Regioselective Synthesis of α-Fluorinated Cyclopentenones by Organocatalytic Difluorocyclopropanation and Fluorine-Directed and Fluorine-Activated Nazarov Cyclization

Article abstract of DOI:10.1002/chem.201604578

Silyl dienol ethers, prepared from α,β-unsaturated ketones, underwent proton sponge-catalyzed difluorocyclopropanation with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in a regioselective manner, leading to 1,1-difluoro-2-siloxy-2-vinylcyclopropanes in good yields. The cyclopropanes thus obtained were in turn subjected to fluoride-ion-catalyzed ring opening to afford 1-fluorovinyl vinyl ketones (i.e., Nazarov precursors). Treatment of the precursors with Me₃Si⁺B(OTf)₄^?regioselectively promoted the Nazarov cyclization, the rate and regioselectivity of which were drastically enhanced by the fluoro substituent, which thus facilitated efficient synthesis of biologically promising α-fluorocyclopentenone derivatives.

Full text of DOI:10.1002/chem.201604578

A Journal of
Accepted Article
Title: Regioselective Synthesis of α-Fluorinated Cyclopentenones via
Organocatalytic Difluorocyclopropanation and Fluorine-Directed
and -Activated Nazarov Cyclization
Authors: Kohei Fuchibe, Ryo Takayama, Takaharu Yokoyama, and
Junji Ichikawa
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Regioselective Synthesis of α-Fluorinated Cyclopentenones via
Organocatalytic Difluorocyclopropanation and Fluorine-Directed and -
Activated Nazarov Cyclization
Kohei Fuchibe,[a] Ryo Takayama,[a] Takaharu Yokoyama,[b] and Junji Ichikawa[a]*
Abstract: Silyl dienol ethers, prepared from α,β-unsaturated
group because of the stability of the fluoride ion (leaving group
ability, Figure 1c).
ketones,
underwent
proton
trimethylsilyl
sponge-catalyzed
2,2-difluoro-2-
difluorocyclopropanation
with
fluorosulfonylacetate (TFDA) in a regioselective manner, leading to
1,1-difluoro-2-siloxy-2-vinylcyclopropanes in good yields. The
cyclopropanes thus obtained were in turn subjected to fluoride ion-
catalyzed ring opening to afford 1-fluorovinyl vinyl ketones (i.e.,
Nazarov precursors). Treatment of the precursors with Me3Si+
O
OLA
LA+
R2
R1
R2
R1
+
–
R3
R3
B(OTf)4 regioselectively promoted the Nazarov cyclization, whose
rate and regioselectivity were drastically enhanced by the fluorine
substituent, thereby facilitating efficient synthesis of biologically
promising α-fluorocyclopentenone derivatives.
A
OLA
OLA
R2
R2
4π conr.
+
+
R1
R1
R3
R3
H
Introduction
H
B
The Nazarov cyclization[1] is one of the most versatile methods
for the construction of cyclopentenone frameworks. Because
cyclopentanoids are ubiquitously encountered in natural
products,[2] the Nazarov cyclization have been extensively
studied within the last decades.[3] However, the Nazarov
cyclization suffers from the lack of control in the position of the
double bond introduced to products. In the Nazarov cyclization,
treatment of divinyl ketones with Lewis or Brønstead acids forms
pentadienyl cation intermediates A (Scheme 1). Subsequent
electrocyclization of A proceeds to generate cyclic oxyallyl
cation intermediates B. Deprotonation of B typically proceeds to
afford the more substituted (thermodynamically more stable)
isomers of cyclopentenone derivatives. With the aim to
overcome the issue of substrate dependency, stabilizing charge
localization of B by silicon,[4] tin,[5] or oxygen[6] functionalities
have been conducted.
O
O
– H+
R2
R2
+
then H3O+
R1
Major
Product
R1
R3
R3
Minor
Product
Scheme 1. Pathway of the Nazarov Cyclization.
We have previously reported two types of fluorine-directed
Nazarov cyclizations, in which the position of the introduced
double bond was governed by the β-cation destabilizing effect of
fluorine.[9] Thus, 2,2-difluorovinyl vinyl ketone
1
and 1-
(trifluoromethyl)vinyl vinyl ketone
2
were treated with
trimethylsilyl trifluoromethanesulfonate (TMSOTf) in 1,1,1,3,3,3-
hexafluoropropan-2-ol (HFIP)[10]/dichloromethane (Eqs 1 and 2).
The Nazarov cyclization proceeded in a regioselective manner
Fluorine has a number of characteristic electronic effects
and properties (Figure 1):[7] (i) a fluorine substituent inductively
destabilizes β-cation because of its high electronegativity (–I
effect, Figure 1a), (ii) a fluorine substituent stabilizes α-cation via
donation of its unshared electron pair to a vacant 2p orbital (+R
effect, Figure 1b),[8] (iii) a fluorine substituent acts as a leaving
to
afford
3-fluorocyclopent-2-en-1-one
3
and
high
5-
yields,
(trifluoromethyl)cyclopent-2-en-1-one
4
in
respectively. In the case of intermediary oxyallyl cations B1 and
B2, positive charges are localized mainly on the carbon δ to the
fluorine substituents owing to the β-cation destabilizing effect of
fluorine. Elimination of a proton adjacent to the less destabilized
δ cation proceeded with the subsequent regioselective formation
of the products. However, rate enhancement is not expected in
these systems because cationic B1 and B2 are destabilized by
inductive effect of fluorine.
