
2
3
4
5
6
7
2.2.3. DFT calculations.
8
9
(a) transition state analysis for generation of ·CF2H from 1a
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
O
NTs
S
spontaneous
S– C homolysis
during refinement
Ph
CF2H
1a
(b) transition state analysis for generation of ·CF2H from 1d
∆Ea = 36.2 kJ mol– 1
O
S
O
S
N
CF2H
∆E = 19.7 kJ mol– 1
1d
Scheme 3. Reaction Diagrams for Formation of the CF2H radical from Anionic Radicals of
the CF2H Reagents (1a and 1d)
Secondly, transition state analysis for the generation of the CF2H radical from the
corresponding anionic radical species [1]·– was performed by DFT calculations (UB3LYP/6-
31G(d)/SMD-DMSO level of theory)15. Anionic radical species [1]·– should be formed by
1e-reduction of 1. Subsequent carbon–sulfur bond cleavage process leads to generation
of the CF2H radical. During refinement of the anionic radical of 1a, it spontaneously
decomposes without substantial activation energy to generate the CF2H radical (Scheme
3a). In contrast, the reactions of the other reagents (1b–d) should overcome the transition
ACS Paragon Plus Environment
13

ACS Catalysis
Page 14 of 39
1
2
3
4
5
6
7
8
9
states though not so significant (∆Ea: 5.41 kJ mol–1(1b), 23.5 kJ mol–1 (1c), and 36.2 kJ mol–1
(1d)). In addition, calculations suggest that the CF2H radical generation from 1c and 1d is
thermodynamically unfavorable (∆E: –13.7 kJ mol–1(1b), 4.99 kJ mol–1 (1c), and 19.7 kJ mol–
1 (1d)) as is shown for 1d in Scheme 3b (for data on the other reagents, see the Supporting
Information).
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
In brief summary, 1d is most susceptible to 1e-reduction among the reagents 1a–d, but
1a serves as a better CF2H radical source as mentioned above (section 2.1 Table 1 (entries
1–4)). These results suggest that, for the CF2H radical precursors, efficient S–C bond
homolysis of the electronically activated species, i.e., anionic radical species, is a more
important factor than the lower reduction potential and the faster quenching rate.
2.3. Photocatalytic Keto-Difluoromethylation of Alkenes: Preparative-Scale Flow
Synthesis.
As it was found that keto-difluoromethylation proceeds smoothly on NMR-scale
experiments (Table 1), we conducted preparative scale experiments next. In addition, to
prove synthetic utilities of the -CF2H-ketones (section 2.4.), gram-scale synthesis is
essential. Thus, we adopted the MiChS flow photoreactor L-1 (M) with a single lane (2 mm
in width, 1 mm in depth, 1.35 m in length: total volume 2.7 mL) covered with quartz.16
2.3.1. Scope of keto-difluoromethylation.
ACS Paragon Plus Environment
14

Page 15 of 39
ACS Catalysis
1
2
3
4
The scope of the present flow synthesis of the CF2H-ketones is summarized in Table 2.
5
6
7
t
Styrenes with p-substituents such as Me (2a), H (2c), Bu (2d), and halogens ( F (2e), Cl
8
9
(2f), and Br (2g)) underwent base-free keto-difluoromethylation in flow (residence time
tR= 30 min.) to give the products in good yields (3a, 3c–g: 43–67%) (entries 1, 3–7 in Table
2). In addition, ester (2h), aldehyde (2k), and pyridyl (2l) groups are compatible with the
present reaction system (3h: 66%, 3k: 44%, 3l: 15%) (entries 8, 11, 12). Reactions of
electron-rich styrene derivatives with p-substituents such as OMe (2b), OtBu (2i), and two
alkoxy substituents (2j) in the presence of sodium benzoate (1 equiv.) gave the
corresponding CF2H-ketones without significant deterioration of the yields (3b: 69%,17 3i:
49%, 3j: 66%) (entries 2, 9, 10). Furthermore, the present reaction systems could be also
applied to internal alkenes such as trans-stilbene (2m), isosafrole (2n), indene (2o), and
2-methylindene (2p) (3m: 31%, 3n: 64%, 3o: 47%, 3p: 33%) but they needed longer
residence time (entries 13–16). It should be noted that the reactions of aliphatic alkene,
4-phenyl-1-butene, and electron-deficient alkenes, acrylonitrile and methyl acrylate, did
not afford the corresponding difluoromethylated products at all. These results suggest
that the present photocatalytic system is useful for the reaction of aromatic alkenes with
a variety of functional groups such as ether, carbonyl, halogens and pyridyl groups.
Noticeably, it was found that most of CF2H-ketones 3 easily underwent
dehydrofluorination (see below) upon purification by silica gel column chromatography.18
Thus, automated flash column chromatography was performed for purification.
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
ACS Paragon Plus Environment
15

