Visible light-promoted metal-free sp3-C-H fluorination

Article abstract of DOI:10.1039/c4cc05650g

Photoexcited acetophenone can catalyze the fluorination of unactivated C(sp³)-H groups. While acetophenone, a colorless oil, only has a trace amount of absorption in the visible light region, its photoexcitation can be achieved by irradiation with light generated by a household compact fluorescent lamp (CFL). This operational simple method provides improved substrate scope for the direct incorporation of a fluorine atom into simple organic molecules. CFL-irradiation can also be used to promote certain classic UV-promoted photoreactions of colorless monoarylketones and enones/enals.

Full text of DOI:10.1039/c4cc05650g

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Visible light-promoted metal-free sp3-C–H
fluorination†
Cite this: Chem. Commun., 2014,
50, 11701
Ji-Bao Xia, Chen Zhu and Chuo Chen*
Received 23rd July 2014,
Accepted 14th August 2014
DOI: 10.1039/c4cc05650g
www.rsc.org/chemcomm
Photoexcited acetophenone can catalyze the fluorination of unacti- N-oxyl radical and silver salts can catalyze or promote C–H
vated C(sp3)–H groups. While acetophenone, a colorless oil, only has a fluorination. More recently, photolytic activation methods have
trace amount of absorption in the visible light region, its photoexcita- also been reported by Britton,12 Lectka,8c and Tan13 using
tion can be achieved by irradiation with light generated by a household decatungstate, 1,2,4,5-tetracyanobenzene (TCB), and anthra-
compact fluorescent lamp (CFL). This operational simple method quinone (AQN) as the catalyst, respectively.
provides improved substrate scope for the direct incorporation of a
We have been interested in developing vanadium and ketone
fluorine atom into simple organic molecules. CFL-irradiation can also catalysts for C–H fluorination reactions.3 Previously, we showed
be used to promote certain classic UV-promoted photoreactions of that CFL-irradiation14 could activate 9-fluorenone, a yellow solid,
colorless monoarylketones and enones/enals.
to catalyze the benzylic fluorination of ethylbenzene (1) with
Selectfluor to give 3 (Table 1, entries 1 and 2).3a Intriguingly,
Direct C–H functionalization is a powerful new method for small- we recently found that the photolytic fluorination of 4-ethyl-
molecule synthesis.1,2 Recently, we have reported that visible light acetophenone (2) did not require 9-fluorenone (entries 3 and 4).
can activate diarylketones to catalyze C(sp3)–H fluorination at We suspected that CFL-irradiation led to the photoexcitation of
benzylic positions.3a 9-Fluorenone catalyzes benzylic C–H mono- 2. The resulting diradical-like 2* mediated this C–H fluorination
fluorination while xanthone catalyzes benzylic C–H difluorination reaction by abstracting a benzylic hydrogen atom from another
(Fig. 1a). We now show that the violet light (375–400 nm) generated molecule of 2. Subsequent fluorine atom transfer from Select-
by a household compact fluorescent lamp (CFL) can activate fluor gave 4.
acetophenone, a monoarylketone, to catalyze the fluorination of
unactivated C(sp3)–H groups (Fig. 1b). Acetophenone is a colorless
oil that has only a trace amount of absorption above 375 nm (n - p*
transition lmax B 325 nm). Herein, we demonstrate that CFL-
irradiation (4375 nm) can effectively promote its photoexcitation.
We further show that certain classic UV-promoted photoreactions
of monoarylketones and enones/enals can also be induced by
CFL-irradiation.
Several catalytic C–H fluorination reactions have been devel-
oped to introduce fluorine atoms directly without prior func-
tionalization.4–13 For example, the Sanford,4 Yu,5 and Doyle6
groups have each reported an efficient palladium catalyst
system while the Groves7 and the Lectka8 groups have disclosed
a manganese and a copper catalyst system, respectively. The
Inoue,9 Tang,10 and Hartwig11 groups have also shown that the
Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas,
75390, USA. E-mail: Chuo.Chen@UTSouthwestern.edu; Fax: +1 214 6480320;
Fig. 1 Photolytic C–H fluorination reactions catalyzed by photoexcited
arylketones. The reactivity and selectivity of the catalysts can be tuned by
the ketone substituent groups.