[a]
[b]
Dr. K. Fuchibe, R. Takayama, and Prof. Dr. J. Ichikawa
Division of Chemistry, Faculty of Pure and Applied Sciences
University of Tsukuba
Tsukuba, Ibaraki 305–8571, Japan
E-mail: junji@chem.tsukuba.ac.jp
T. Yokoyama
Department of Applied Chemistry, Faculty of Engineering
Kyushu Institute of Technology
Kitakyushu, Fukuoka 804–8550, Japan
Supporting information for this article is given via a link at the end of
the document.
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(a) β-Cation Destabilizing Effect
stabilizing effect of fluorine, thereby promoting the rate-
determining ring closure and enhancing the reactivity of the
substrates (i.e., fluorine substituent acting as an activator). Their
positive charge localized at the carbon α to the fluorine
substituent in B3 would cause regioselective formation of 2-
fluorocyclopent-2-en-1-ones (i.e., fluorine substituent acting as a
controller).[11] Thus, the fluorine-directed and -activated Nazarov
cyclization has potential to provide the 2-fluorocyclopentenones
as new candidates and intermediates for pharmaceuticals and
agrochemicals.[12–14]
+
Electron-withdrawing
Inductive Effect
(–I effect)
F
C
C
(b) α-Cation Stabilizing Effect
+
Electron-donating
Resonace Effect
(+R effect)
F
C
stabilized cation
(c) Leaving Group Ability
F
O
OLA
O
X
LA+
+
F
F
F
α
R
R
H
R
Figure 1. Properties of Fluorine Substituents.
B3 (Stabilized)
We revisited the fluorine-directed Nazarov cyclization, in
which a fluorine substituent would act not only as a controller but
also as an activator (Scheme 2). In the case of this fluorine-
directed and -activated Nazarov cyclization, we used 1-
fluorovinyl vinyl ketones as substrates. The predicted oxyallyl
cation intermediates B3 would be stabilized by the α-cation
Scheme 2. Strategy for Fluorine-Directed and -Activated Nazarov Cyclization.
Results and Discussion
Preparation of 1-Fluorovinyl Vinyl Ketones: Organocatalytic
Difluorocyclopropanation of Silyl Dienol Ethers
less destabilized cation
We envisioned that the synthesis of the required Nazarov
precursors (i.e., 1-fluorovinyl vinyl ketones) would be facilitated
by the following difluorocyclopropanation/ring opening sequence
of silyl dienol ethers (Scheme 3):[15] silyl dienol ethers 5, readily
prepared from α,β-unsaturated ketones, would be subjected to
Me3SiOTf
(1 equiv)
Me3SiO
H
O
+
n-Bu
n-Bu
n-Bu
β
n-Pr
δ
RT, 0.1 h
difluorocarbene
to
give
1,1-difluoro-2-siloxy-2-
CF2
F
HFIP/CH2Cl2
F
vinylcyclopropanes 6. Ring opening of the siloxy cyclopropanes
(i.e., elimination of a fluorosilane) catalyzed by a fluoride ion
might afford the desired fluorovinyl ketones 7.[16]
1
B1 (Destabilized)
O
n-Bu
(1)
F
n-Pr
OSiR'3
O
– H+
F
OSiR'3
cat. F–
: CF2
F
F
– FSiR'3
R
R
3 82%, E/Z =99/1
R
5
7
6
less destabilized cation
Scheme 3. Approach to the Nazarov Precursors.
Me3Si
O
Me3SiOTf
(1 equiv)
F
O
+
However, difluorocyclopropanation of silyl enol ethers has
been quite limited until recently[17] because of the instability of
these substrates under the harsh conditions required for
conventional difluorocarbene generation.[18] In particular,
difluorocyclopropanation of silyl dienol ethers has remained
largely unexplored.[14a,c] Meanwhile, we have developed
methods for the organocatalytic generation of difluorocarbene
under mild conditions and the O- and S-difluoromethylation of
aliphatic ketones, secondary amides, and thioamides.[19] We
thus used the generation of difluorocarbene from trimethylsilyl
CF3
CH3
CF2
CH3
RT, 0.1 h
β
δ
HFIP/CH2Cl2
H
2
B2 (Destabilized)
O
(2)
CF3
CH3
– H+
4 87%
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2,2-difluoro-2-fluorosulfonylacetate
(TFDA)[20]
for
the
In order to achieve the required difluorocyclopropanation of
silyl dienol ethers, the organocatalyst was optimized (Table 1).