ACS Catalysis
Page 16 of 39
1
2
3
4
Table 2. Scope of the Keto-Difluoromethylation in Flowa,b
5
6
7
8
9
fac-[Ir(ppy)3]
(5 mol %)
O
R1
O
NTs
CF2H
R1 R2
Ar
S
+
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
Ar
R2
Ph
CF2H
1:1.2
2
1a
DMSO, rt
tR = 30 min.
blue LEDs
3
Entry
Substrate 2
Product 3
O
CF2H
R
R
1
2a: R = Me
3a: 67%
3b: 69%17
3c: 51%
3d: 65%
3e: 53%
3f: 56%
3g: 43%
3h: 66%
2c
3
2b: R = MeO
2c: R = H
4
2d: R = tBu
2e: R = F
5
6
2f: R = Cl
7
2g: R = Br
2h: R = AcO
2i: R = tBuO
8
9c
10c
3i: 49%
O
MeO
MeO
BnO
CF2H
BnO
2j
3j: 66%
O
H
O
O
H
11
CF2H
ACS Paragon Plus Environment
16

Page 17 of 39
ACS Catalysis
1
2
3
4
2k
3k: 44%
5
6
7
O
12
CF2H
8
9
N
N
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
2l
3l: 15%
O
13d
14c
CF2H
Ph
Ph
Ph
Ph
2m
3m: 31% (tR = 9 h)
O
Me
O
O
CF2H
Me
O
O
2n
3n: 64%
O
CF2H
R
R
15e
16e
2o: R = H
2p: R = Me
3o: 47% (tR = 60 min.)
3p: 33% (tR = 7 h)
aA mixture of photocatalyst (15 mol, 5 mol%), 1a (0.30 mmol, 1 equiv.), 2 (0.36 mmol,
1.2 equiv.) in DMSO (9.2 mL) was placed in a syringe, and was pumped into the
photoreactor at a rate of 5.4 mL/h (residence time tR = 30 min.) using a syringe pump. The
reactor was irradiated by blue LED lamps (405 nm (3.85 mW x 20), 450 nm (20 mW x 20),
470 nm (20 mW x 20)) at room temperature. bIsolated yields. cSodium benzoate (1 equiv.)
was added. d1.1 equiv. of 1a were used. e1.7 equiv. of 1a were used.
2.3.2. Gram-scale synthesis in flow and batch.
The flow system is highly beneficial for large-scale photoreaction because a thin lane
enhances transmittance of light to cause efficient light absorption.16 We conducted the
ACS Paragon Plus Environment
17

ACS Catalysis
Page 18 of 39
1
2
3
4
5
6
7
8
9
gram-scale synthesis of 3b in flow (tR = 20 min.) (Scheme 4). As a result, 3b was obtained
in a 67% yield (1.44 g) after irradiation for 21 h. When the batch reaction (200 mL-Schlenk
tube) was examined on the same scale, 3b was isolated only in a 22% isolated yield even
after prolonged reaction time, 24 h. In addition, a part of the CF2H reagent 1a still
remained unreacted (89% conversion). Furthermore, we observed formation of by-
products, which were not detected for the NMR-scale experiments (section 2.1.). Enol
benzoate 5b (vide infra) was detected as a major by-product (13%) together with CF2H-
alkene 4b (6%). Then, we investigated the stability of the product 3b in the presence of
sodium benzoate. The reaction of 3b with 2 equiv. of sodium benzoate gave 5b in a 77%
yield in a highly E-selective manner (Scheme 5a). Further investigation about the action
of triethylamine on 3b disclosed formation of E-3-fluoropropenone 6b in a 76% isolated
yield (Scheme 5b). Furthermore, 5b was formed in a 71% yield by the reaction of the
isolated 6b with 1 equiv. of sodium benzoate. These results suggest that the CF2H-ketones
3 are so unstable under basic reaction conditions as to undergo dehydrofluorination.18
These side reactions are remarkable, especially in the case of the prolonged reaction of
the batch system. On the other hand, the flow system can shorten the residence time (tR),
resulting in prevention of the secondary reactions of the product 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
ACS Paragon Plus Environment
18

