Transition-metal-free C-H oxidative activation: Persulfate-promoted selective benzylic mono- and difluorination

Article abstract of DOI:10.1039/c4ob02418d

An operationally simple and selective method for the direct conversion of benzylic C-H to C-F to obtain mono- and difluoromethylated arenes using Selectfluor as a fluorine source is developed. Persulfate can be used to selectively activate benzylic hydrogen atoms toward C-F bond formation without the aid of transition metal catalysts.

Full text of DOI:10.1039/c4ob02418d

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ARTICLE TYPE
Transition-Metal-Free C-H Oxidative Activation: Persulfate-Promoted
Selective Benzylic Mono- and Difluorination
Jing-jing Ma[a], Wen-bin Yi[a]*, Guo-ping Lu[a] and Chun Cai[a]
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Scheme 1 Persulfate-promoted benzylic C-H fluorination.
An operationally simple and selective method for the direct
conversion of benzylic C-H to C-F to get the mono- and
difluoromethylated arenes using SelecfluorTM as a fluorine
source was developed. Persulfate can be used to selectively
10 activate benzylic hydrogen atoms toward C-F bond formation
without the aid of transition metal catalysts.
Fluorine-containing molecules are of particular interest in the
fields of pharmaceuticals, perfumes, flavorings, dyes, agricultural
15 chemicals, monomers, and polymers, as well as many other
applications due to fluorine’s low surface energy,
biocompatibility and extreme hydrophobic properties.1 For
instance, monofluoromethyl (-CFH2) and difluoromethyl (-CF2H)
arenes have been used as oxygen mimics in molecules such as
20 nucleotides, phosphate esters and sulfate esters.2-3 Recently, a
variety of methods have been successfully developed for the
preparation of these fluorine-containing compounds, including
functional group transformation, transition-metal-catalyzed C-H
insertion/abstraction4-8 and direct benzylic C-H fluorination.9-18
25 Direct benzylic C−H fluorination is an ideal protocol for the
synthesis of fluoromethylarenes without prior installation of a
functional group at the reaction site. There are two main
strategies of direct benzylic C−H fluorination: transition-metal-
catalyzed C-H activation9-15 and radical (induced via
30 organocatalysts and visible light) reactions under transition-
metal-free conditions.16-18
55
different functional groups applying residence times below 30
min.18
With our interest in radical fluorination systems that use simple
and relatively cheap reagents, we found recently that this stable,
60 inexpensive,19 and commercially available potassium persulfate
can smoothly promote direct benzylic C-H fluorination to form
mono- and difluoromethylated arenes under transition metal free
conditions using SelectfluorTM(1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), A) as fluorine
65 source. To the best of our knowledge, there is no example using
such a simple and easily system for oxidative C-H fluorination
(Scheme 1).
Our initial investigations were focused on the mono-
fluorination of benzylic C-H bonds promoted by persulfate,
70 which is a well-known economic and efficient radical initiator.20
1a was selected as a standard substrates to carry out this
monofluorination reaction, and a set of conditions were screened
(Table1). The best results was achieved by using 1.5 equiv. of
The challenge of direct C-F functionalization of benzylic sp3
C-H bonds has been overcame using copper(I) or iron(II)
catalysts by Lectka’s group in recent two years.9-10 In 2012, a
35 Pd(OAc)2-catalyzed direct fluorination of functionalized 8-
methylquinolinyl substrates in the presence of hypervalent iodine
and silver fluoride (AgF) via redox process was reported by
Sanford and co-workers.11,12Groves et al. developed a late stage
method for C-H fluorination with [18F]fluoride for PET imaging
40 by using Mn(Salen)OTsas F-transfer catalyst, enabling the facile
labeling a variety ofbioactive molecules and building blocks with
monofluorobenzylic group in 2014.13,14 Tang’s group reported the
SelectfluorTM
and 1.5 equiv. of potassium persulfate in
75 MeCN/H2O (v/v=1:1) at 80 ℃ for 4 h, giving 4'-fluoromethyl-2-
cyanobiphenyl (2a) in 84% yield (entry 4).There was only trace
of product could be detected at 45 ℃ by GC-MS (entry 1)
indicating that the fluorination is temperature-dependent. Lower
