Fe(III)/NaBH4-mediated free radical hydrofluorination of unactivated alkenes

Article abstract of DOI:10.1021/ja3063716

A powerful Fe(III)/NaBH₄-mediated free radical hydrofluorination of unactivated alkenes is disclosed using Selectfluor reagent as a source of fluorine and resulting in exclusive Markovnikov addition. In contrast to the traditional and unmanageable free radical hydrofluorination of alkenes, the Fe(III)/NaBH₄-mediated reaction is conducted under exceptionally mild reaction conditions (0 °C, 5 min, CH₃CN/H₂O). The reaction can be conducted open to the air and with water as a cosolvent and demonstrates an outstanding substrate scope and functional group tolerance.

Full text of DOI:10.1021/ja3063716

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Communication
Fe(III)/NaBH4-Mediated Free Radical Hydrofluorination of Unactivated Alkenes
Timothy J. Barker, and Dale L. Boger
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja3063716 • Publication Date (Web): 03 Aug 2012
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Fe(III)/NaBH4-Mediated Free Radical Hydrofluorination of
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Timothy J. Barker and Dale L. Boger*
Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037, United States
Supporting Information Placeholder
od would introduce the hydrogen and fluorine from separate
reagent sources, effecting a Markovnikov free radical
ABSTRACT: A powerful Fe(III)/NaBH4-mediated free rad-
ical hydrofluorination of unactivated alkenes is disclosed
hydrofluorination of alkenes.
using Selectfluor as a source of fluorine and resulting in
Examination and optimization of the reaction parameters
exclusive Markovnikov addition. In contrast to the tradition-
using Fe(III) oxalate (Fe2(ox)3) and NaBH4 were first ex-
al and unmanageable free radical hydrofluorination of al-
plored with the hydrofluorination of 9-decen-1-ol in con-
kenes, the Fe(III)/NaBH4-mediated reaction is conducted
junction with various sources of potential fluorine radical
under exceptionally mild reaction conditions (0 °C, 5 min,
donors (Table 1). Selectfluor and N-fluorobenzene-
CH3CN/H2O). The reaction can be conducted open to the
sulfonimide (NFSI) were screened as sources of fluorine for
air and with water as a cosolvent and demonstrates an out-
this reaction, because their 18F derivatives are available and
standing substrate scope and functional group tolerance.
used to incorporate 18F labels.10,11 Although typically re-
garded as sources of electrophilic fluorine (F+), a recent
study demonstrated that they may also serve as effective
sources of atomic fluorine (F·).12 Selectfluor and NFSI pro-
The growing presence of fluorine in pharmaceuticals and
agrochemicals1 as well as the use of 18F as a positron emitter
vided comparable and modest yields of 1a in a THF/H2O
(1:1) solvent mixture, whereas tosyl fluoride was ineffective
for positron emission tomography (PET) molecular imaging2
as a source of a radical fluorine trap under these conditions
(Table 1, entries 1-3). Adjusting the solvent mixture to
CH3CN/H2O (1:1) to improve the solubility of Selectfluor
substantially improved the yield (entry 4). The solvent mix-
ture was found to be critical to providing good yields of the
desired products since each solvent alone was ineffective (0-
14%) compared to the mixture (entries 5-7). Remarkably,
the reaction time could be reduced to only 5 min (entry 8),
an important consideration for 18F radiolabeling because of
the 110 min half-life of 18F. Compared to prior studies where
the
have stimulated a renewed interest in methods for the intro-
duction of fluorine under mild reaction conditions often
using transition metals.3 In spite of this recent interest, the
hydrofluorination of alkenes has remained a challenging
transformation. Olah and coworkers developed conditions
using HF/pyridine or HF with other amines that provide the
hydrofluorination of alkenes in good yields. However, this
method has limitations with respect to substrate stability and
functional group tolerance under the relatively harsh reac-
tion conditions.4 The complementary free radical
hydrofluorination of alkenes is typically regarded as an un-
manageable reaction. Fluorine (F2) and related sources of
atomic fluorine (F·) including hypofluorites exhibit an un-
controllable reactivity that precludes their use.5 In part, the
hazards of such reactions may be addressed using the more
Table 1. Optimization of Reaction Parameters.