TFDA was originally designed to generate difluorocarbene upon
treatment with fluoride ion at 105 °C. Silyl dienol ether 5a,
prepared from methyl styryl ketone, was thus treated with TFDA
(2.0 equiv) in the presence of sodium fluoride in toluene at 80 °C.
However, the desired difluorocyclopropane 6a was obtained in
9% yield presumably because of the lower temperature (i.e.,
lower than the original conditions, entry 1). NHC catalysts 10a
and 10b afforded cyclopropane 6a in higher yields (17% and
49%, respectively, entries 2 and 3).
The catalytic activity of nitrogen nucleophiles was examined
to improve the yield of 6a. Although pyridine and
benzo[h]quinoline were not effective as catalysts for the
production of 6a (20% and 0% yields, respectively, entries 4 and
5), 1,10-phenanthroline (10 mol%) exhibited high catalytic
efficiency, affording 6a in 58% yield (entry 6). Aliphatic amines
such as triethylamine and N,N,N′,N′-tetramethylethylenediamine
cyclopropanation of silyl dienol ethers (Scheme 4). Treatment of
TFDA with a suitable organic nucleophile as an organocatalyst
would release difluorocarbene at the rates required for
difluorocyclopropanation of silyl dienol ethers 5 under mild
conditions. This leads to efficient formation of 1,1-difluoro-2-
siloxy-2-vinylcyclopropanes 6.
Organocatalyst
(organic nucleophilies)
:Nu
OSiMe3
O
O O
S
: CF2
– SO2, – CO2, – FSiMe3
F
F
F
TFDA
Scheme 4. Organocatalytic Generation of Difluorocarbene.
Table 1. Catalyst Optimization.[a]
catalyst
F
FSO2CF2CO2SiMe3
(TFDA, 2.0 equiv)
OTBS
OTBS
O
F
OTBS
F
+
+
F
toluene
Ph
Ph
Ph
Ph
5a
6a
8
9
Recovery of
Entry
Catalyst [mol%]
Temp [°C]
t [min]
6a [%]
8 [%]
9 [%]
5a [%] [b]
TFDA [equiv] [b]
1
NaF (20)
80
80
80
80
80
80
80
80
80
70
60
50
30
30
30
30
60
10
30
120
30
10
10
10
9
nd
nd
8
40
40
20
62
55
16
5
37
9
0.91
nd
2
10a·HCl (10) + Na2CO3 (20)
10b·HBr (10) + Na2CO3 (20)
pyridine (20)
17
3
49
26
7
nd
4
20
nd
nd
5
0.75
0.96
0.02
trace
nd
5
benzo[h]quinoline (10)
1,10-phenanthroline (10)
NEt3 (20)
nd
35
1
6
58
7
47
11
22
11
2
21
nd
nd
nd
nd
nd
8
TMEDA (16)
38
20
16
1
9
11 (5)
75
trace
trace
trace
trace
10 [c]
11 [c]
12 [c]
11 (5)
75
11 (5)
77 (76)
74
trace
trace
5
11 (5)
7
[a] 19F NMR yield based on an internal standard (CF3)2C(C6H4p-Me)2 (for 6a, 8, and TFDA) or 1H NMR yield based on 6a (for 5a and 9). Isolated yield
is shown in parentheses. TBS = Sit-BuMe2. TMEDA = N,N,N′,N′-Tetramethylethylenediamine. nd = Not detected by 19F NMR spectroscopy (for 6a, 8,
and TFDA) or 1H NMR spectroscopy (for 5a). [b] Recovery. [c] TFDA 1.5 equiv.
N
N
N
SMe
Me2N
NMe2
+
N
MesN
NMes Cl–
+
PhN
NPh Br–
10b·HBr
benzo[h]quinoline
1,10-phenanthroline
11
10a·HCl
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(TMEDA) were found to be less effective (47% and 38% yields
of 6a, respectively, entries 7 and 8). Finally, silyl dienol ether 5a
afforded difluorocyclopropane 6a in the presence of 5 mol% of
1,8-bis(dimethylamino)naphthalene (i.e., proton sponge, 11) in
75% yield (entry 9).[20b] It was also found that the proton sponge
catalyst 11 was active even at low temperatures (entries 10–12).
When TFDA (1.5 equiv) was added to a toluene solution of silyl
dienol ether 5a and 5 mol% of 11, the reaction was completed
within 10 min at 60 °C to afford difluorocyclopropane 6a in 76%
isolated yield (entry 11).
installed on the aromatic ring at the terminal position (R1) did not
affect the reaction, leading to the corresponding products 6b and
6c in 79% and 83% yields, respectively (entries 2 and 3).
