Iron- or silver-catalyzed oxidative fluorination of cyclopropanols for the synthesis of β-fluoroketones

Article abstract of DOI:10.1039/c5ob00632e

The Fe^III- or Ag^I-catalyzed oxidative fluorination of cyclopropanols via radical rearrangement is disclosed. This process features a straightforward and highly effective protocol for the site-specific synthesis of β-fluoroketones and represents an expedient method for the synthesis of γ-, δ- and ε-fluoroketones. Notably, this reaction proceeds at room temperature and tolerates a diverse array of cyclopropanols.

Full text of DOI:10.1039/c5ob00632e

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Organic & Biomolecular Chemistry
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Iron- or Silver-Catalyzed Oxidative Fluorination of
Cyclopropanols for the Synthesis of β-Fluoroketones
Shichao Ren,a Chao Feng, a,b* and Teck-Peng Loh a,b*
The FeIII- or AgI-catalyzed oxidative fluorination of and Li have demonstrated hydrofluorination and aminofluorination
cyclopropanols via radical rearrangement is disclosed. This of unactivated alkene respectively. 2) Functional group
process features a straightforward and highly effective interconversion.8 Representative examples of decarboxylative
protocol for the site-specific synthesis of
represents an expedient method for the synthesis of
-fluoroketones. Notably, this reaction proceeds at room alkylboronates was also reported by Li group.8a 3) Aliphatic C-H
β
-fluoroketones and fluorination were developed by Li and Sammis groups. Very
γ
-, - and recently, an elegent work of silver-catalyzed fluorination of
δ
ε
temperature and tolerates a diverse array of cyclopropanols.
fluorination.9 In this respect, Groves and co-workers have developed
a Mn/phorphyrin-mediated fluorination of aliphatic molecules.
While Lectka and co-workers used Cu/Schiff base complex to
accomplish the same procedure. Notwithstanding considerable
advances being attained in the arena of C(sp3)-F bond construction,
prominent limitations still remain, such as heavy reliance on
electronic biased substrates as those having benzylic or allylic C-H
bonds or requirement of substrate prefunctionalization as well as low
regioselectivity in the case of radical based fluorination of
unactivated alkanes which possess different potential reaction sites
and the situation becames more complicated when the generated C-F
moieties possessed acidic protons, such as those of β-fluoroketones,
which would easily lose the incorporated fluorine atom through
facile dehydrofluorination process. Electrophilic fluorination,
however, is mainly restricted to the synthesis of α-fluoro carbonyl
compounds.8b As such, the development of a general protocol which
affords β- or even γ-fluoroketone analogues with high efficiency and
praticality would be of high synthetic importance.
Fluorine-containing molecules have become increasingly important
in material sciences, agrochemicals, pharmaceuticals and life science
because of its intrinsic properties. The introduction of fluorine into
pharmaceutical molecules was routinely adopted as an effective
strategy for the drug development by increasing their lipophilicity,
metabolic stability, membrane permeability and bioavailability,1 in
addition, 18F-labeled organic compounds are also widely used in
positron-emission tomography (PET).2 Despite its importance, there
are only 30 natural organofluorides identified till date.3 Therefore,
considerable efforts were thus invested in the development of new
methods for the incorporation of fluorine into organic frameworks
during the past decade. While significant progress has been achieved
in the realm of C(sp2)-F bond formation,4,5 the construction of the
C(sp3)-F counterpart has been comparatively less well explored.6
Breakthrough in this field comes with the identification of radical
based protocols, which makes the incorporation of fluorine atom
possible using the following strategies: 1) Terminal C(sp3)-F bond
formation through radical addition to alkenes.7 For example, Boger
a Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui, P. R. China 230026.
b Division of Chemistry and Biological Chemistry, School of Physi-cal
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371. E-mail: fengchao@ntu.edu.sg; teckpeng@ntu.edu.sg
Electronic Supplementary Information (ESI) available: Experimental
procedure and characterization data of the new compounds. See
DOI: 10.1039/c000000x/
Scheme 1. Oxidative Fluorination of Cyclopropanols.