Tel: +1 213 6485048
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc05650g
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Table 1 Effects of the light source and the ketone catalyst on the benzylic
fluorination of 1 and 2
Table 2 Effects of the catalyst on the fluorination of 5a
Entry 5 (equiv.)
Yieldb (%)
90
R = CH3, X = OMe 82
R = CH3, X = NO2 18
Ketone catalyst
Entry Substrate Catalyst
Light source
Time Yieldi (%)
1
2
3
4
5
23
23
23
23
23
R = CH3, X = H
1
2
3
4
5
6
7
8
1
1
2
2
2
2
2
1
1
1
1
1
1
1
1
1
9-Fluorenone 1 Â CFLa
9-Fluorenone 1 Â CFLa
24 h
24 h
24 h
30 h
89 (85) j
0
—
1 Â CFLa
R = CF3, X = H
R = H, X = H
63
59
80 (76) j
89
—
—
—
—
1 Â CFLa
16 Â RPR-3000 Åb 30 min 46
6
7
8
23
23
23
X = H
X = OMe
X = NMe2
78
76
17
16 Â RPR-3500 Åc 1 h
16 Â RPR-4190 Åd 6 h
73
96
88
70
0
85
61
50
0
Acetophenone 16 Â RPR-4190 Åd 6 h
Acetophenone 16 Â RPR-4190 Åd,e 20 h
Acetophenone 16 Â RPR-4190 Åd, f 20 h
9
9
10
11
23
23
5
X = —
X = O
X = O
75
87
81
10
11
12
13
14
15
16
Acetophenone 1 Â violet LED g
Acetophenone 1 Â CFLa
Acetophenone 1 Â CFLa,e
Acetophenone 1 Â CFLa, f
3 h
20 h
20 h
20 h
20 h
24 h
12
13
14
5
1.5
1.0
88
76
59
Acetone
1 Â CFLa
0
0
Acetophenone —h
a
Reaction conditions: 0.01 mmol catalyst, 0.2 mmol Selectfluor, 2 mL
a
b
c
19 W, household lamp. 21 W, 250–375 nm. 24 W, 300–420 nm.
CH3CN. Determined by 19F NMR using C6H5F as an external standard.
b
d
e
f
375–465 nm. With a 375 nm longpass filter. With a 400 nm long-
pass filter. 9 W, 370–405 nm. 50 1C. Determined by 19F NMR using
C6H5F as an external standard. Isolated yield.
g
h
i
j
heating the solution at 50 1C in the dark (entry 16). Therefore,
we believe that short violet light (375–400 nm)16 could effec-
4-Ethylacetophenone (2) is a monoarylketone that has no tively promote the photoexcitation of acetophenone under the
apparent absorption above 375 nm (n - p* transition lmax
B
regular reaction conditions.
325 nm). Its photoexcitation has been traditionally carried out
We envisioned that, with a larger n/p* energy gap, acetophenone
by irradiation with o360 nm UV light. Indeed, UV-irradiation would be more reactive than diarylketones toward unactivated C–H
improved the quantum yield significantly but also promoted groups. To test this hypothesis, we examined the fluorination of
considerable decomposition (entries 5 and 6). In contrast, cyclohexane (5) catalyzed by a series of different ketones (Table 2).
irradiation with violet light (375–465 nm, lmax 419 nm) resulted Indeed, acetophenone was found to be the most effective catalyst
in a clean transformation (entry 7), suggestive of productive (entry 1). Introducing a methoxy group to acetophenone led to a
absorption at 4375 nm.
slightly reduced catalyst activity (entry 2) while adding a nitro group
Because acetophenone and 4-ethylacetophenone (2) have resulted in a low yield of 6 (entry 3). Trifluoroacetophenone and
very similar UV absorption spectra, we hypothesized that violet benzaldehyde are also less effective catalysts (entries 4 and 5).