Page 19 of 39
ACS Catalysis
1
2
3
4
5
flow reactor
O
NTs
O
S
CF2H
6
7
8
9
Ph
CF2H
1a
3.73 g
+
fac-[Ir(ppy)3]
(5 mol %)
PhCO2Na
(1 equiv.)
MeO
3b
flow: tR = 20 min.
DMSO, rt
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
67% isolated yield
(1.44 g)
batch reactor
MeO
batch: 24 h
2b
1.74 g
26% NMR yield
before purification
aFor detailed reaction conditions, see the Supporting Information.
Scheme 4. Application to Gram-Scale Synthesisa
Ar = 4-methoxyphenyl. aYields are isolated values.
Scheme 5. Stability of the Product Under Basic Conditionsa
2.4. Synthetic Applications of the CF2H-Ketone.
To explore usefulness of the CF2H-ketones as fluorine-containing building blocks, some
fundamental reactions with respect to the product 3b were investigated (Scheme 6). (a)
Reduction with NaBH4 afforded the corresponding CF2H-containing alcohol 7b in an 89%
ACS Paragon Plus Environment
19

ACS Catalysis
Page 20 of 39
1
2
3
4
5
6
7
8
9
yield. (b) Asymmetric reduction by 1 equiv. of oxazaborolidine catalyst ((S)-Me-CBS
catalyst)19 at 0 ˚C produced optically active CF2H-alcohol ((R)-7b) in a 73 % yield with
>99% ee. (c) -Bromoketone 8b was synthesized by bromination with [BnNMe3](Br3) (58%
yield).20 (d) The carbonyl group was protected by treatment with
ethylenedioxybis(trimethylsilane) in the presence of the Bi(OTf)3 catalyst at room
temperature21 to give the acetal product 9b in a 56% yield. (e) Silylcyanation22 afforded
cyanohydrin derivative 10b (79%). Subsequent (f) hydration of 10b followed by (g)
desilylation led to the CF2H-containing -hydroxyamide product 13b, a CF3 analogue of
which is an anticonvulsant compound.23,24 The CF2H-containing cyanohydrin 11b was also
obtained from desilylation of 10b (87% yield). These results suggest that the CF2H-
ketones 3 can serve as promising building blocks for CF2H-containing compounds under
appropriate 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
O
CBS
OH
[BnNMe3](Br3)
(c)
reduction
CF2H
Ar
CF2H
Ar
Br
(R)-7b
73%, >99% ee
(b)
8b: 58%
O
OH
Bi(OTf)3 cat.
NaBH4
(d)
O
O
Ar
CF2H
CF2H
(a)
Ar
Ar
9b: 56%
TMSO
CF2H
3b
(e)
OTMS
7b: 89%
ZnI2
TMSCN
In cat.
hydration
HO CONH2
RO CN
Ar
RO CONH2
CF2H
CF3
CF2H
Ph
(f)
Ar
anticonvulsant
activity
12b: 71% (R = TMS)
13b: 90% (R = H)
10b: 79% (R = TMS)
11b: 87% (R = H)
(g)
(g)
a
Ar = 4-methoxyphenyl. Isolated yields. For detailed reaction conditions, see the
Supporting Information. (a) NaBH4 (1.1 equiv.), EtOH, rt, 3 h. (b) (S)-Me-CBS cat (1.0 equiv.),
ACS Paragon Plus Environment
20