6
manageable, but still highly reactive XeF2 or potentially
perfluoroalkanes7 although the reagent availability (XeF2)
and scope of their behavior as free radical traps remain to be
fully established. Neither is adaptable to 18F labeling proce-
dures. Recently, we described an Fe(III)/NaBH4-mediated
free radical oxidation of a trisubstituted alkene for introduc-
tion of the vinblastine C20′ tertiary alcohol,8 that proved
general for the oxidation of unactivated alkenes.9 In the lat-
ter studies, we defined the alkene substrate scope, estab-
lished the exclusive Markovnikov addition regioselectivity,
introduced the use of alternative free radical traps, and ex-
amined the Fe(III) salt and initiating hydride source. Due to
the excellent functional group tolerance and its mild reaction
conditions (0 °C, 5-30 min) that are relatively insensitive to
the reaction parameters, including the use of water as a
cosolvent, we sought to develop a method for the free radi-
cal incorporation of fluorine using this strategy. This meth-
aReaction time was 5 min. bNaBH4 (3.2 equiv).
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companion reagent coordination to Fe(III) may compete,9
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the Fe(III)/NaBH4-mediated hydrofluorination reaction
proved relatively insensitive to the Fe(III) source (Fe2(ox)3,
75% = Fe(NO3)3, 75%, Fe(acac)3, 71% > Fe2(SO4)3, 55%, >
FeCl3, 25% + 66% chloride > FeF3 (insoluble), 0%). Omis-
sion of the Fe(III) reagent from the reaction mixture provid-
ed only recovered starting alkene substrate confirming its
essential role. Additional control experiments revealed that
the reaction was surprisingly insensitive to air, so all reac-
tions were run open to an atmosphere of air. Sodium and
lithium borohydride (NaBH4 and LiBH4) were effective as
the initiating hydride source, while PhSiH3, Bu3SnH,
NaCNBH3, and NaB(OAc)3H did not support the desired
reactivity (NaBH4, 75% = LiBH4, 73% > BH3, 45% >
NaCNBH3, NaB(OAc)3H, 0%). Aside from its availability,
cost, and ease of use, NaBH4 is especially attractive as a
formal hydrogen radical source because the availability of
NaBD4 and NaBT4 provides the opportunity for the introduc-
tion of additional isotopic and radiolabels using this method.
Although this was not investigated in detail, related systems
(Co(acac)2/PhSiH3, Selectfluor) used for the oxidation or
functionalization of unactivated alkenes did not support the
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,
hydrofluorination reaction.13 14 Finally, the reaction proved
sensitive to the reaction concentration (0.05 M < 0.025 M <
0.0125 M > 0.00625 M for 1a, see Supporting Information)
and reductions in the stoichiometric reagent amounts below
those indicated (2 equiv of Fe2(ox)3, 3.2-6.4 equiv of NaBH4,
see Supporting Information) led to progressively lower con-
versions.
The alkene substrate scope proved quite general with
unactivated terminal alkenes, as well as di- and trisubstituted
alkenes participating in the hydrofluorination reaction effec-
tively (Scheme 1). A wide range of substrates and functional
groups are tolerated including unprotected and protected
alcohols, protected and free amines, phenols, epoxides,
ketals, acetals, carboxylic acids, carbamates, amides, esters,
peptides, and carbohydrates. Notably, the free radical
hydrofluorination is so fast that the competitive fluoro-
lactonization of 4-pentenoic acid with Selectfluor is not ob-
served,15 instead providing product 1i in 66% yield. This
result also provides mechanistic insight into this reaction,
indicating that it does not proceed through a carbocation
intermediate. In fact, a series of substrates capable of proxi-
mal nucleophilic participation in an alkene functionalization
reaction (1f, 1h-1l) failed to display this competitive behav-
ior, providing only the free radical hydrofluorination prod-
aNaBD4 (6.4 equiv). bReaction conditions: Fe2(ox)3 (4 equiv),
NaBH4 (12.8 equiv), Selectfluor (4 equiv), THF/MeCN/H2O
(4:2:3).
Complementary to prior mechanistic studies,8,9 we further
probed the mechanism of the reaction using the substrates 2,
4 and 6 (Scheme 2). Substrates 2 and 4 provided a 1:1 mix-
ture of product diastereomers, indicating that the addition of
hydrogen and fluorine across the double bond is non-
diastereospecific, consistent with the previously established
free radical mechanism of Fe(III)/NaBH4-mediated reac-
tions.8,9 The reactions of 2 and 4, like that of 1d, also con-
firm that NaBD4(NaBH4) serves as the reagent source of the
hydrogen atom and not solvent, highlighting the additional
reagent labeling potential (D,T) of the reaction, and pro-
duced the pharmaceutically important pyrrolidine 5 in the
case of 4. Substrate 6 served to further probe the presence
of a radical intermediate in this hydrofluorination reaction.
