10.1002/chem.201904366
Chemistry - A European Journal
COMMUNICATION
difluoropropargyl groups. Many alkynes were found to be suitable
Raman tags for live-cell imaging, and substituents on alkyne were
known to effect the wavelength and intensity of the Raman
signals.[20] We thus measured and compared the alkyne Raman
signals of several gem-difluoropropargyl ethers and their non-
substituted propargyl ones. Interestingly, alkyne Raman signals
of gem-difluoropropargyl ethers appeared at higher wavenumbers
compared to those of propargyl ethers, without changing their
intensities (see the Supporting Information). These results
suggested that gem-difluoropropargyl groups may be useful
Raman tags for multi-imaging with several alkynes.
Acknowledgements
This work was partially supported by The Naito Foundation, by a
Grant-in-Aid for Scientific Research on the Innovative Area
"Frontier Research on Chemical Communications” (No.
18H04603)” from The Ministry of Education, Culture, Sports,
Science, and Technology of Japan, by the Platform Project for
Supporting Drug Discovery and Life Science Research (Platform
for Drug Discovery, Informatics, and Structural Life Science) (No.
JP18am0101100) from the Japan Agency for Medical Research
and Development (AMED), and by a Grant-in-Aid for JSPS fellows
(No. 172575 to T.O.) from The Japan Society for the Promotion of
Science (JSPS).
Finally, we applied gem-difluoropropargyl compounds to the
synthesis of various -difluoroethers by using proxyphylline
derivative 36 (Scheme 3). As mentioned above, gem-
difluoropropargyl groups react at ambient temperature with azides
to give triazoles such as 46.[7] When phenyl nitrile oxide was used
as a reactant, isoxazole 47 was obtained with good selectivity. It
was possible to convert 36 to the fluoropropyl ether 48 by
reducing the alkyne.
Conflict of interest
The authors declare no conflict of interest.
F
F
O
N
N
N
N
N
O
N
N
Keywords: difluoropropargylation • dicobalt complex•drug
O
Bn
development
46
BnN3 (1.5 equiv.), Cu(OAc)2 (5 mol%)
sodium ascorbate (20 mol%)
tBuOH-H2O (1:1), rt, 12 h, 89%
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48
Scheme 3. Syntheses of various difluoroethers.
In conclusion, we developed gem-difluoropropargylation of
alcohols using complex 2. Our developed methods could be
applied to various substrates including several naturally occurring
compounds and amino acid derivatives. Notably, complex 2
reacted with aliphatic alcohol selectively even if the substrates
contained other nucleophilic functional groups. The introduced
gem-difluoropropargyl dicobalt cluster was easily removed by
CAN or N,N,N’-trimethylethylene diamine, and then desilylation
by TBAF converted the resulting compound to useful terminal
gem-difluoropropargyl groups. The Raman spectral property of
gem-difluoropropargyl ethers was clarified, and the obtained
gem-difluoropropargyl ethers were successfully converted to
various -difluoroethers. We hope that the method developed
herein will provide new opportunities to use -difluoroethers in
drug development. Further studies using complex 2 to synthesize
other difluoroethers are underway in our laboratory.
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