light could also activate acetophenone to catalyze the benzylic Consistent with our previous observations, benzaldehyde reacted
fluorination of ethylbenzene (1). Indeed, a clean fluorination with Selectfluor to give benzoyl fluoride under the reaction
occurred to give 3 in 88% yield when irradiating a solution of conditions.3a,17 Benzophenones and 9-fluorenone were less effec-
1 with violet light (375–465 nm) in the presence of 5 mol% tive despite significantly better absorption (entries 6–9). Xanthone
acetophenone and 2 equiv. Selectfluor (entry 8).
was nearly as good as acetophenone when a large excess of 5 was
Similar to 2, acetophenone is a colorless oil that has no used (entry 10). However, acetophenone showed better catalyst
apparent absorption above 375 nm. To exclude the possibility activity when the amount of 5 was reduced to 5 equiv. (entries 11
of UV-contamination,15 we repeated the fluorination of 1 cata- and 12). The substrate to Selectfluor ratio could be further
lyzed by acetophenone (reagent grade, 498%; analytical grade, reduced to B1.5 : 1 for acetophenone (entries 13 and 14).
Z99.5%; or freshly redistilled from calcium hydride) in the
The scope of this acetophenone-catalyzed photolytic C–H
presence of a 375 nm longpass filter. The reaction proceeded fluorination reaction is shown in Fig. 2. The fluorination of
slower but smoothly (entry 9). Consistently, using a 370–405 nm cycloalkanes proceeded smoothly. Monofluorides 7–10 were
LED flashlight as the light source led to the formation of 3 in obtained in good yields with only a small (B5%) amount of
85% yield in only 3 h (entry 11). No reaction occurred in the difluorination products as judged by the 19F NMR spectra of the
presence of a 400 nm longpass filter (entry 10). CFL-irradiation crude reaction mixtures. The site selectivity of this reaction
also promoted the acetophenone-catalyzed benzylic fluorina- follows the general trend of innate C–H oxidation reactions
tion of 1 in the presence of a 375 nm filter but not a 400 nm (31 4 21 4 11).18 For example, the fluorination of norbornane
filter (entries 12–14). No reaction occurred when using acetone provided 11 with good regio- and stereoselectivity (exo/endo =
(n - p* transition lmax B 280 nm) as the catalyst (entry 15) or 15/1) because of hyperconjugation effects.18a The fluorination
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of propionic acid, butyric acid, and isovaleric acid gave 12, 13,
and 14 in o5%, 55%, and 81% yield, respectively. The b- and
g-positions of cycloheptanone were fluorinated at comparable
rates (b : g = 1 : 1). While attempts to isolate b-fluorocyclo-
heptanone (15-b) resulted in elimination of the fluoride,
g-fluorocycloheptanone (15-g) could be isolated in 35% yield.
Fluorination of N-phthaloyl-L-valine methyl ester gave 16 in 85%
yield. Monoterpenes 1,4-cineole and L-menthone reacted selec-
tively at the tertiary positions to give 17 and 18 in 73% and 71%
yield, respectively. We have also re-examined the fluorination
of N-phthaloyl-L-valine and L-menthone under UV-irradiation
(250–375 nm) conditions. The reactions proceeded significantly
faster but the products degraded under the reaction conditions,
leading to low yields (o40%) of 16 and 18.
Fig. 3 Site selectivity of the acetophenone-catalyzed photolytic C–H
fluorination reaction. Reaction conditions: CFL-irradiation, 19 (5.0 equiv.),
20 and 21 (1.5 equiv.), acetophenone (5 mol%), Selectfluor (1.0 equiv.).
We have used hexane (19), 2-hexanone (20), and sclareolide
(21) to further study the site selectivity of this acetophenone-
catalyzed photolytic C–H fluorination reaction (Fig. 3). The
fluorination of 19 occurred primarily on the methylene groups
(C1 : C2 : C3 = 1 : 17 : 7). Introducing a carbonyl group deacti-
vated the C3 methylene group, rendering the C4 and C5
methylenes the only detectable reaction sites of 20 (C4 : C5 =
1 : 1.3). Similar to other innate radical C–H oxidation reac-
tions,7a,18 sesquiterpenoid 21 reacted predominately at the C2
position (C2/C3 = 3.6/1).
