Visible-light-initiated difluoromethylation of arene diazonium tetrafluoroborates

Article abstract of DOI:10.1039/c6cc00177g

A mild and efficient method for the radical addition of α-aryl-β,β-difluoroenol silyl with arene diazonium tetrafluoroborates at room temperature has been disclosed, which involves an innate radical long chain cycle, so only a small amount (0.05 mol%) of photocatalyst and a short light exposure time are required as radical initiators. A proposed mechanism for the transformation is also illustrated based on the results of control experiments and quantum calculations. A variety of α-aryl-α,α-difluoroketones were formed in moderate to high yields, and can be easily further transformed into various difluoromethylarenes under basic conditions.

Full text of DOI:10.1039/c6cc00177g

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Visible-light-initiated Difluoromethylation of Arene Diazonium
Tetrafluoroborates †
Ye-bin Wu a, Guo-ping Lu* a, Bao-jing Zhou a, Mei-jie Bu a, Li Wan c, and Chun Cai* a,b
He sort of agreedReceived 00th
January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild and efficient method for the radical addition of α-aryl-β,β- reactions (Scheme 1).4,5 Although remarkable progresses have
difluoroenol silyl with arene diazonium tetrafluoroborates at been made, the problems still exist, such as elevated
room temperature has been disclosed, which contains an innate temperatures, long reaction time and high catalyst loadings.
long chain cycle so only small amount (0.05 mol%) of Therefore, it is still urgent to develop a milder and more
photocatalyst and short timescale light are required as an radical environment friendly transformation for this.
initiator. A proposed mechanism of the transformation is also
O
R1
illustrated based on the results of control experiments and
quantum calculations. A variety of α-aryl-α,α-difluoroketones
were formed in moderate to high yields, which can be easily
further transformed into various difluoromethylarenes under
basic conditions.
+
Ar'
X
Ar' N2+X-
1
ref. 4
previous
F
R2
Ar
CF2H
F
cat. Pd 1-2 mol%
100-110oC
photocatalyt
visible light
work
0.05 mol%
cat. Ru
rt, 2 h
cat.Pd 5 mol%
OTMS
O
2
reagent
F
+
Ar'
Ar'
Ar' Br
Ar
2
Ar
85 oC, 8 h
The incorporation of fluoroalkyl groups into organic
molecules is widespread utilized in synthetic chemistry due to
the apparent impact on the physical and biological properties
of the material, such as enhanced lipophilicity and membrane
permeability, elevated electronegativity and oxidation
resistance.1 Meanwhile, difluoroalkylation compared with
perfluoroalkylation can not only introduce fluorine atoms into
this work
F
F
F
ref. 5
short reaction time
mild conditions
low catalyst loading
Scheme 1. The strategies for the preparation of α-aryl-α,α-difluoroketones
Diazonium salts especially arenediazonium salts, are
important intermediates and have been commonly used in
organic synthesis.6 Recently, several intriguing researching
studies have been reported on introducing the per- and
difluoroalkylation of diazonium salts or aromatic amines via
Sandmeyer-type reactions. Goossen and coworkers achieved
trifluoro-methylation and difluoromethylation of diazonium
salts,7 and copper-promoted trifluoromethylation of aromatic
amines was described by Fu’s groups.8 In the same year,
Wang’s groups explored the reaction of anilines with [AgCF3],
which can be considered as variation of the classic Sandmeyer
reaction.9 However, unstable tri- or difluoromethyl metal
complexes (such as [AgCF3] and [CuCF2H]), which should be
prepared in situ and handled carefully, are employed in these
strategies. Moreover, these methods require excess transition
metal salts and harsh conditions, reducing their versatility and
simplicity.
a
molecule, but also install a nonfluorinated moiety
simultaneously which can be further modified into various CF2
containing functional groups.2 Thus, compounds containing-
CF2R groups are widely applied in the preparation of
pharmaceuticals, agrochemicals, and enzyme inhibitors.3
The carbonyl functionality is an important cornerstone of
organic chemistry, since it can be smoothly transformed into a
range of functional groups including hydroxyl, amino, alkyl and
ester. The typical approaches for the introduction of a
difluorocarbonyl group onto an aromatic ring rely on the
conversion of halogen substituents through Pd-catalyzed
On the one hand, visible-light photoredox catalysis has been
widely applied in modern catalysis and synthesis, due to its low
cost, easy availability and environmental friendliness.10 On
theother hand, aryl diazonium salts are an excellent precursor
of aryl radicals through photoelectron transfer (PET) process,11
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which can be easily trapped by vinyl group. Inspired by these contained in the reaction. Therefore, further investigations
results, we propose that aryl radicals generated in situ from were made to testify the proposed assumption.