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substituents containing carbon atom via selective cleavage of C-C
bonds (1l-1q). To prove the scalability of this method, a gram scale
reaction of 1m was attempted and provided product 2m in 78% yield.
Cyclopropanols are versatile compounds which can be easily
prepared by the Kulinkovich10,11 reaction or by treatment of sily enol
ether with diiodomethane in the presence of Et2Zn.12 Because of its
unique structure, cyclopropanol can be treated as the equivalent of
homoenolate in the case of transition metal catalysis13,14 on one hand
and as β-keto radical, provided that suitable oxidants such as
manganese salts,12a CAN,15b persulfate15c were employed. Based on
our continuing interest in fluorine chemistry, we envisage that
oxidative fluorination of cyclopropanol would be an efficient and
straightforward protocol for the ready access to β-fluoroketones by
taking advantage of such radical rearrangement (Scheme 1).16 Herein
we would like to report a silver- or iron-catalyzed ring opening
fluorination of cyclopropanol with Selectfluor® reagent in aqueous
solution under mild reaction conditions, which provides a convenient
and efficient method for the access to β-fluoroketones. It also needs
to be pointed out that this strategy could be further extended to
cyclobutanol or even cyclopentanol thus providing site-specific
formation of γ- or δ-fluoroketones.17
To test our hypothesis, 1-phenylcyclopropan-1-ol (1a) and
Selectfluor® were employed as model substrates and the reaction
parameters were systematically investigated. We were rather pleased
to find that the desired fluorination product 2a was produced in 13%
yield with AgNO3 as catalyst, MeOH/H2O (1:1) as solvent (refer to
supporting information for details of reaction condition
optimization). Upon screening diverse solvents, DCM/H2O (1:1)
mixed solvent was proved to be the optimal choice, which delivered
2a in 92% yield. It was found that K2S2O8, which is widely used in
silver-catalyzed fluorination reaction as a co-oxidant, was not
required in this reaction.18 Although Fe(acac)3 stood out as a more
effective catalyst in the model reaction, which gave 2a in 96% yield,
limited substrate scope was observed in the following investigations
(vide infra). When NFSI was employed in place of Selectfluor® as
the fluorine donor, no desired fluorination product 2a was detected.
Finally, the control experiment clearly demonstrated the pivotal role
of silver or iron as catalysts in this transformation as only 8% yield
of product was obtained in their absence.
Table 1 Substrate scope of oxidative fluorination.a
Entry
1
Substrate
Product
Yielda (%)
96b
2
3
4
5
6
7
89
95b
99
92
97
83
With the optimal reaction conditions in hand, the reaction
generality with respect to cyclopropanol was examined, and the
results were summarized in Table 1. It was found that Fe(acac)3 was
the proper catalyst in the case of aryl substituted cyclopropanols,
with 1a, 1c, 1o smoothly transformed into 2a, 2c, 2o in 96%, 95%,
94% yields, respectively. However, with respect to alkyl and
electron-deficient or stericallly encumbered aryl derived
cyclopropanols, Fe(acac)3 proved to be unsuitable.19 In contrast,
8
9
74c
93
AgNO3 based protocol accommodated
a
wide variety of
cyclopropanols ranging from monosubstituted to trisubstituted ones,
thus affording the desired fluorination products in high to excellent
yield. Alkyl substituted cyclopropanols, which exhibited low
reactivity with Fe(acac)3, were soomthly transformed into the desired
products in the yields ranging from 74% to 94% (1j – 1n). A variety
of synthetically useful functional group, such as methoxyl, acetal,
ester, and trifluoromethyl, as well as halogen, which would provide
the opportunity for further elaboration via traditional coupling
strategies, were all well tolerated. It is worth mentioning that when
1,2-disubstituted or 1,2,2-trisubstituted cyclopropanols were
employed, the fluorine atom was introduced onto the more
10
11
91
94
12
74
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were examined with slight modification of reaction condition,
corresponding γ-, δ- and ε-fluoroketone products 4c-4e were readily
obtained, albeit with decreased reactivity with the enlargement of the
ring size (Equation 3). It is well known that cyclopropanols could
deliver reactive β-keto radicals under suitable oxidative conditions.15
The selective cleavage of C-C bonds with respect to 1,2-
disubstituted cyclopropanols also indicated the radical pathway of
this protocol. Furthermore, with the addition of 1 equivalent of
2,2,6,6-tetramethylpiperidinooxy (TEMPO) as a radical scavenger,
the desired reaction between 1d and selectfluor was totally inhibited
while product 5d, a putative β-keto radical trapped by TEMPO, was
instead obtained in 48% isolated yield (Equation 4).