Substrate 5d bearing an alkyl substituent (i.e., isopropyl group)
on the reacting alkene moiety (R3) afforded the corresponding
cyclopropane 6d in 78% yield (entry 4). The silyl dienol ether
bearing a butyl group as a R1 substituent also reacted smoothly
(75% yield of 6e, entry 5). Difluorocyclopropanation of these silyl
dienol ethers proceeded in a diastereospecific manner, with 5d
and 5e (91:9 and 92:8 Z/E ratios, respectively) leading to 6d and
6e (82:18 and 92:8 diastereomer ratios, respectively).[22]
19F NMR analysis revealed that TFDA used for the
experiments contained 2 mol% (at maximum) of inseparable free
carboxylic acid FSO2CF2CO2H (not shown). Proton sponge 11
likely promoted removal of a proton from the free acid, followed
by elimination of CO2, difluorocarbene, and SO2, to generate the
HF salt of 11. The formed fluoride ion bearing a stable
ammonium ion exerted high nucleophilicity, thereby allowing
catalytic generation of difluorocarbene from TFDA even at low
temperatures.[21]
Substrates bearing
a methyl group (5f) and a bromine
substituent (5g) at the internal position (R2) afforded 6f and 6g in
92% and 96% yields (entries 6 and 7), respectively. Apart from
silyl dienol ethers, silyl enol ethers also underwent
organocatalytic difluorocyclopropanation. Silyl enol ether 5h,
derived from acetophenone, afforded the corresponding
cyclopropane 6h in 80% yield (entry 8). Thus, the required
difluorocyclopropanation of silyl dienol ethers 5 was successfully
achieved by the organocatalytic difluorocarbene generation with
proton sponge 11.
Under the optimized conditions, additional 1,1-difluoro-2-
siloxy-2-vinylcyclopropanes were synthesized in
a similar
manner (Table 2). Electron-donating and -withdrawing groups
Table 2. Difluorocyclopropanation of Silyl Dienol Ethers.[a]
F
5 mol% 11
TFDA (1.5 equiv)
OTBS
R2
OTBS
R2
F
R3
R3
toluene, 60 °C
R1
R1
5
6
Entry
5
R1
Ph
R2
R3 (Z/E) [b]
t [min]
Yield [%] (dr), 6
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
H
H
10
15
15
25
15
15
15
15
76, 6a
C6H4p-Me
C6H4p-Cl
Ph
H
H
79, 6b
H
H
83, 6c
H
i-Pr (91:9)
78 (82:18), 6d
75 (92:8), 6e
92, 6f
n-Bu
H
n-Bu (92:8)
Ph
Me
Br
H
H
H
5g
5h
Ph
96, 6g
–(CH=CH)2– [c]
80, 6h
[a] Isolated yield, unless otherwise noted. TBS = Sit-BuMe2. [b] Geometry of siloxyalkene moiety. [c] 1-(tert-butyldimethylsilyloxy)styrene.
The Nazarov precursors (i.e., 1-fluorovinyl vinyl ketones 7)
were prepared by ring opening of 1,1-difluoro-2-siloxy-2-
vinylcyclopropanes 6 (Table 3). Treatment of the obtained
difluoro(vinyl)cyclopropane 6a with cesium fluoride at 60 °C in
THF did not afford the desired 7a (72% recovery of 6a, entry 1).
In contrast, utilization of tetrabutylammonium fluoride (TBAF, 20
mol%) led to the formation of 7a at room temperature in 70%
entry
3).
While
tris(dimethylamino)sulfonium
difluorotrimethylsilicate afforded a complex mixture (entry 4),
tetrabutylammonium difluorotriphenylstannate was inactive even
at 60 °C (97% recovery of 6a, entry 5).
Several 1-fluorovinyl vinyl ketones 7 were prepared by the
abovementioned method (Table 4). Cyclopropanes bearing
phenyl (6a), p-methylphenyl (6b) and p-chlorophenyl (6c) groups
underwent ring opening to afford the corresponding Nazarov
precursors 7a–c in 53–76% yields, respectively (entries 1–3).
Substrates 6d and 6e bearing an alkyl group on the cyclo-
yield
(entry
2).
Utilization
of
tetrabutylammonium
–
difluorotriphenylsilicate (TBAT, n-Bu4N+ SiF2Ph3 ) instead of
TBAF at room temperature resulted in a higher yield of 7a (94%,
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Table 3. Catalyst Optimization.[a]
propane moiety were stable under the TBAT system at room
temperature and decomposed at elevated temperatures (not
shown). Ring opening of 6d and 6e was conducted with water-
deactivated TBAF at controlled temperatures to give 7d and 7e
F
O
F
OTBS
20 mol% F– source
F
in 74% and 61% yields, respectively (entries
4 and 5).
THF, conditions
Methylated and brominated vinylcyclopropanes 6f and 6g
afforded divinyl ketones 7f and 7g in 77% and 75% yields,
respectively (entries 6 and 7).