Page 21 of 39
ACS Catalysis
1
2
3
4
5
6
7
8
BH3•SMe2 (2.0 equiv.), THF, 0˚C, 1 h. (c) [BnNMe3](Br3) (1.4 equiv.), CH2Cl2/MeOH, 50 ˚C, 48
h. (d) TMSOCH2CH2OTMS (1.8 equiv.), Bi(OTf)3 (1 mol%), MeOH, rt, 20 h. (e) ZnI2 (1 equiv.),
TMSCN (2.5 equiv.), CH2Cl2, rt, 24 h. (f) InCl3 (5 mol%), acetaldoxime, toluene, 45 ˚C, 3 days.
(g) 1 M HCl, MeOH.
9
Scheme 6. Synthetic Applications of the CF2H-Ketone 3ba
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
2.5. Mechanistic Studies.
On the basis of the previous reports,3j,9,11,25 plausible reaction mechanisms are illustrated
in Scheme 7. The reaction sequence involving the first SET photoredox process mediated
by the Ir photocatalyst produces -CF2H-substituted carbocationic intermediate A, which
undergoes nucleophilic attack of DMSO to afford an alkoxysulfonium intermediate B.
Deprotonation from A gives CF2H-alkene by-product 4. Conversion of B into the CF2H-
ketone 3 may follow the two possible pathways: (i) Kornblum-type oxidation via the ylide
species C under basic conditions and (ii) the second SET photoredox processes via an
alkoxy radical intermediate D. In the present section, (a) detection of the CF2H radical, (b)
involvement of the photoredox processes rather than radical chain processes, and (c)
details of DMSO oxidation processes will be discussed.
ACS Paragon Plus Environment
21

ACS Catalysis
Page 22 of 39
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
Scheme 7. Plausible Reaction Mechanisms
2.5.1. The CF2H radical trap experiment.
The radical trapping experiment with TEMPO gave CF2H–TEMPO in an 86% NMR yield
(Scheme 8), supporting involvement of the ·CF2H radical in the present reaction.
aThe reaction conditions were identical to those of entry 1 in Table 1 except for addition
of TEMPO.
Scheme 8. Radical Trap Experimenta
ACS Paragon Plus Environment
22

Page 23 of 39
ACS Catalysis
1
2
3
4
2.5.2. Photoredox processes vs. radical chain processes.
5
6
7
8
9
To clarify involvement of radical chain processes (noncatalytic reduction of 1a by E), (i)
an intermittent light irradiation experiment and (ii) determination of the quantum yield of
the reaction were carried out. As shown in Figure 3, the present photocatalytic reaction
proceeded only during the visible light irradiation periods. In addition, the quantum yield
of the photocatalytic keto-difluoromethylation of 1a with 2a was 0.28 (Scheme 9). These
results indicate that the present reaction does not proceed through radical chain
processes as a main component, but through photoredox processes.
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
O
standard conditionsa
O
NTs
CF2H
S
+
425 nm blue LEDs
Ph
CF2H
Me
Me
1a
2a
3a
1:1.2
or
ON
OFF
100
80
OFF
ON
OFF
60
40
20
ON
OFF
ON
0
0
20
40
60
time (min.)
80
100
120
ACS Paragon Plus Environment
23

ACS Catalysis
Page 24 of 39
1
2
3
4
Figure 3. Intermittent light irradiation experiment. aThe reaction conditions were identical
5
6
7
to those of entry 1 in Table 1 except for light irradiation.
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
aFor detailed procedures, see the Supporting Information.
Scheme 9. Determination of Quantum Yielda
2.5.3. Detection of dimethylsulfides.
In general, DMSO oxidation accompanies formation of dimethylsulfide. Monitoring the
reaction in the presence of sodium benzoate (entry 10 in Table 1) by 1H NMR spectroscopy
revealed that the CF2H-ketone 3b was formed from alkene 2b without detection of any
intermediates such as the alkoxysufonium salt B shown in Scheme 7. Furthermore, the
characteristic quintet signal at 2.00 ppm (2JHD = 1.8 Hz) indicates formation of
dimethylsulfide-d5 (Figure 4). In contrast, under the base-free reaction conditions (entry1
1
in Table 1), the signal of dimethylsulfide-d5 was not detected by H NMR spectroscopy,
indicating formation of dimethylsulfide-d6, which was confirmed by GC-MS analysis of the
ACS Paragon Plus Environment
24

Page 25 of 39
ACS Catalysis
1
2
3
4
5
6
7
8
9
reaction mixture (Scheme 10) (see the Supporting Information). These results indicate that
the reaction in the presence of base (entry 10 in Table 1) follows Kornblum oxidation (path
(i) in Scheme 7). For path (ii), see the next section.
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
Figure 4. 1H NMR spectra of the reaction of 2b in the presence of PhCO2Na. aThe reaction
conditions were identical to those of entry 10 in Table 1. Ar = 4-methoxyphenyl.
aThe reaction conditions were identical to those of entry 1 in Table 1. Ar = 4-
methylphenyl.
Scheme 10. Detection of Dimethylsulfide in Keto-Difluoromethylation under Base-free
Conditions
ACS Paragon Plus Environment
25

