Silver-catalyzed Meerwein arylation: Intermolecular and intramolecular fluoroarylation of styrenes

Article abstract of DOI:10.1039/c5cc02446c

The first example of silver-catalyzed intermolecular and intramolecular Meerwein fluoroarylation of styrenes with aryl diazonium salts has been developed. This reaction is operationally simple, scalable and proceeds under mild conditions. Furthermore, fluorinated dihydrobenzofurans and indolines were easily accessed using this method. This journal is

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Silver-Catalyzed Meerwein Arylation: Intermolecular
and Intramolecular Fluoroarylation of Styrenes
Cite this: DOI: 10.1039/x0xx00000x
Rui Guo, a Haodong Yanga and Pingping Tang*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
scope and side products, it is a valuable synthetic transformation
based on aryl radical chemistry, which has recently become an even
more powerful tool for the functionalization of alkenes.6 However,
to the best of our knowledge, no examples of transition-metal
catalyzed meerwein fluoroarylation with aryl diazonium salts have
been reported. Recently, Ma group reported a copper catalyzed
tandem Nazarov cyclization/electrophilic fluorination transformation
for the preparation of fluorinated indanone derivatives.7 Gouverneur
group reported an asymmetric metal-free electrophilic intramolecular
fluorocyclization for synthesis of various tetracyclic molecules.8
Toste group reported an asymmetric palladium-catalyzed
intermolecular fluoroarylation of styrenes with aryl boronic acid in
the presence of the amide-based directing groups.9 Heinrich reported
the first intermolecular meerwein-type fluoroarylation of non-
activated alkenes from arylhydrazines without metal. The yield of
this reaction was moderate (up to 57%), and only 11%
fluoroarylation yield was observed with styrenes.10 Despite the
advances of these methods, the development of a more general and
practical method for fluoroarylation of alkenes is highly desirable.
The first example of a silver-catalyzed intermolecular and
intramolecular meerwein fluoroarylation of styrenes with
aryl diazonium salts has been developed. This reaction is
operationally simple, scalable and proceeds under mild
conditions. Furthermore, fluorinated dihydrobenzofurans
and indolines were easily accessed using this method
.
Fluorinated molecules are of particular interest in the
pharmaceutical, agrochemical and materials.1 As a result, the
development of new methods for fluorination under mild conditions
has received increasing attention in the past few years.2 Among
numerous approaches to fluorinated compounds, transition-metal-
catalyzed difunctionalization of C-C double bonds have recently
received significant attention, because it enables the introduction of
both fluorine and other functional groups to organic molecules in
one synthetic operation, and provides facile access to functionalized
fluorinated compound.3 However, fluoroarylation of alkenes remains
largely unexplored. In this communication, we report the first
example of a silver-catalyzed intermolecular and intramolecular
Meerwein fluoroarylation of styrenes with aryl diazonium salts
under mild conditions (Scheme 1).
Herein we report the first example of
a silver-catalyzed
intermolecular and intramolecular fluoroarylation of styrenes with
aryl diazonium salts under mild conditions. As briefly illustrated in
Table 1, our initial studies began with the attempted reaction of 4-
fluorobenzenediazonium tetrafluoroborate 1 with 4-fluorostyrene 2
using Selectfluor as fluorinating reagent in DMA at 25 °C for 10 h
under inert atmosphere, the desired product 3k was obtained in 56%
yield (entry 1). We then examined the influence of silver salt,
fluorinating reagent, solvent and the number of equivalents of
styrene (see the Supporting Information for more details). To our
delight, the reaction yields of 3k were increased by the use of
catalytic silver salts, and AgOTf gave the highest yield (entries 2-7).
Solvents affect was dramatic with DMA being the solvent of choice;
no fluorinated products were formed in toluene, EtOAc, acetone,
DCM and lower yield (54%) was observed in DMF. The amount of
styrene significantly affected the reaction yield and 5 equivalents of
styrene were used to achieve the highest yield (entries 7-9) due to
less protonation byproduct of diazonium salts observed. Various
fluorinating reagents were evaluated and Selectfluor gave the best
results (entries 10-13). Under the optimized reaction conditions, the
Scheme 1. Silver-catalyzed intermolecular or intramolecular fluoroarylation
of styrenes.