diazonium salts induced by visible light can react with
The reaction is inhibited in the presence of TEMPO (4
are detected by GC-MS,
difluoroalkylation reagents containing vinyl groups. To the best equiv.), and compounds
7, 8
of our knowledge, no report has mentioned the photo catalytic suggesting a radical process is existed in this transformation
difluoromethylation with aryl diazonium salts. Along this line, (Table 2). “Light/dark” experiments were also used to prove
we have introduced
a
visible-light-initiated difluoro- the occurrence of chain processes in this photoredox reaction
methylation of arenediazonium salts for the synthesis of α- (Figure 1).13 The reaction was irradiated with a LED at first half
aryl-α,α-difluoroketones using α-aryl-β,β-difluoroenol silyl as minute, then carried out in dark. Because the formation of
the difluoroalkylation reagent, which can be easily prepared product 3a still occurs, a radical long chain process is
from trifluoroacetophenone (Scheme 1).12
confirmed. Further control experiments (Scheme S1, ESI) were
carried out to investigate the role of Cs2CO3. It was found the
desired product 3a was generated in 25% yield when the by-
product 3a’ was treated with 2a and Cs2CO3. Thus, 3a can be
produced through another pathway in the presence of Cs2CO3,
which was also confirmed by the results of 19F NMR (Figure S1,
ESI).
Table 1. Optimization of reaction conditionsa
Entry
1c
Catalyst
Additive
None
3a/3a’ (%)b
64/24
Table 2. Mechanistic studies experimentsa
Ru(bpy)3Cl2·6H2O
EosinY
2c
None
25/58
3c
Rhodamine B
None
16/65
4
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
None
None
48/33
5d
None
43/42
6
None
0/94
7
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
None
Cs2CO3
Na2CO3
KOH
83/Trace
58/Trace
65/Trace
20/Trace
73/Trace
15/Trace
11/Trace
84/Trace
87 (80)i/Trace
88/Trace
82/Trace
8
9
10
11e
12
13f
14g
15h
16h,j
17k
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
aCondition A: Ru(bpy)3Cl2•6H2O (0.05 mol%), TEMPO (4 equiv.). Condition B:
Ru(bpy)3Cl2•6H2O (2 mol%), TEMPO (4 equiv.). bYield based on GC. cIsolated
yields.
100
aReaction conditions: 1a (0.25 mmol), 2a (1.5 equiv.), catalyst (2 mol%), additive
light/dark experiments
(3 equiv.), MeCN (2 mL), irradiation with visible light under an Ar atmosphere at
c
room temperature, 2 h. bYield based on GC. 10 h. d2a (2 equiv.). eAdditive (1
80
equiv.). fThe experiment was carried out without light. gCatalyst (0.5 mol%).
i
j
hCatalyst (0.05 mol%). Value in parentheses refers to isolated yield. Sunlight
60
instead of LED lamps irradiation. kCatalyst (0.01 mol%).
light/dark
light
40
20
0
Initially, we treated 4-bromobenzenediazonium tetrafluoro-
borate
(
1a)
with 2a in the presence of
2
mol%
Ru(bpy)3Cl2
·
6H2O in MeCN at room temperature under LED
lamps irradiation. To our delight, the reaction provided a 64%
yield of the desired product 3a. After screening different
photocatalysts, the ruthenium complex gave the best result
0
10
20
30
Time (min)
(Table 1, entries 1-3). To eliminate the undesired product 3a’
,
various bases were applied in the process. The results
indicated that excess base was required to suppress the side
reaction completely (entries 6-12). Not surprisingly, little
product was generated either in the dark or in the absence of
a photocatalyst (entries 12-13). The reaction also proceeded
smoothly using sunlight instead of LED lamps irradiation (entry
16). Remarkably, a satisfactory yield can be afforded in the
reaction even using 0.01 mol% photocatalyst (entry 17),
indicating a plausible radical natural chain cycle may be
Figure 1. “light/dark” experiments
Based on these preliminary results, a purposed mechanism
was iullstrated in Figure 2. Initially, aryl radical is formed by
SET from the excited state of Ru(bpy)3 initiated by visible
4
2+
light to diazoniym salt
1
. Subsequent addition of aryl radical
gives radical intermediate , which is
via SET from
is transformed to the
by losing the trimethylsilyl group (path I).