Ph
– FSit-BuMe2
Ph
6a
7a
Recovery of
Entry
F– Source
CsF [c]
Conditions
7a [%]
6a [%] [b]
Fluorine-Directed and -Activated Nazarov Cyclization:
Regioselective Synthesis of α-Fluorocyclopentenones
1
2
3
60 °C, 30 min
nd
70
94
72
nd
nd
n-Bu4N+ F– (TBAF)
rt, 15 min,
rt, 20 min
The Nazarov cyclization of 1-fluorovinyl vinyl ketones was
examined using Z-7e as a model substrate (Table 5). Treatment
of Z-7e with 3 equiv of trimethylsilyl trifluoromethanesulfonate
n-Bu4N+ SiF2Ph3
–
(TBAT)
(TMSOTf)
in
HFIP/dichloromethane
(1:1)
led
to
–
4
5
(Me2N)3S+ SiF2Me3
60 °C, 20 min
60 °C, 20 min
nd [d]
nd
nd [d]
97
hydroxycyclopentenone 12e (i.e., a hydrolyzed product of the
desired 2-fluorocyclopent-2-en-1-one 13e) in 57% yield (entry 1).
We assumed that the hydrolysis was caused by trace amounts
of water present in HFIP. Although the reaction was conducted
in dichloromethane, no reaction was observed even under reflux,
presumably because of the lack of cation-stabilizing effect of
HFIP (entry 2). Thus, we examined other Lewis acids to
efficiently generate pentadienyl cations. Utilization of BF3·OEt2 in
dichloromethane was fruitless (entry 3), whereas SnCl4 afforded
the desired 13e in 41% yield (entry 4). Eventually, a strong
n-Bu4N+ SnF2Ph3
–
[a] 19F NMR yield based on an internal standard (CF3)2C(C6H4p-Me)2. TBS =
Sit-BuMe2. nd = not detected by 19F NMR spectroscopy. [b] Recovery. [c] 45
mol%. [d] Complex mixture.
Table 4. Preparation of 1-Fluorovinyl Vinyl Ketones.[a]
F
O
–
[23]
silylation reagent Me3Si+ B(OTf)4
successfully induced the
OTBS
R2
F
R3
20 mol% TBAT
THF
F
R2
R1
desired Nazarov cyclization to afford 13e in 89% yield within 15
min (entry 5).
R3
R1
As expected, the Nazarov cyclization proceeded in
a
6
7
regioselective manner (Table 6). 1-Fluorovinyl vinyl ketone 7a
bearing a phenyl group at the terminal carbon (R1) afforded the
corresponding 13a in 51% yield (entry 1). It must be emphasized
that the undesired isomer concerning the position of the double
bond was not observed by 19F NMR and GC-MS analyses.
Electron-donating (7b) and -withdrawing (7c) groups installed on
the aromatic ring at the terminal position (R1) did not affect the
reaction, leading to 13b and 13c in 57% and 74% yields,
respectively (entries 2 and 3). Divinyl ketones 7d, Z-7e, and E-
7e bearing an alkyl substituent (i.e., isopropyl or butyl group) on
the fluoroalkene moiety readily underwent cyclization upon
increasing loadings of the Lewis acid to afford the products 13d
(88%, entry 4) and 13e (79% and 70% yields, entries 5 and 6),
respectively. The Nazarov cyclization of cyclohexenyl ketone
7i[11a] allowed the construction of a bicyclic structure, leading to
13i in 79% yield (entry 7).
Entry
6a (dr) [b]
Conditions
Yield [%] (Z/E),[c]
76, 7a
7
1
6a
rt, 1 h
2
6b
rt, 20 min
53, 7b
3
6c
rt, 20 min
59, 7c
4 [d]
5 [e]
6
6d (82:18)
6e (91:9)
6f
–78 °C to rt, 82 h
–78 to –5 °C, 17 h
50 °C, 1 h
74 (97:3), 7d
61 (62:38), 7e [f]
77, 7f
7
6g
50 °C, 1 h
75, 7g
[a] Isotated yield, unless otherwise noted. TBS = Sit-BuMe2, TBAT = n-Bu4N+
SiF2Ph3–. [b] Diastereomer ratio of cyclopropane moiety. [c] Geometry of
fluoroalkene moiety. [d] 60 mol% TBAF, H2O 4 equiv. [e] 20 mol% TBAF, H2O
7 equiv. [f] 19F NMR yield based on an internal standard C6H5CF3.
The oxygenated cyclopentenone skeleton of 12e is found in
cyclotenes, which are used as food additives with a caramel-like
flavor.[24] Fluorovinyl ketone 7f bearing a methyl group at
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Table 5. Optimization of Lewis Acid for Regioselective Nazarov Cyclization.[a]
O –LA
O
OH
O
Lewis Acid (LA)
+
F
F
F
O
– H+, – LA
solvent, conditions
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Z-7e
13e
12e
Entry
LA
Equiv
Solvent
Conditions
13e [%]
12e [%]
1
2
3
4
5
Me3SiOTf
Me3SiOTf
BF3·OEt2
SnCl4
3
3
1
HFIP/CH2Cl2 (1:1)
CH2Cl2
rt, 5 h
nd
57
reflux, 3 h
reflux, 3 h
reflux, 1 h
rt, 15 min
no reaction
CH2Cl2
nd
41
89
nd
nd
nd
3
CH2Cl2
Me3Si+ B(OTf)4
1
CH2Cl2
–
[a] 19F NMR yield based on an internal standard (CF3)2C(C6H4p-Me)2. Tf = trifluoromethanesulfonyl. HFIP = 1,1,1,3,3,3-
hexafluoropropan-2-ol. nd = Not detected by 19F NMR spectroscopy (for 13e) or 1H NMR spectroscopy (for 12e).