yields were obtained by reducing the content of fluorine source
80 and persulfate (entries 2-3). It was found that difluorination
product occurred when the loading of SelectfluorTM was increased
(entry 5). K2S2O8/AgNO3 system, which is already known for the
C-H activation,21 did not significantly improve this reaction (entry
6). Beside the potassium persulfate, other persulfates were also
85 screened, but there was no obvious difference was found (entries
7-8), which proved that S2O82- plays a crucial role in this reaction.
In terms of different fluorination reagents, it was found that
SelectfluorTM (II)(1-methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]
octanebis(tetrafluoroborate), B) could also give the corresponding
90 product with satisfactory yield (entry 9). Other electrophilic
2-
difluorination of benzylic C-H under Ag(I)/S2O8 co-catalytic
system, in which the benzylic radical model induced by persulfate
45 oxidative intermediate Ag(Ⅱ) was proposed.15 Metal-free
fluorination of C(sp3)-H bonds using a catalytic N-oxyl radical
was reported by Inoue et. al. in 2013.16 Chen and co-workers first
demonstrated a visible light promoted metal-free C-H activation
in the presence of diarylketone to selectively form mono- and
50 difluoromethylarenes in 2013.17 Very recently, Kappe found a
light-induced fluorination of benzylic compounds bearing
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Table 1 Screenings of the monofluorination
Table 2 Scope of K2S2O8-promoted the monofluorination
Entry
Promoter
[F](eq.)
Yield (%)
T (℃)
1
2
3
4
5
6
7
8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
A(1.5)
A(0.5)
A(1.0)
A(1.5)
A(2.0)
A(1.5)
A(1.5)
45
80
80
80
80
80
80
80
80
80
RT
80
80
Trace
37
61
84
71
85b
81
82
83
Trace
N.D.a
N.D.a
N.D.a
(NH4)2S2O8 A(1.5)
9
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
B(1.5)
C(1.5)
D(1.5)
AgF(1.5)
LiF(1.5)
10
11
12
13
Reaction condition: 1a (0.2 mmoL) in MeCN/H2O (1:1, 4 mL),
isolated yield; a not detected by GC-MS; b 0.1 equiv. of AgNO3 was
added.
fluorination reagent, such as NSFI (N-fluorobenzenesulfonimide,
C), could not serve as efficient fluorination reagents to produced
fluorinated arene 2a and only trace of fluorinated product could
be detected (entry 10). No fluorinated product was observed in
the reaction with nucleophilic fluorination reagent DAST (diethyl
-aminosulfurtrifluoride, C) and metal fluoride AgF and LiF
5
Reaction condition: 1 (0.2 mmoL), A (1.5 equiv.) and K2S2O8 (1.5
equiv.) in MeCN/H2O (v/v = 1:1, 4 mL), isolated yield; a 1H-NMR
yield based on 1c; b GC yield (challenging to get purification due to
high volatility and the reported yields are the average GC yields of
three trials and determined by 19F-NMR).
10 (entries 11-13).
The scope of reactions promoted by the K2S2O8 system under
the optimize conditions described above were explored. As the
results displayed in Table 2, a wide variety of functional groups,
including cyanide (2a), phenyl (2b-2c), tert-butyl (2d), ketones
15 (2e-2g), halos (2h-2j), derivatives of carboxylic acid (2k-2m）
were tolerated in the reaction, and the monofluorinated products
were obtained in moderate to good yields. However, benzyl
bromide and anisole failed to give the desired outcome (2o-2p).
Steric hindrance was shown to significantly affect the efficacy of
20 the fluorinations and demonstrated by the reactions of the three
nitrotoluene isomers (2q-2s) (o: m: p = 49% : 68% : 87%). α-
branched benzylic substrates, afforded the corresponding mono-
fluorinated products (2t-2v) smoothly. However, the present
method did not work for α,α-disubstituted benzylic arenes, such
25 as isopropyl benzene. Fused cyclic compounds 2-methyl
-anthracene-9,10-dione and 8-methylquinoline were also
investigated, providing the desired fluorinated products 2w and
2x in 48% and 80% respectively.
35
Table 3 Screenings of the difluorination
Entry
K2S2O8 (eq.)
A (eq.)
Yield (2a/3a, %)
71/13
41/26
15/50
0/75
1
2
3
4
5
1.5
2.5
3
3
4
2
2
2
3
4
0/63
We suspected that the difluorinated product could be obtained
30 by increasing of the amount of SelectfluorTM and K2S2O8 and
difluorination could be easily achieved in 75% yield in the
presence of 3 equiv. of fluorination regent and K2S2O8 with no
Reaction condition: 1a (0.2mmoL), MeCN/H2O (v/v = 1:1, 4 mL),
isolated yield.