Aryl diazonium salts have attracted chemists as an important
source of aryl radicals.4 It has several advantages such as easily
prepared from aniline derivatives in large quantities, N2 as the
leaving group, and the reactions proceed with high chemoselectivity.
In 1939, Meerwein reported the arylation of olefins with aryl
diazonim salts catalyzed by copper salts.5 Although the original
meerwein arylation has disadvantages, such as a limited substrate
silver-catalyzed fluoroarylation of 4-fluorostyrene
2 with 4-
fluorobenzenediazonium tetrafluoroborate 1 using Selectfluor as
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fluorinating reagent in DMA at 25 °C for 10 h under inert (56%) also worked and Ts gave the best yields (71% for 5l). It is
atmosphere led to formation of fluoride 3k in 69% NMR yield (entry worth mentioning that this is the first report of intramolecular
7).
meerwein
fluoroarylation
to
form
the
fluorinated
dihydrobenzofurans and indolines.
Table 1. Optimizing reaction conditions.
Table 2. Silver-catalyzed intermolecular fluoroarylation of styrenes.a
entry
1
Conditionsa
No silver salts, Selectfluor, 2 (5 equiv)
AgNO3, Selectfluor, 2 (5 equiv)
Ag2CO3, Selectfluor, 2 (5 equiv)
Ag2O, Selectfluor, 2 (5 equiv)
AgBF4, Selectfluor, 2 (5 equiv)
AgSCN, Selectfluor, 2 (5 equiv)
AgOTf, Selectfluor, 2 (5 equiv)
AgOTf, Selectfluor, 2 (3 equiv)
AgOTf, Selectfluor, 2 (1 equiv)
AgOTf, Selectfluor(PF6), 2 (5 equiv)
AgOTf, NFSI, 2 (5 equiv)
Yield(%)b
56
63
65
68
65
55
69
60
43
50
0
2
3
4
5
6
7
8
9
10
11
12
13
AgOTf, NFPY, 2 (5 equiv)
0
AgOTf, AgF, 2 (5 equiv)
0
a 20 mol% of silver salts and 2.0 equiv of fluorinating reagents were used.
bYields were determined by 19F NMR with 1-fluoro-3-nitrobenzene as a
standard.
With the optimized conditions in hand, we then investigated the
substrate scope for intermolecular fluoroarylation of styrenes as
displayed in Table 2. Aryl diazonium salts or styrenes bearing
electron-withdrawing, -neutral, and -donating substituents reacted
smoothly and afforded the corresponding products in moderate to
good yields. Several functional groups including ester, carboxylic
acid, bromide, chloride, and alkyl groups are tolerated in the
reaction. For styrenes 2a and 2c, 3 equivalents of aryl diazonium
salts were used to give the corresponding fluorinated products in
moderate yield. Heteroaryl diazonium salt 1r was also successfully
employed to provide corresponding fluorinated product 3r in 34%
yield. Notably, sterically hindered aryl diazonium salt 1d reacted
smoothly to give the desired product 3d, albeit in lower yield (22%).
The reaction also worked with more complex styrenes, for example,
fluoroarylation of tyrosine derivative (2s) and estrone derivative (2t)
gave the corresponding products 3s and 3t in good yields. Less than
10% desired product yield was observed with unactivated alkenes
and heterocyclic alkenes. To prove both practicality and
effectiveness of this method for large-scale synthesis, 3k was
prepared on a gram scale under the reaction conditions in 62%
isolated yield.
As an extension of the above fluoroarylation of styrenes,
intramolecular cyclization reaction was then successfully
implemented as displayed in Table 3. The fluorinated
dihydrobenzofurans and indolines were obtained from various aryl
diazonium salts with isolated yields ranging from 41% to 81%. The
formation of trans-fluorinated dihydrobenzofurans was the major
product with high diastereoselectivity, which was confirmed by X-
ray analysis of compound 5d, while lower diastereoselectivity was
found in the formation of fluorinated indolines. For the reactions
with substrates bearing nitrogen tethers (4l to 4t), no fluorinated
products were observed in the absence of protecting group on
nitrogen. Other protecting group for nitrogen such as Ac (44%), Ms
a The reaction was performed with aryl diazonium salts 1 (0.30 mmol),
styrene 2 (1.50 mmol), AgOTf (20 mmol%), Selectfluor (0.600 mmol) in 1.2
mL DMA for 10 h at 25°C unless otherwise noted. The ratio of isomers was
determined by 19F NMR. Yields refer to isolated product. b Aryl diazonium
salts 1 (0.90 mmol) and styrene 2 (0.30 mmol) were used. c Aryl diazonium
salts 1 (0.15 mmol) and styrene 2 (0.45 mmol) were used.