ACS Catalysis
Page 26 of 39
1
2
3
4
5
6
7
2.5.4. Reaction of -alkylstyrene.
8
9
It should be noted that the reaction of -cyclohexylstyrene (2q) gave the parent -
CF2H-ketone 3c in an 65% NMR yield, resulting from C–C bond cleavage (Scheme 11).
Elaborative examination revealed that the eliminated cyclohexyl group was converted into
the corresponding dimethylsulfonium salt 14, which was characterized by NMR and ESI-
MS spectroscopies (see the Supporting Information). The present C–C bond cleavage
process should follow -scission of alkoxy radical D formed by 1e-reduction of B and O–
S bond homolysis, and the resultant cyclohexylradical is converted to 14 through 1e-
oxidation processes and reaction with dimethylsulfide-d6. The reduction potential of the
styrene derivative B was estimated by the theoretical method26 to be Ecalc = –0.43 vs. Cp2Fe
in MeCN, suggesting that fac-[Ir(ppy)3]* can reduce B (see the Supporting Information).
These results support occurrence of the reaction pathway (path(ii) in Scheme 7) involving
alkoxy radical.
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
ACS Paragon Plus Environment
26

Page 27 of 39
ACS Catalysis
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
Scheme 11. Reaction of -Alkylstyrene.
3. CONCLUSION
We have developed the first example of operationally simple and step-economical
synthesis of -CF2H-substituted ketones from readily available aromatic alkenes through
keto-difluoromethylation mediated by photoredox catalysis. The combination of the fac-
[Ir(ppy)3] catalyst and N-tosyl-S-difluoromethyl-S-phenylsulfoximine (1a) turns out to be
a key to the successful transformation. Efficient radical generation depends not only on
redox balance between the excited photocatalyst and the precursor relevant to 1e-
reduction but also on the easiness of the homolytic bond cleavage process from the
resultant anionic radical species. In addition, the flow system is efficient for gram-scale
production of the CF2H-ketone 3 because of (i) efficient of light absorption and (ii)
prevention of the secondary reactions of the product. The additive effect of sodium
benzoate reveals occurrence of two mechanisms for the present keto-difluoromethylation.
ACS Paragon Plus Environment
27

ACS Catalysis
Page 28 of 39
1
2
3
4
5
6
7
8
9
The obtained CF2H-ketone is regarded as a promising synthetic intermediate for CF2H-
containing molecules because it can be applied to typical transformation of the carbonyl
group such as reduction, -bromination, and cyanation. Further studies on photocatalytic
difluoromethylation are underway in our laboratory.
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
AUTHOR INFORMATION
Corresponding Authors
*E-mail: koike.t.ad@m.titech.ac.jp & *E-mail: makita@res.titech.ac.jp
Present Addresses
†Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo
Institute of Technology, R1-27, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503,
Japan
‡School of Material and Chemical Technology, Tokyo Institute of Technology, R1-27,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
§ Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1
Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
ACS Paragon Plus Environment
28

Page 29 of 39
ACS Catalysis
1
2
3
4
Notes
5
6
7
8
9
The authors declare no competing financial interest.
ASSOCIATED CONTENT
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
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Experimental procedures, characterization, crystallographic data of 3b, photo- and
electro-chemical experiments, laser flash photolysis, control experiments, DFT calculations
and 1H, 13C, and 19F NMR spectra (PDF)
ACKNOWLEDGMENT
The authors thank the JSPS (KAKENHI Grants 22350026, JP16H06038, and JP18H04241
in Precisely Designed Catalysts with Customized Scaffolding), JST CREST (Grant Number
JPMJCR18R4) and the Naito Foundation. This work was performed under the
Cooperative Research Program of the “Network Joint Research Center for Materials and
Devices”.
ABBREVIATIONS
DMSO, dimethyl sulfoxide; LHMDS, lithium hexamethyldisilazide; DDQ, 2,3-dichloro-5,6-
dicyano-p-benzoquinone; Me-DAST, N,N-dimethylaminosulfur trifluoride, ppy, 2-
pyridylphenyl; bpy, 2,2’-bipyridine; dtbbpy, 4,4’-di-tert-butyl-2,2’-bipyridine; TEMPO,
2,2,6,6-tetramethylpiperidine 1-oxyl; tBu, tertiary butyl; nBu, normal butyl; Bn, benzyl; Me,
ACS Paragon Plus Environment
29