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Scheme 2 Radical trapping experiment
monofluorinated product being detected (entry 4). Further
30
increasing the content of fluorination reagent and persulfate led to
oxidation byproducts (entry 5).
5
Table 4 Scope of K2S2O8-promoted the difluorination
results demonstrate that such a fluorination process may involve a
radical reaction mechanism.
35
Figure 1 Persulfate-promoted competitive benzylic oxidation and
fluorination.
40
To better understand this temperature-dependent fluorination,
which was shown by Figure 1, competitive mechanism between
the oxidation and fluorination was systematically studied using
the model reaction of Scheme 2 monitored by GC-MS. The
45 compound distribution in the reaction mixture at different
temperature shown in Figure 1 indicates the oxidation product 4a
dominates the reaction below 60 ℃ and then slowly decreased to
<1% yield at 80℃, while the GC yield of fluorination product 2a
dramatically increases to 87% at 80℃from 8% at 60 ℃.
Reaction condition: 1 (0.2 mmoL), A (3.0 equiv.) and K2S2O8 (3.0
a
equiv.) in MeCN/H2O (v/v =1:1, 6 mL), isolated yield; GC yield50
Scheme 3The fluorination of 4-phenylbenzaldehyde
based (challenging to get purification due to high volatility and the
reported yields are the average GC yields of three trials and
determined by 19F-NMR)
Under the new conditions, a broad range of substrates can be
10 difluorinated cleanly (Table 4). A variety of substituent groups
(cyanide, 3a; tert-butyl, 3b; ketones, 3c-3e; halos, 3f-3g;
carboxylic acid derivatives, 3h-3k; phenyls, 3n-3p) on the
aromatic ring can be tolerated. Similar to the monofluorination
reaction, steric factors have a significant effect on the outcome
15 shown by o-nitrotoluene (3m, 0%) and biphenyl cases (3n-3p)(o :
m : p = 41% : 42% : 96%). Ethyl-4-nitrobenzoate and 1-(4-
ethylphenyl)ethanone, as α-branched benzylic substrates, were
also difluorinated to the desired products (3p-3q). However,
diphenylmethane failed to deliver difluorinated product (3s). 8-
20 methylquinine provided the difluoromethyl product in 61% yield
(3r).
Scheme 4The one-pot two step fluorination
55
Attempts were made to obtain insights into this reaction. Tetra-
methylpiperidine N-oxide (TEMPO) and 1,1-diphenylethylene
25 (diyldibenzene), two typical radical scavengers, were employed
in the reaction (Scheme 2). Although no trapped products could
be isolated, the incorporation of scavengers at any point during
the reaction was found to inhibit the reaction (Table 3). These
The reaction of 4'-formyl-[1,1'-biphenyl]-2-carbonitrile failed
to give the corresponding fluorinated products (Scheme 3),
60 proving experimentally that aldehyde is not an intermediate for
the fluorination22. The sequence of this persulfate-promoted

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DOI: 10.1039/C4OB02P41a8gDe 4 of 4
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protocol (Scheme 4).
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Figure 2 The plausible mechanism for persulfate-promoted
benzylic C-H fluorination
5
60
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19 The price of the >90% potassium persulfate on Sigma Aldrich is
$282.47/Kg.
Although the precise reaction mechanism remains to be
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10 clarified, we prefer a plausible radical mechanism is shown in
-
Figure 2. Firstly, a benzylic hydrogen is abstracted by a SO4
75
radical, which is generated from the homolytic cleavage of
persulfate23, gives rise to a benzylic radical 5. Next, a fluorine
atom is transfered to the benzylic radical 5 to provide the
15 monofluoride product 2. Difluorinated arenes were formed
according ananalogous protocol via a fluorinated benzylic radical
6.
In conclusion, we have disclosed a direct benzylic C-H
20 fluorination under transition-metal-free conditions in the presence
of cheaper and readily available potassium persulfate. By
modulating the amounts of SelectfluorTM and persulfate, mono-
and difluoromethylarenes could be selectively obtained in
moderate to good yields. Further studies on the application to
25 other fluorinations are currently undergoing in our laboratory.
85
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Notes and references
We thank the Fundamental Research Funds for the Central Universities
30 (30920130111002), National Natural Science Foundation of China
(21476116), Natural Science Foundation of Jiangsu (BK20141394). We
also thank the Center for Advanced Materials and Technology for
financial support.
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