Based on these experiment results and precedents, the reaction
pathways were tentatively proposed as shown in Scheme 2.20 The
reaction starts with the oxidation of Ag(I) by Selectfluor® reagent to
generate Ag(III)-F intermediate, presumably via oxidative addition.7a,
7b, 8a, 8b Single electron transfer between 1 and Ag(III)-F intermediate
happens to generate oxygen centered radical I, which undergoes fast
and selective rearrangement to deliver a carbon centered β-keto
radical II. The subsequent abstraction of the fluorine atom from the
adjacent Ag(II)-F occurs to produce the β-fluoroketone 2 and
regenates the Ag(I) species. At this stage, the reaction pathway that
proceeded through the formation of dinuclear Ag(II) intermediate
but not Ag(III)-F congener could not be precluded.5g
13
14
88
79
15
16
17
94b
90b
99
a Unless otherwise noted, the reactions were carried out at rt using 1a (0.1
mmol), Selectfluor® (0.2 mmol), AgNO3 (0.01 mmol) in DCM/H2O (1:1,1
b
mL) for 24 h. Yield of isolated products are given. Using Fe(acac)3 as
catalyst. c Reaction was run at 50 oC.
To further probe the reaction profile with respect to fluorine
atom incorporation step, 7-phenylbicyclo[4.1.0]heptan-7-ol 3a was
synthesized and subjected to the optimized reaction condition, which
produced product 4a as a mixture of 1.2:1 diastereoisomers in 68%
yield, implying a non-stereoselective C-F bond formation step in this
case (Equation 1). In stark contrast to the selective C-C bond
scission in the cases of 1l-1q, the bicyclic substrate 3b underwent
unselective C-C bond cleavage to provide a mixture of 4b and 4b' in
56% and 41% yields, which could be ascribed to the torsion effect
encountered during the ring enlargement process (Equation 2). With
the success obtained for the expedient synthesis of β-fluoroketone
via oxidative ring opening fluorination of cyclopropanol, we
wondered if the fluorination could also be implemented with four-
membered or even higher-membered substrates to synthesize γ- or δ-
fluoroketones. To our delight, when expanded cyclic substrate 3c-3e
Scheme 2. Proposed reaction mechanism.
In conclusion, we have reported an efficient and general method
for the synthesis of β-fluoroketone under very mild conditions using
Selectfluor® as the fluorine source. This reaction works efficiently
and delivers the desired β-fluoroketones in high to excellent yields.
In addition, because of the mild reaction conditions, this reaction
exhibits tolerance of a variety of synthetically useful functional
groups. Furthermore, by simply employing cyclobutanol,
cyclopentanol and cyclohexanol as substrates, γ-, δ- and even ε-
fluoroketone could be readily obtained with this protocol.
Acknowledgements
We gratefully acknowledge USTC Research Fund, the Nanyang
Technological University, Singapore Ministry of Education
Academic Research Fund (ETRP 1002 111, MOE2010-T2-2-
067, MOE 2011-T2-1-013) for the funding of this research. The
authors are grateful to Mr. Koh Peng Fei Jackson for his careful
proofreading of the final manuscript.
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20 Another possible mechanistic pathway which proceed through
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