Although a detailed mechanism of this reaction is currently
unclear, some preliminary studies were conducted to gain
mechanistic insight into this process. Less than 5% yields of
fluorinated products were formed when 1.0 equivalent of the
radical inhibitor butylated hydroxytoluene (BHT) or 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was added to the
intermolecular and intramolecular reactions. In addition, yields
in the absence of O2 are higher than in its presence.11 The aryl
diazonium salt
TEMPO to the dihydrobenzofuran 6 by a 5-exo cyclization
(Scheme 2),12 which is consistent with
free radical
4 was converted in the presence of 2.5 equiv of
a
mechanism. Furthermore, no fluoroarylated products were
found when CsF, TBAF or AgF was used as the fluorinating
2 | J. Name., 2012, 00, 1-3
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Table 3. Silver-catalyzed intramolecular fluoroarylation of styrenesa
R1
N2BF4
X
AgOTf (20 mol%)
F
Cl
N
Selectfluor (2.0 equiv)
R
N
2 BF4
R1
R
F
DMA, 25°C
X = O, N
X
Selectfluor
4
5
Me
tBu
CF3
Ph
F
F
F
F
F
O
O
O
O
O
, 71%
5b
, 64%
5c
, 81%
5a
, 56%
5d
, 46%
5e
(dr = 7:1)
(dr = 14:1)
(dr = 14:1)
(dr = 13:1)
(dr = 13:1)
F
F
F
F
F
F
Cl
O
O
O
O
O
MeO2C
Me
F
, 61%
5g
, 62%
5h
, 53%
5j
, 71%
, 51%
5i
5f
(dr = 14:1)
(dr = 14:1)
(dr = 9:1)
(dr = 7:1)
(dr = 7:1)
Me
Me
Me
F
F
F
F
F
Br
N
Ts
N
Ts
N
Ts
N
Ts
O
, 41%
5k
, 65%
5m
, 70%
5l
, 61%
5n
, 75%
5o
(dr = 11:1)
(dr = 4:1)
(dr = 5:1)
(dr = 4:1)
(dr = 3.7:1)
Ph
F
CF3
tBu
Br
F
F
F
F
F
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts
, 57%
5p
, 51%
, 42%
5q
5r
, 77%
5s
, 77%
5t
(dr = 5:1)
(dr = 3.5:1)
(dr = 4.3:1)
(dr = 3.4:1)
(dr = 4:1)
a The reaction was performed with 4 (0.30 mmol), AgOTf (20 mmol%), Selectfluor (0.600 mmol) in 2.0 mL DMA for 20 h at 25°C. The ratio of isomers was
determined by 19F NMR. Yields refer to isolated product.
reagent in the presence of silver salts (see the Supporting
Information for more details), which indicates that the reaction may
not proceed through a carbocationic intermediate. To get further
Conclusions
insights into the reaction mechanism, EPR (electron paramagnetic
resonance) experiments were performed with the addition of free
radical spin trapping agent DMPO (5,5-dimethyl-1-pyrroline N-
oxide). Some signals of unknown organic radicals were observed.
Together, these observations indicated that a radial chain mechanism
or single-electron transfer (SET) may be involved in this
transformation.
In conclusion, we have reported the first example of a silver-
catalyzed intermolecular and intramolecular meerwein
fluoroarylation of styrenes with aryl diazonium salts under mild
conditions. The new reaction offers a complementary method
for difunctionalization of alkenes to form fluorinated
compounds and extends the scope of the meerwein arylation.
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Additionally, the reaction is amenable to gram-scale synthesis
and fluorinated dihydrobenzofurans and indolines were easily
prepared through this method. Mechanism studies suggested
that the reaction proceeded through a free-radical process. With
its operational simplicity this method could find practical
applications in pharmaceutical and agrochemical research and
development for the synthesis of fluorinated compounds.
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