Angewandte
Communications
Chemie
Organofluorine Compounds
Azidoperfluoroalkanes: Synthesis and Application in Copper(I)-
Catalyzed Azide–Alkyne Cycloaddition
ˇ
Zsꢀfia E. Blastik, Svatava Voltrovꢁ, Vꢁclav Matousek, Bronislav Jurꢁsek, David W. Manley,
ˇ
Abstract: We report an efficient and scalable synthesis of
azidotrifluoromethane (CF3N3) and longer perfluorocarbon-
chain analogues (RFN3; RF = C2F5, nC3F7, nC8F17), which
enables the direct insertion of CF3 and perfluoroalkyl groups
into triazole ring systems. The azidoperfluoroalkanes show
good reactivity with terminal alkynes in copper(I)-catalyzed
azide–alkyne cycloaddition (CuAAC), giving access to rare
and stable N-perfluoroalkyl triazoles. Azidoperfluoroalkanes
are thermally stable and the efficiency of their preparation
should be attractive for discovery programs.
Scheme 1. Synthetic strategies toward azidoperfluoroalkanes (1).
O
rganic compounds containing trifluoromethyl and per-
fluoroalkyl motifs find numerous applications as crop pro-
tection agents, pharmaceuticals, and functional materials.[1] In
drugs, for example, the trifluoromethyl group is introduced
mainly to increase metabolic stability and lipophilicity (which
leads to better membrane permeability) and to modulate the
pKa of neighboring ionizable functional groups. It is also
two steps from trifluoronitrosomethane (Scheme 1a). Intui-
tively, such a compound might be considered explosive;
however; 1a is relatively thermally stable and explodes only
when heated above 3008C.[7,9] Nevertheless, the preparation
of 1a from trifluoronitrosomethane, which is toxic and
requires gas handling techniques, has precluded the use of
1a in synthesis.
[1a,b,2]
À
capable of imparting weak C F···X interactions.
Per-
fluoroalkyl (RF) groups are most commonly attached directly
to aromatic rings; however, more recently, there has been
a surge of interest in the synthesis of heteroatom-bound
structures (RFO, RFS).[1d,3] In comparison, the RFN motif is
relatively rare and its chemistry has hardly been explored.
This is either due to low stability or difficulty in accessing such
compounds.[4] Filling this niche offers new prospects for the
creation of compounds with unique physical, chemical, and
biological properties.
Organic azides are valuable intermediates in synthetic
chemistry. Their ability to react with nucleophiles or electro-
philes, to access nitrene chemistry, or to act as dipoles in
cycloadditions, underscores their versatility.[5] Copper(I)-
catalyzed azide–alkyne cycloaddition (CuAAC), for example,
is widely used across medicinal chemistry, polymer science,
and chemical biology.[6] However, a drawback of azides is
their potentially explosive nature. Azidotrifluoromethane
(1a) was prepared by Makarov[7] and later by Christe[8] in
Improving the synthesis of 1a in order to explore and
develop its synthetic utility was the focus of this research. The
reaction of CF3I with sodium azide under thermal or photo-
lytic conditions (SRN1 mechanism) proved unsuccessful
(Scheme 1b). However, a formal polarity reversal of the
reaction constituents did offer a more fruitful approach
(Scheme 1c). CF3TMS (2a, Ruppert–Prakash reagent) is
a well-known and easily accessible reagent for nucleophilic
trifluoromethyl addition. Upon activation by Lewis bases, it
transfers the CF3 group to a variety of electrophiles.[10]
Importantly, we found that stable electrophilic azides such
as p-toluenesulfonyl azide (3, TsN3) or nonaflyl azide (NfN3)
are competent partners in this reaction. Longer carbon chain
azidoperfluoroalkanes are not known, and our aim was to
prepare them in an analogous manner from trimethyl(per-
fluoroalkyl)silanes (2) or from 1H-perfluoroalkanes (Sche-
me 1c). Some azidopolyfluoroalkanes have been synthesized
through the reaction of sodium azide with polyfluoroal-
kenes[11] or halodifluoromethyl compounds.[12]
Optimization of the synthesis of CF3N3 (1a) was carried
out using the strategy outlined in Scheme 1c. Unlike the
reactions of silane 2a with carbonyl compounds, where
a catalytic amount of initiator is sufficient (the catalytic
cycle is maintained by the intermediate alkoxide), in our case,
an equimolar amount of the initiator was necessary. Anhy-
drous fluoride- or oxygen-containing initiators were explored
and the reaction was monitored by 19F NMR to determine
yields of 1a and the side products fluoroform (4) and
difluorosilicate 5 (Table 1). With K2CO3 in DMF, silane 2a
was converted slowly at ambient temperature or within one
[*] Z. E. Blastik, Dr. S. Voltrovꢀ, B. Jurꢀsek, Dr. D. W. Manley,
ˇ
Dr. B. Klepetꢀrovꢀ, Dr. P. Beier
The Institute of Organic Chemistry and Biochemistry
of the Czech Academy of Sciences
Flemingovo nam. 2, 16610 Prague 6 (Czech Republic)
E-mail: beier@uochb.cas.cz
ˇ
Dr. V. Matousek
CF Plus Chemicals s.r.o.
Kamenice 771/34, 625 00 Brno (Czech Republic)
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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