Under the reaction conditions (Fe(III)/NaBH4) in the pres-
ence of Selectfluor, the cyclized product 7 was observed in a
40% yield, along with the cyclized, but reduced byproduct 8
ucts in good yields.
Eugenol provided the desired
hydrofluorination product 1m instead of the known
Selectfluor oxidation of 4-substituted phenols to the corre-
sponding 4-fluorocyclohexadienones.16 Diethyl trans-4-
cyclohexene-1,2-dicarboxylate provided a 52% yield of the
fluorinated product 1p (5:1 dr). The 5:1 axial/equatorial
diastereoselectivity of this reaction is consistent with previ-
ously reported radical additions to cyclohexenes.17 The
sterically hindered trisubstituted alkene in cholesterol was
fluorinated to provide 1q in 41% yield (97% brsm) as a sin-
gle diastereomer. Only styrenes proved to be ineffective
alkene substrates, instead yielding the benzylic alcohols and
corresponding dimers of the benzylic radicals under the re-
action conditions.18
Scheme 1. Scope of Hydrofluorination of Unactivated
Alkenes.
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(6%). In previously reported mechanistic studies on the Sadighi and coworkers reported that a Au-catalyzed reaction
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electrophilic fluorination of alkenes with Selectfluor, no
analogous cyclization onto a pendant alkene was observed
and was indicative of reactions that proceed through an ionic
mechanism. In contrast, the reaction of 6 provided the cy-
clized products 7 and 8, inconsistent with an ionic mecha-
nism and further supportive of free radical intermediates
generated under these reaction conditions.19 It is not yet
clear whether the reaction involves generation of an initiat-
ing Fe–H and its unusual Markovnikov migratory insertion
onto the alkene followed by subsequent homolytic cleavage
of the resulting C–Fe bond for alkyl radical generation, or
whether an Fe–H or oxidized borane/borohydride (e.g.,
BH3·/BH4·) simply serve as an initiating hydrogen atom do-
nor.
of alkynes with Et3N·3HF provides the vinyl fluoride prod-
ucts.20 Our complementary results with 9 are consistent with
an Fe/NaBH4-mediated free radical reduction of the alkyne
followed by addition of a hydrogen atom to the alkene to
form an alkyl radical which is then trapped with a fluorine
atom from Selectfluor.21
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An initial examination of an Fe(III)/NaBH4-mediated reac-
tion for the hydrofluorination of unactivated alkenes is re-
ported. Complementary to the more traditional approaches
for the introduction of fluorine into organic substrates using
nucleophilic (F-) or electrophilic (F+) reagents and reactivity,
the studies detailed herein provide the first general method
for the effective free radical fluorination (F·) of unactivated
alkene substrates. The broad alkene scope of the reaction,
the exclusive Markovnikov addition regioselectivity, the
facile nature of this method, its insensitivity to air and mois-
ture, and the excellent functional group tolerance make this
reaction an attractive method for the hydrofluorination of
alkenes. Because of the availability of labeled reagents,12 the
well-defined and broad substrate scope, the superb function-
al group compatibility required for late stage utilization, the
technically non-demanding reaction protocol, and especially
Scheme 2
the rapid reaction times (5 min, 0 °C), the extension of this
method to 18F introduction for PET imaging should prove
especially useful.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, additional
optimization studies, and analytical data and spectra for all
products and new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
boger@scripps.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Finally, subjecting the alkyne 9 to the reaction conditions
resulted in the generation of the monofluorinated product 1e
in 34% yield, with no vinyl fluoride or difluorinated product
observed (eq 1). The isolation of benzyl hex-5-enoate (10)
from the reaction mixture suggests the alkene is an interme-
diate en route to formation of the monofluorinated product
1e and that reduction of the initial vinyl radical occurs faster
and in preference to fluorination. Previously, Olah has re-
ported that the ionic reaction of alkynes with HF/pyridine
provides the difluorinated products4 and more recently,
We gratefully acknowledge the financial support of the National
Institute of Health (CA042056, CA115526). T.J.B. is a NIH
postdoctoral fellow (CA165303).
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