Late-stage deoxyfluorination of alcohols with phenofluor

Article abstract of DOI:10.1021/ja3125405

An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting the selectivity in substrates with multiple alcohols is given.

Full text of DOI:10.1021/ja3125405

Communication
pubs.acs.org/JACS
Late-Stage Deoxyfluorination of Alcohols with PhenoFluor
Filippo Sladojevich, Sophie I. Arlow, Pingping Tang, and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
S
* Supporting Information
PhenoFluor was originally developed for deoxyfluorination of
phenols,7 and we found that appropriate modification of the
ABSTRACT: An operationally simple protocol for the
selective deoxyfluorination of structurally complex alcohols
is presented. Several fluorinated derivatives of natural
products and pharmaceuticals have been prepared to
showcase the potential of the method for late-stage
diversification and its functional group compatibility. A
series of simple guidelines for predicting the selectivity in
substrates with multiple alcohols is given.
reaction conditions allows deoxyfluorination of aliphatic
alcohols. Deoxyfluorination of alcohols can be accomplished
with several commercially available reagents, such as DAST5a
and Deoxo-fluor,5b but is normally not compatible with a
variety of functional groups and is often plagued by elimination
or other side reactions.5a,6 Table 1 shows the utility of
Table 1. Comparison of PhenoFluor with Other
Commercially Available Deoxyfluorinating Reagents
a
he selective modification of natural products and druglike
T
molecules can rapidly generate new pharmaceutical
candidates with potentially improved pharmacological profiles.1
Late-stage fluorination2 is particularly promising in this regard
because incorporation of fluorine into molecules can increase
their metabolic stability, bioavailability, and blood−brain barrier
penetration.3 However, late-stage fluorination is challenging,
and to the best of our knowledge, no general late-stage aliphatic
fluorination method is currently available. Here we report the
first functional-group-tolerant aliphatic deoxyfluorination re-
action of complex primary, secondary, and tertiary alcohols.
Deoxyfluorination of structurally simple alcohols is known, and
several reagents for deoxyfluorination have been described.4,5
However, current deoxyfluorination methods are commonly
characterized by limited functional group tolerance, side
reactions such as elimination, and instability or explosion of
the reagents upon heating.4c,5a,6 The method presented herein
(eq 1) employs commercially available PhenoFluor (1), a
a
Yields were determined by 19F NMR spectroscopy using 1-fluoro-3-
b
nitrobenzene as an internal standard. Best yield obtained from
reactions run in toluene, in dioxane and under the optimized reaction
conditions previously reported for the reagent (see the Supporting
Information for details).
PhenoFluor compared with other commercially available
deoxyfluorination reagents and illustrates the fact that
PhenoFluor gives access to fluorinated molecules that are
practically inaccessible by deoxyfluorination using other
reagents. Fmoc-serine methyl ester was selected as a simple
but challenging test substrate for evaluation. The β-hydroxy
ester moiety of Fmoc-serine methyl ester is prone to formal
crystalline, nonexplosive solid that does not suffer from
competing side reactions to the extent that other deoxyfluori-
nation reagents do. The conceptual advantage of PhenoFluor,
beyond its better safety profile, is manifested in its chemo-
selectivity, which results in the ability to introduce fluorine
selectively and predictably into complex small molecules with
several hydroxyl groups, which has not been shown with other
reagents.
Received: December 22, 2012
Published: February 11, 2013
© 2013 American Chemical Society
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Table 2. Late-Stage Deoxyfluorination of Alcohols with PhenoFluor
a
The natural product/pharmaceutical used as the starting material or the natural product/pharmaceutical from which the starting material was
b
c
d
derived. Isolated yields of single compounds are shown. A 16% yield of the corresponding primary allylic fluoride was isolated. Deoxyfluorination
with retention was observed. No KF was used.
e
elimination of water when the hydroxyl group is converted into
a leaving group, and the carbamate group can form the
corresponding aziridine by intramolecular cyclization subse-
quent to alcohol activation; both of these side reactions were
observed with the conventional reagents shown in Table 1.
Evaluation of each reagent was performed in toluene, in
dioxane, and under the optimized conditions previously
reported for each reagent.5a−e Fluoroserine 2 was obtained at
best in 11% yield with conventional deoxyfluorination reagents
but could be obtained in up to 80% yield with PhenoFluor.
Deoxyfluorination of aliphatic alcohols with PhenoFluor can
be carried out at room temperature, enabling fluorination of
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Communication
temperature-sensitive substrates. For example, for everolimus8