Mechanistically, it is rather intriguing that CFL-irradiation could
promote the photoexcitation of acetophenone that is a colorless oil.
Recently, the Melchiorre and Bach groups have demonstrated that
Lewis base and Lewis acid can react with carbonyl groups to induce
a bathochromic shift.19 However, we did not observe significant
Fig. 4 The R band (n - p* transition) of acetophenone extends to
B400 nm at high concentrations.
bathochromic shift when mixing acetophenone, benzophenone, or 9-fluorenone with Selectfluor and 1 in acetonitrile (Fig. 4 and ESI†),
indicating that the photoexcitation of acetophenone was not
facilitated by Selectfluor through a fluoronium transfer. In contrast,
we detected a trace amount of absorption between 375 and 400 nm
with acetophenone at high concentrations. We thus believe that
this weak absorption is responsible for driving this C–H fluorina-
tion reaction.20
We believe that, similar to our previous fluorenone-catalyzed
fluorination reactions,3a acetophenone functioned as a C–H
abstraction catalyst instead of an electron- or energy-transfer
catalyst.8c,13 To test this hypothesis and to further exclude the
possibility that Selectfluor reacted with acetophenone to form a
transient reactive species not detectable by UV, we examined if
CFL-irradiation could also promote unimolecular C–H abstraction
of monoarylketones. Indeed, CFL-irradiation induced the Norrish
type II cleavage and Norrish–Yang cyclization of valerophenone
(22) (n - p* transition lmax B 325 nm) to give 23–26 (Fig. 5).
Addition of trifluoroacetic acid did not accelerate these reactions
or cause a bathochromic shift of the R band of 22, indicating
that the photoactivation of 22 was not promoted by adventitious
acid protonating its carbonyl group. Furthermore, results of the
light–dark cycle experiments suggest that acetophenone-catalyzed
fluorination of cyclooctane is not a free radical chain reaction
(ESI†).21 The unimolecular photoreaction of 22 further suggests
that acetophenone can function as a C–H abstraction catalyst
instead of a photosensitizer in activating Selectfluor toward C–H
abstraction.8d,13
Fig. 2 Scope of the acetophenone-catalyzed photolytic C–H fluorination
a
reaction. endo-2-Fluoronorbornane was also formed in 4% NMR yield.
b
c
Isolated as the corresponding benzyl ester.
Substrate (1.0 equiv.),
d
Selectfluor (1.5 equiv.). Acetophenone (20 mol%).
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(UT Southwestern) for repeating and confirming the reactions in
Fig. 4 and 5.
Notes and references
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Fig. 6 CFL-irradiation promoted photoreactions of 27 and 30.
Further support for the hypothesis that CFL-irradiation can
promote the photoexcitation of simple monoarylketones follows
the observation that CFL-irradiation could also promote photo-
reactions of colorless enones/enals (n - p* transition lmax
B
9 Y. Amaoka, M. Nagatomo and M. Inoue, Org. Lett., 2013, 15, 2160.
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16 Light in the range of 375–400 nm has been referred to as both UV
and visible light.
In conclusion, we have shown that, despite low quantum
yields, short violet light (375–400 nm) generated by a low-energy
household CFL can promote photoreactions of monoarylketones
and enones/enals that have an R band lmax B 320 nm.
By avoiding the harmful high-energy UV light, these photoreac-
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lysis method, photoexcited acetophenone can be readily gener-
ated to catalyze the fluorination of unactivated C(sp3)–H groups.
This new fluorination reaction is operationally simple and
utilizes a cheap, readily available catalyst. Further investigation
of the utility of this photolytic fluorination method is underway.
Financial support was provided by NIH (NIGMS R01-
GM079554), the Welch Foundation (I-1596) and UT Southwestern.
We thank Mr Wenhan Zhang of Prof. Joeseph Ready’s lab
´
´
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21 These experiments do not exclude that possibility that a radical
chain reaction with non-negligible rates of chain termination is
operating.
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