Organic Letters
Letter
Notes
contrast, affords 4 in up to 79% yield and, generally, can enable
deoxyfluorination of challenging substrates that cannot be
deoxyfluorinated by other reagents, such as PyFluor.
The authors declare the following competing financial
interest(s): T.R. may financially benefit from sales of
AlkylFluor.
In optimizing the deoxyfluorination reaction with AlkylFluor,
we found two complementary reaction protocols. Most
alcohols react directly with AlkylFluor in satisfactory yield, in
the presence of excess fluoride with mild heating. Potassium
fluoride was found to be generally the best fluoride source, and
1,4-dioxane the best solvent. Certain challenging substrates give
low yields under these conditions, however. For these cases, we
found that AlkylFluor can be converted to PhenoFluor in situ
by preheating with cesium fluoride in toluene before the
for details). This reaction modification can increase yield, often
dramatically, for otherwise low-yielding substrates. While it
adds an additional manipulation, it allows access to the full
scope of fluorination with PhenoFluor without the associated
difficulties of storage and handling. Testosterone, for example,
is fluorinated in 50% yield by direct reaction with AlkylFluor,
but in 79% yield by preformed PhenoFluor (Table 1).
Deoxyfluorination with AlkylFluor generally proceeds cleanly,
with only elimination as a minor side reaction for certain
alcohols. For optimal results, all reactions should be performed
under anhydrous conditions with dried solvents. Alkali metal
fluoride salts absorb moisture from air but can be sufficiently
dried immediately prior to use by heating under vacuum (100−
120 °C, 1 h).
ACKNOWLEDGMENTS
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We thank Erica M. D’Amato, Jeffrey A. O. Garber, and
Debashis Mandal (Harvard) for helpful discussion. We thank
the National Institutes of Health (NIH) National Institute of
General Medical Sciences (GM088237) for funding.
REFERENCES
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Fluorination with AlkylFluor is applicable to a variety of
small molecule classes (Scheme 1), including carbohydrates (9,
12), amino acids (6), steroids (4, 15), and pharmaceutical
compounds (5, 8, 10). Carbonyl functionality is well tolerated,
including ketones, esters, amides, and carbamates, as well as
protected and unprotected amines, acetals, heterocycles, and
azo groups.
In conclusion, we have developed a new, bench-stable
reagent that allows access to convenient and practical
deoxyfluorination of alcohols. AlkylFluor is insensitive to
moisture and air. Deoxyfluorination with AlkylFluor demon-
strates a broad substrate scope and high functional group
tolerance, larger than with any other commercially available
reagent, and can be performed on the bench. We expect that
this method will provide easy and rapid access to a broad range
of late-stage fluorinated molecules once AlkylFluor is
commercially available.
ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
Detailed experimental procedures and spectroscopic
characterization for all new compounds (PDF)
AUTHOR INFORMATION
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Corresponding Author
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Org. Lett. XXXX, XXX, XXX−XXX