Table 6. Regioselective Synthesis of α-Fluorocyclopentenones.[a]
OSiMe3
F
R2
+
O
O
–
Me3Si+ B(OTf)4
CH2Cl2, rt
R2
R1
F
R2
R1
F
R3
R3
R1
R3
7
13
Entry
7
R1
R2
H
R3
Me3Si+ B(OTf)4– [equiv]
t [h]
Yield [%], 13
1
2
3
4
5
6
7
7a
Ph
H
H
H
1.0
1.0
1.0
1.2
2.0
2.0
1.0
1
51, 13a
57, 13b
74, 13c
88, 13d
79, 13e
70, 13e
79, 13i
7b
C6H4p-Me
C6H4p-Cl
Ph
H
H
H
H
H
1
7c
0.5
1
Z-7d
Z-7e
E-7e
7i
Z-i-Pr [b]
n-Bu
Z-n-Bu [c]
E-n-Bu [c]
Et
2
n-Bu
2
–(CH2)4– [d]
0.25
[a] Isolated yield. TBS = Sit-BuMe2. [b] Z/E = 98:2. [c] Single diastereomer. [d] Cyclohexenyl 1-fluorobut-1-en-1-yl ketone.
an internal position (R2) also underwent defluorinative Nazarov
cyclization (Eq 3). When methylated ketone 7f was treated with
TMSOTf (1.0 equiv) in HFIP/dichloromethane (1:1) at 0 °C, 2-
hydroxycyclopent-2-en-1-one 12f was obtained in 68% yield.
Thus, the fluorine-directed and -activated Nazarov cyclization is
Effect of Fluorine Substituent on Reactivity and
Regioselectivity
In order to elucidate the regioselectivity of the fluorine-directed
Nazarov cyclization, the structures of key oxyallyl cation
intermediates were analyzed by theoretical calculation. Figure 2
shows the calculated electrostatic potential maps and selected
charge values of the optimized model structures of oxyallyl
cation intermediates [(a) s-cis and (b) s-trans forms] and their
fluorine-free counterpart [(c) blank].
The theoretical calculation indicated that the carbons α to
the fluorine substituent (C1) present strongly positive charges
[i.e., +0.362 (s-cis) and +0.354 (s-trans)], whereas the C3
carbons have slightly negative charges [–0.032 (s-cis) and –
0.064 (s-trans)]. These charge distributions were not found in
a
useful synthetic method to fluorinated cyclopentanone
derivatives and their fluorine-free analogues.
OH
O
Me3SiOTf (1.0 equiv)
F
O
(3)
HFIP/CH2Cl2 (1:1)
0 °C, 15 min
Ph
Ph
12f 68%
7f
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10.1002/chem.201604578
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the blank structure, where the C1 and C3 carbons showed
slightly negative and positive charges (–0.015 and +0.027,
respectively). Thus, positive charge was localized mainly on the
carbon α to the fluorine substituent. Differences in bond orders
were also observed. The Lowdin bond orders for C1–C2 bonds in
s-cis and s-trans forms (1.28 and 1.26) were significantly lower
than those for C2–C3 bonds (1.58 and 1.45), respectively. On the
other hand, the bond orders of C1–C2 and C2–C3 bonds in the
blank structure were nearly equal (1.39 and 1.38). These
electronic and structural perturbations suggested that the
fluorinated oxyallyl cations have a localized allyl cation structure,
thereby leading to regioselective deprotonation and selective
formation of 2-fluorocyclopent-2-ene-1-ones.
When fluorine-free divinyl ketone 14 was separately treated
–
with Me3Si+ B(OTf)4 (1.0 equiv), the Nazarov cyclization
proceeded, although very slowly (Scheme 6). It required 20 h for
completion (i.e., 80 times slower than 7j) to give a regioisomeric
mixture concerning the position of the double bond (15 and 15’
in 24% and 65% yields, respectively). Theoretical calculation
suggested that phenyl-non-conjugated cyclic intermediate C1,
leading to 13j, is less stable as compared to phenyl-conjugated
C2 by 2.80 kcal/mol (DFT, B3LYP/6-31G**). Thus, the fluorine
substituent governed the cyclization to exclusively afford the
non-conjugated cyclopentenone 13j as
a kinetic product,
whereas fluorine-free substrate 14 afforded 15’ as a major
product under the influence of the higher stability of phenyl-
conjugated C4 by 3.16 kcal/mol.
