Ring-opening fluorination of cyclobutanols and cyclopropanols catalyzed by silver

Article abstract of DOI:10.1246/cl.150138

Cyclobutanols and cyclopropanols underwent ring-opening fluorination upon treatment with Selectfluor in the presence of a substoichiometric amount of a silver salt. The reaction provides an efficient method to synthesize γ- and β-fluoroalkyl ketones.

Full text of DOI:10.1246/cl.150138

Received: February 11, 2015 | Accepted: March 4, 2015 | Web Released: March 12, 2015
CL-150138
Ring-opening Fluorination of Cyclobutanols and Cyclopropanols Catalyzed by Silver
Naoki Ishida, Shintaro Okumura, Yuuta Nakanishi, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510
(E-mail: murakami@sbchem.kyoto-u.ac.jp)
Cyclobutanols and cyclopropanols underwent ring-opening
fluorination upon treatment with Selectfluor in the presence of a
substoichiometric amount of a silver salt. The reaction provides
an efficient method to synthesize γ- and β-fluoroalkyl ketones.
O
2+
F
Cl
Ph
N
2[BF4]-
2a
N
F
Ag(I)
Organofluorine compounds have attracted significant atten-
tion in pharmaceuticals, agrochemicals, and materials science.1
The strong demand for organofluorine compounds has spurred
the development of new synthetic means for organofluorine
compounds.2,3 Herein we report a ring-opening fluorination
reaction of cyclobutanols and cyclopropanols catalyzed by
silver. A fluorine atom is introduced in a site-selective manner to
afford the γ- and β-fluoroalkyl ketones.
+
O
Cl
[BF4]-
N
Ph
CH2
N
B
+
+
[AgIIIF]+[BF4]-
AgIIF
Ph
Cyclobutanols are facilely prepared by well-established
methods such as [2+2] cycloaddition of alkenes with ketenes
followed by an addition reaction of Grignard reagents.4 They
undergo ring-opening reactions upon treatment with transition-
metal catalysts.5 Oxidation of cyclobutanols also induces ring
opening.6 As a continuation of our previous studies on the ring-
opening reactions of cyclobutanol derivatives,7 we examined a
reaction with fluorinating agents to find that cyclobutanol 1a
underwent a ring-opening fluorination reaction when treated
with Selectfluor (4 equiv)8 in the presence of AgIF (20 mol %) in
a benzene/water biphasic solvent at 60 °C for 5 h (Scheme 1).3c
γ-Fluoroalkyl ketone 2a was obtained in 60% isolated yield.
Other Ag(I) salts like AgBF4 and AgNO3 exhibited comparable
reactivities, and no reaction took place in the absence of Ag(I)
salts. Fluorinating agents such as N-fluorobenzenesulfonimide
and N-fluoropyridinium salts were totally ineffective. Treatment
of 1a with a stoichiometric amount of either AgIF or AgIIF2
in the absence of Selectfluor failed to induce any reactions,
suggesting that a reactive species is generated in situ from AgIF
and Selectfluor to initiate the ring-opening fluorination reaction.
The formation of 2a from 1a can be explained by assuming
a radical-type reaction mechanism depicted in Scheme 2,
although we have no experimental evidence for it.9 Initially,
Ag(I) is oxidized to Ag(III) by Selectfluor. The resulting Ag(III)
OH
Ph
OAgIIIF
1a
2+
Cl
A
N
2[BF4]-
N
H
Scheme 2. Proposed mechanism.
reacts with cyclobutanol 1a to furnish silver cyclobutanolate A.
One-electron transfer from the cyclobutanolate moiety to
Ag(III), i.e., homolytic cleavage of the Ag-O bond induces
ring opening to give the alkylradical intermediate B together
with AgIIF species. Finally, the carbon-centered radical B is
fluorinated with the AgIIF, resulting in the formation of 2a and
Ag(I) species, the latter of which re-enters the next cycle.
The ring-opening fluorination reaction was significantly
dependent on the substituent at the 1-position of cyclobutanols.
No reaction was observed with the 1-octadecylcyclobutanol.
When a phenyl group is present in the 1-substituent, however,
the fluorination reaction took place. 1-Phenylcyclobutanol (1b)
underwent the ring-opening fluorination to produce the corre-
sponding γ-fluoroalkyl ketone 2b in 77% yield (Table 1). 1-
Benzylcyclobutanol (1c) was also reactive (83% conversion) and
2c was obtained in 30% yield along with various unidentified
by-products. The reaction of 1-(3-phenylpropyl)cyclobutanol
(1d) was sluggish and transformed only partially under the same
reaction conditions. 1-[2-(4-Methoxyphenyl)ethyl]cyclobutanol
(1e) was so reactive that 1.2 equiv of Selectfluor was enough for
full conversion. On the other hand, 1-[2-(4-chlorophenyl)ethyl]-
cyclobutanol (1f) was unreactive under the same reaction
conditions. These results may indicate that the electron-donating
phenyl group located in proximity to the hydroxy group
facilitates the approach of the catalytically active silver species
to the hydroxy group.10
AgIF (20 mol %)
Ph
Selectfluor (4 equiv)
O
OH
F
benzene, H2O
60 °C, 5 h
Ph
2a 60%
1a
2+
Cl
N
2[BF4]-
N
F
Selectfluor
Scheme 1. Ring-opening fluorination of 1a.
Chem. Lett. 2015, 44, 821–823 | doi:10.1246/cl.150138
© 2015 The Chemical Society of Japan | 821