(see 15) or oligomycin A (see 17), fluorination was performed
at room temperature to avoid decomposition (Table 2). The
profile and higher chemoselectivity. The chemoselectivity of
PhenoFluor enables access to complex fluorinated molecules;
other deoxyfluorination reagents do not discriminate well
between reactive functional groups. For example, DAST affords
several (at least five) more fluorinated analogues upon reaction
with 18 as a result of the indiscriminate reaction of DAST with
secondary alcohols, including β,β′-substituted carbinols. The
source of the differentiated chemoselectivity of PhenoFluor is
not yet understood but likely is more complex than could be
rationalized simply on the basis of its larger size compared with
the other deoxyfluorination reagents. We have observed that
unanticipated hydrogen bonding between the hydrogen atoms
of the imidazoline ring of PhenoFluor and bifluoride is
important for reactivity.7 The better safety profile is another
benefit of PhenoFluor. Several conventional reagents are
unstable toward heat or even explosive. An exotherm of only
0.15 kcal·g−1 was observed by differential scanning calorimetry
(DSC) at PhenoFluor’s decomposition temperature of 213 °C.
In conclusion, we have developed a general method for the
selective, predictable, direct deoxyfluorination of complex
alcohols. The substrate scope and functional group tolerance
surpass those of any aliphatic fluorination reaction reported to
date. One drawback of PhenoFluor is its molar mass of 427
g·mol−1, which makes it a convenient reagent for subgram-and
gram-scale reactions but a wasteful reagent for larger-scale
reactions. We are currently investigating the potential of
extending the reported method to late-stage 18F radiolabeling9
for positron emission tomography (PET) applications.
addition of Hunig’s base was beneficial to shorten the reaction
̈
time, and KF was found to reduce side products resulting from
elimination but was not generally required for the reaction to
proceed. The formation of reaction products resulting from
elimination could also be reduced by increasing the reaction
temperature from 23 to 80 °C when toluene was used as the
solvent. For example, while the deoxyfluorination of testoster-
one (see 3) and epi-androsterone (see 13) proceeded at 23 °C,
they were performed at 80 °C because elimination was found to
be the main side reaction for epi-androsterone and testosterone
at 23 °C. Appropriate reaction solvents in addition to toluene
are dioxane and CH2Cl2, depending on the solubility of the
alcohol substrate. Chiral secondary alcohols could typically be
deoxyfluorinated with inversion without observed epimeriza-
tion or elimination. In addition, secondary allylic alcohols
afforded allylic fluorides consistent with an SN2 mechanism and
only small amounts (if any) of allylic fluorides consistent with
an SN2′ mechanism. Ketones and especially aldehydes are
challenging substrates for deoxyfluorination reactions because
they are often converted to the corresponding geminal
difluorides,4a yet PhenoFluor can tolerate carbonyl functional
groups (e.g., see 3, 6, and 13).
Complex molecules, such as several of those depicted in
Table 2, frequently contain more than one carbinol. Typically,
PhenoFluor can discriminate between different carbinols and
afford a single fluorinated analogue with synthetically useful
selectivity; for example, a 71% yield of the fluorinated
oligomycin A analogue 17 was isolated, despite the presence
of five hydroxyl groups in oligomycin A (18) (Figure 1). We
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, spectroscopic character-
ization for all new compounds, and details of the comparison
of PhenoFluor with other commercially available reagents. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ritter@chemistry.harvard.edu
■
Notes
The authors declare the following competing financial
interest(s): PhenoFluor is currently sold by Sigma-Aldrich
and Strem and licensed by SciFluor Life Sciences. P.T. and T.R.
have financial interest in PhenoFluor sales.
Figure 1. Rationale for the site-selective deoxyfluorination of
oligomycin A (18).
ACKNOWLEDGMENTS
■
We thank S. Huang (Harvard) for help with NMR data
collection and structure elucidation, E. Lee (Harvard) for X-ray
data collection and analysis, and the NIH (GM088237) and the
European Community (Marie Curie IOF fellowship to F.S.) for
financial support.
observed several trends that enable the prediction of the
fluorination site in the presence of several hydroxyl groups: (1)
Primary alcohols are selectively deoxyfluorinated in the
presence of secondary and tertiary alcohols. (2) Secondary
alcohols react significantly slower or not at all when they are
β,β′-dibranched, unless the secondary alcohol is allylic. (3)
Tertiary alcohols do not react, unless they are allylic. (4) On
the basis of previous observations,7 hydroxyl groups engaged in
hydrogen bonding are not reactive. For the substrates
evaluated, these four guidelines were sufficient to predict the
deoxyfluorination reactivity and selectivity correctly.
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