SiH3
C3
H3Si
H3Si
O
O
O
–
Me3Si+ B(OTf)4
(1.0 equiv)
O
O
C2
C2
C2
+
+
+
F
F
H
F
H
C1
C3
C1
C1
C3
+
CH2Cl2, RT
15 min
Et
Ph
Et
Ph
7j
14
OLA
O
X
F
+
+
14
H
F
535 kJ/mol
F
Et
Ph
Et
Ph
H H
X = F or H
13j 89%
92%
Scheme 5. Effects of Fluorine Substituent (1): Activation.
(c) blank
(a) s-cis
(b) s-trans
(+0.58 kcal/mol)
(0.00 kcal/mol)
290 kJ/mol
–
Me3Si+ B(OTf)4
(1.0 equiv)
OSiMe3
O
electrostatic charge
C1
C2
C3
s-cis
s-trans
blank
X
X
+
+0.362
+0.250
–0.032
s-cis
+0.354
+0.264
–0.064
s-trans
1.26
–0.015
+0.348
+0.027
blank
1.39
CH2Cl2, RT
Et
Ph
Et
Ph
H H
7j (X = F)
14 (X = H)
Lowdin bond order
C1–C2
1.28
OSiMe3
Ph
OSiMe3
Ph
C2–C3
1.58
1.45
1.38
X
X
and/or
Figure 2. Calculated Electronic and Structural Properties of Oxyallyl Cation
Intermediates (DFT, B3LYP/6-31G**).
Et
Et
X = F
C1 2.80 kcal/mol
C3 3.16 kcal/mol
C2 0.00 kcal/mol
C4 0.00 kcal/mol
The effect of fluorine substituents on the reactivity and
selectivity of the Nazarov cyclization was experimentally
investigated by using fluorinated (7j,[11a] X = F, Scheme 5) and
fluorine-free (14, X = H) substrates. Competition experiment
demonstrated the rate enhancement effect of the fluorine
substituent. A 1:1 mixture of 7j and 14 was treated with 1.0
X = H
O
O
X
Et
X
Et
and/or
Ph
Ph
–
equiv of Me3Si+ B(OTf)4 in dichloromethane at room
temperature. Fluorinated 7j exclusively underwent the Nazarov
cyclization to afford the corresponding product 13j in 89% yield
as a single product, whereas fluorine-free counterpart 14
remained unreacted. Thus, the fluorine substituent activated the
substrates in the Nazarov cyclization via fluorine-stabilized
oxyallyl cation intermediates.
13j' –
15' 65%
X = F, t = 15 min
X = H, t = 20 h
13j 89%
15 24%
Scheme 6. Effects of Fluorine Substituent (2): Direction.
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TBAT-Catalyzed Ring Opening of Difluoro(vinyl)cyclopropanes: to a
solid TBAT (83 mg, 0.15 mmol) was added a THF solution (5 mL) of
difluoro(vinyl)cyclopropane 6a (240 mg, 0.774 mmol) at rt. After the
reaction mixture was stirred for 1 h, CH2Cl2 (5 mL) and aqueous NaHCO3
(5 mL) were added to quench the reaction at rt. Organic materials were
extracted with CH2Cl2 four times. Combined extracts were dried over
anhydrous Na2SO4, filtered, and then concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/AcOEt 100:1 to
50:1) to give fluorovinyl viny ketone 7a (104 mg, 76% yield) as colorless
crystals.
Conclusions
We developed a synthetic sequence for 2-fluorocyclopent-2-ene-
1-ones (α-flurocyclopentenones) via (i) organocatalyzed
difluorocyclopropanation of silyl dienol ethers and (ii) fluorine-
directed and -activated Nazarov cyclization. The synthesis of the
Nazarov precursors (i.e., 1-fluorovinyl vinyl ketones) was
facilitated via proton sponge-catalyzed generation of
difluorocarbene. The mild reaction conditions allowed efficient
preparation of 1,1-difluoro-2-siloxy-2-vinylcyclopropanes, whose
ring opening afforded the required precursors in good yields.
Regioselective synthesis of 2-fluorocyclopent-2-en-1-ones was
achieved by the Nazarov cyclization enhanced and directed
through α-cation stabilizing effect of fluorine. The treatment of
The Nazarov Cyclization of 1-Fluorovinyl Vinyl Ketones: to a CH2Cl2
solution (2 mL) of Me3Si+ B(OTf)4– (0.29 mol/L, 0.57 mmol) was added a
CH2Cl2 solution (4 mL) of fluorovinyl vinyl ketone 7a (101 mg, 0.573
mmol) at rt. After the reaction mixture was stirred for 1 h, aqueous
NaHCO3 (4 mL) was added to quench the reaction at rt. Organic
materials were extracted with CH2Cl2 three times. Combined extracts
were washed with aqueous NaHCO3, dried over anhydrous Na2SO4,
filtered, and then concentrated in vacuo. The residue was purified by
preparative thin layer chromatography (SiO2, hexane/AcOEt 5:1) to give
fluorocyclopentenone 13a (52 mg, 51% yield) as a colorless oil.
the precursors with Me3Si+ B(OTf)4 readily induced the Nazarov
cyclization allowing the efficient synthesis of biologically
–
promising α-fluorocyclopentenone derivatives.