Table 1. Ring-opening fluorination of 1-substituted cyclobutanolsa
Phenyl-substituted cyclopropanols 5a-5c also underwent
the ring-opening fluorination reaction under the same reaction
conditions to afford β-fluoroalkyl ketones (Table 2).13 In the
case of unsymmetrical cyclopropanol 5c, the ring opening took
place site-selectively at the more substituted position to afford
sec-alkyl fluoride 6c. This result is consistent with the proposed
radical mechanism, since generation of a more substituted
carbon radical would be favored.
AgIF (20 mol %)
Selectfluor (4 equiv)
R
OH
O
F
benzene, H2O
100 °C, 10 h
R
1
2
Conversion
of 1/%b
Yield of
2/%c
Entry
R
1
2
3
4d
5
Ph- (1b)
PhCH2- (1c)
Ph(CH2)3- (1d)
4-MeOC6H4(CH2)2- (1e)
4-ClC6H4(CH2)2- (1f)
100
83
23
100
<5
77
30
<10
40
In conclusion, we have described the silver-catalyzed ring-
opening fluorination reaction of cyclobutanols and cyclopropa-
nols. The site-selectivity of the ring-opening process can be
rationalized by assuming a radical-type mechanism; the C-C
bond is cleaved to generate a more stabilized carbon radical. The
present reaction offers a convenient way to synthesize γ- and
β-fluorinated ketones.
<5
aReaction conditions: cyclobutanol 1 (0.20 mmol), AgF (0.04 mmol,
20 mol %), Selectfluor (0.8 mmol, 4 equiv), benzene (1 mL), H2O
(1 mL), 100 °C, 10 h. bDetermined by NMR analysis of the crude
c
d
reaction mixture. Isolated yield. 1.2 equiv of Selectfluor was used.
This work was supported in part by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis”, a Grant-in-Aid for
Scientific Research (B) from MEXT, and the ACT-C program of
the JST.
OMe
O
AgIF (20 mol %)
Selectfluor (4 equiv)
benzene, H2O
100 °C, 10 h
OMe
Supporting Information is available electronically on J-STAGE.
OH
F
References and Notes
3
4 85%
Scheme 3. Ring-opening fluorination of 3.
1
2
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Table 2. Ring-opening fluorination of cyclopropanolsa
AgIF (20 mol %)
Selectfluor (4 equiv)
O
R
OH
benzene, H2O
100 °C, 10 h
R
F
5
6
Entry
1
Cyclopropanol 5
Ph OH
β-Fluorinated ketone 6b
O
Ph
F
5a
5b
6a 78%
O
2
3
Ph
OH
Ph
F
6b 55%
3
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aReaction conditions: cyclopropanol 5 (0.20 mmol), AgF (0.04 mmol,
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b
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822 | Chem. Lett. 2015, 44, 821–823 | doi:10.1246/cl.150138
© 2015 The Chemical Society of Japan

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8
9
When 2 equiv of Selectfluor was used, 2 was obtained in
55% yield and 21% of 1 was recovered.
TEMPO suppressed the ring-opening fluorination reaction of
Chem. Lett. 2015, 44, 821–823 | doi:10.1246/cl.150138
© 2015 The Chemical Society of Japan | 823