4
to the double bond of
2
5
further oxidized to carbocation intermediate
another aryl diazonium salt . Finally,
desired product
6
1
6
3
2 | J. Name., 2012, 00, 1-3
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Meanwhile, part of the by-product 3a’ is transformed to 3a via
the electrophilic addition process (path II), which can explain employed quantum mechanical (QM) density functional theory
why only 15% yield of product 3a is obtained without the (DFT) calculations to explore the process from to
photocatalyst (Table 1, entry 12). It should be noted that the (ESI).14 It is found an intermediate
is afforded from and
conversion of path II is poor, so the path may contain an which can provide and , following by a two-step cleavage of
’s C-N bonds (Figure 2). The energy barrier of the process is
To investigate further the innate cycle of path I, we
1,
5
4, 6
9
1
5,
I
4
6
innate cycle, and be the major route for the reaction.
9
around 42.1 kJ/mol (the calculated value in vacuum), which
may be lower owing to the promotion of Cs2CO3 in the
cleavage of
Therefore, the process from
9
’s C-N bonds and the solvation effects15.
1, 5 to 4, 6 may take place under
optimized conditions, and the innate cycle of path
based on the results of quantum calculation.
I is probable
With the optimized conditions in hand, the substrate scope
of the protocol was surveyed (Table 3). A range of aryl
diazonium salts which bear electron-withdrawing and neutral
groups could reacted with 2a to give the corresponding
adducts in moderate to excellent yields (3a-3m). Not
surprisingly, sunlight can also initiate the reactions successfully
(
3a, 3e, 3m). 3-Quinoline diazonium salt was also applied in
the reaction successfully with a moderate yield (3r). However,
ortho-subsituted products (3p-3q) were formed in lower yields
than their para-substituted analogues due to strong electron
repulsion between two fluorine atoms and ortho-subsituted
groups. It was worth noting that diazonium salts bearing
carbonyl groups were selectively dilfluoromethylated at the
arene ring without nucleophilic addition of the difluoromethyl
group to the carbonyl group. This difluoromethylation
procedure was also applied to two other silyl enol ethers (3u-
3y).
Figure 2. A proposed mechanism for the difluoro-methlylation of diazonium salts
Table 3. Visible-light-initiated difluoromethylation of diazonium saltsa,b
Of particular interest, the C-C bond adjacent to the carbonyl
group in these ketones can be readily cleaved to afford
difluoromethyarenes. Aromatic compounds containing
a
difluoromethyl (CF2H) group are valuable for medicinal
chemistry because the CF2H group is considered isosteric and
isopolar with the hydroxyl group.7 As reported by Hartwig et
al.,4a
difluoromethylarenes was developed (Table 4, 4a-4c).
a
one-pot procedure for the synthesis of
Table
4.
The
synthesis
of
difluoromethyarenes
from
α-aryl-α,α-
difluoroacetophenonesa,b
aReaction conditions: [step 1] 1 (0.25 mmol), 2a (1.5 equiv.), Cs2CO3 (3 equiv.),
Ru(bpy)3Cl2·6H2O (0.05 mol%), MeCN (2 mL), irradiation with visible light under
an Ar atmosphere at room temperature, 2 h; [step 2] KOH (8 equiv.), H2O (0.1
mL), 100 oC, 2 h. bIsolated yields.
aReaction conditions:
1 (0.25 mmol), 2a (1.5 equiv.), Cs2CO3 (3 equiv.),
Ru(bpy)3Cl2•6H2O (0.05 mol%), MeCN (2 mL), irradiation with visible light under
an Ar atmosphere at room temperature, 2 h. bIsolated yields. cSunlight instead of
LED lamps irradiation. dyield based on GC-MS.
Conclusions
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2012, 134, 2958; (c) D. A. Nagib, D. W. MacMillan, Nature,
2011, 480, 224; (d) Z. Zhang, X. Tang, W. R. Dolbier, Org.
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In summary, we have developed a convenient and
environment friendly protocol for the visible-light-initiated
difluoromethylation of diazonium salts at room temperature.
Both LED lamps irradiation and sunlight can initiate the
transformation efficiently. Only small amount of
Ru(bpy)3Cl2·6H2O and short timescale light are essential, which
certifies that a radical natural cycle is existed in the chemistry.
The reaction mechanism is also investigated by performing the
control experiments and quantum chemical calculations. These
results indicate that two pathways are existed in the reaction, and
the radical process containing an innate cycle is the major route.
The use of bases can completely suppress the side reaction.
Moreover, mild conditions and the simplicity of this method
underline the great potential for the preparation of more
complicated molecules.
11 M. J. Bu, T. F. Niu, C. Cai, Catal. Sci. Technol., 2015, 5, 830.
12 G. K. S. Prakash, J. Hu, M. M. Alauddin, P. S. Conti, G. A. Olah,
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Acknowledgements
We gratefully acknowledge Nature Science Foundation of
Jiangsu Province (BK 20131346, BK 20140776) for financial
support. This work was also supported by National Natural
Science Foundation of China (21476116, 21402093) and
Chinese Postdoctoral Science Foundation (2015M571761) for
financial support.
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