The Defluorinative Nazarov Cyclization of 1-Fluorovinyl Vinyl
Ketones: to a HFIP/CH2Cl2 solution (4 mL, 1:1) of fluorovinyl vinyl ketone
7f (55 mg, 0.30 mmol) was added TMSOTf (54.0 µL, 0.30 mmol) at 0 °C.
After the reaction mixture was stirred for 15 min, aqueous NaHCO3 (3
mL) was added to quench the reaction at 0 °C. Organic materials were
extracted with CH2Cl2 three times. Combined extracts were washed with
aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and
then concentrated in vacuo. The residue was purified by preparative thin
layer chromatography (SiO2, hexane/AcOEt 5:1 to 1:1) to give
hydroxycyclopentenone 12f (38 mg, 68% yield) as a pale yellow oil.
Experimental Section
General Statements. Tetrahydrofuran (THF), toluene, and CH2Cl2 were
dried by passing through a column of activated alumina followed by a
column of Q-5 scavenger (Engelhard). HFIP supplied by Central Glass
Co., Ltd (purity 99.9%) was distilled from and stored over molecular
sieves 3A. HFIP can be also purchased from commercial suppliers such
as Sigma–Aldrich Co. LLC. TFDA was prepared according to the
literature.[20c] TBAT was purchased from Sigma–Aldrich Co. LLC. and
used as received. Me3Si+ B(OTf)4 was prepared according to the
–
literature.[23] 1,1,1,3,3,3-Hexafluoro-2,2-di(p-tolyl)propane, an internal
standard for 19F NMR yields, were purchased from Tokyo Chemical
Industry Co., Ltd. and used as received.
Acknowledgements
Column chromatography and preparative thin layer chromatography
(PTLC) were conducted on silica gel (Silica Gel 60 N, Kanto Chemical
Co., Inc. for column chromatography and Wakogel B-5F, Wako Pure
Chemical Industries, Ltd. for PTLC) or alumina (Aluminium Oxide 90
Active Basic, Merck KGaA for column chromatography).
This research is supported by MEXT KAKENHI Grant Number
JP16H01002 (J.I.), JP16K13943 (J.I.), JSPS KAKENHI Grant
Number JP26105705 (K.F.), and Asahi Glass Foundation (K.F.).
Central Glass Co., Ltd. is acknowledged for the generous gifts of
(CF3)2CHOH (HFIP) and TfOH. Shin-Etsu Chemical Co., Ltd. is
acknowledged for the generous gifts of TBSCl and Et3SiCl.
IR spectra were recorded on a Horiba FT-300S spectrometer by the
attenuated total reflectance (ATR method). NMR spectra were recorded
on Bruker Avance 500, Jeol Alpha 500, or Jeol JNM ECS-400
spectrometers in CDCl3 at 500, 500, or 400 MHz (1H NMR), at 126, 126,
or 101 MHz (13C NMR), and at 470, 470, or 376 MHz (19F NMR),
respectively. Chemical shifts were given in ppm relative to internal Me4Si
Keywords: carbenes
•
cations
•
fluorine
•
Nazarov
•
1
(for H NMR: δ = 0.00), CDCl3 (for 13C NMR: δ = 77.0), and C6F6 (for 19F
organocatalysis
NMR:
δ = 0.0). High-resolution mass spectroscopy (HRMS) was
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Entry for the Table of Contents
FULL PAPER
Kohei Fuchibe, Ryo Takayama,
Takaharu Yokoyama, and Junji
Ichikawa*
F
O
5 mol% proton sponge
OTBS
F
R3
OTBS
R3
R2
TFDA (1.5 equiv)
i) 20 mol % TBAT
R2
R1
R2
F
ii) Me3Si+ B(OTf)4
(1.1 equiv)
–
toluene, 60 °C, 15 min
R1
R3
R1
Page No. – Page No.
TBS = Sit-BuMe2
TBAT = n-Bu4N+ SiF2Ph3
–
TFDA = FSO2CF2CO2SiMe3
Regioselective Synthesis of α-
Fluorinated Cyclopentenones via
Organocatalytic
Difluorocyclopropanation and Fluorine-
Directed and -Activated Nazarov
Cyclization
Silyl dienol ethers, prepared from α,β-unsaturated ketones, underwent proton
sponge-catalyzed difluorocyclopropanation with trimethylsilyl 2,2-difluoro-2-
fluorosulfonylacetate (TFDA) in a regioselective manner, leading to 1,1-difluoro-2-
siloxy-2-vinylcyclopropanes in good yields. The cyclopropanes thus obtained were
in turn subjected to fluoride ion-catalyzed ring opening to afford 1-fluorovinyl vinyl
ketones (i.e., Nazarov precursors). Treatment of the precursors with Me3Si+
–
B(OTf)4 regioselectively promoted the Nazarov cyclization, whose rate and
regioselectivity were drastically enhanced by the fluorine substituent, thereby
facilitating efficient synthesis of biologically promising α-fluorocyclopentenone
derivatives.
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