Organic Letters
Letter
dramatic impact (Table 1, entries 7−9). Indeed, trifluoroacetic
acid (TFA), camphorsulfonic acid (CSA), or p-toluenesulfonic
acid monohydrate (PTSA) did not provide 2a (Table 1, entries
7−8) or provided it in low yield (Table 1, entry 9). Other
solvents such as 1,2-dichloroethane (1,2-DCE), 1,4-dioxane or
toluene did not perform as well as CH2Cl2 (Table 1, entries
10−12). A significant drop in yield was observed when the
reaction was ran at 0.1 M (Table 1, entry 13), but limited
impact was observed when it was more concentrated (i.e., 0.5
M). Interestingly, the reaction proceeded well without solvent,
although a lower yield of 55% was observed (Table 1, entry
15). Finally, running the reaction with more or less equivalents
of MsOH/Et3N·3HF provided slightly lower yields (Table 1,
entries 16−18). However, the use of an important excess of
Et3N·3HF over MsOH completely shut down the reaction
(Table 1, entry 19). Overall, the conditions reported in entry 6
were determined to be optimal and thus used.
In summary, we have described the use of a methanesulfonic
acid/triethylamine trihydrofluoride combination for the direct
hydrofluorination of a wide range of methallyl alkenes. Under
those metal-free conditions that use readily available, cheap,
and easy to handle reagents, the tertiary fluoride products
could be isolated in up to 78% yield. Finally, a promising result
for the adaptation of this chemistry to continuous flow
conditions is reported, and further optimization of this system
is ongoing.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
With the optimized conditions, we investigated the scope for
various methallyl alkenes,15 and the results are reported in
Scheme 2. Various aromatic esters derived from 3-methylbut-
3-en-1-ol could be used as substrates (1a−n), and the
corresponding products (2a−n) were obtained in moderate
to good yield (45−78%). The aromatic esters vary from
electron-poor to electron-rich and also include hetereoar-
omatic ones. Aliphatic esters could also be used (1o−q). The
ester functionality is not mandatory for the hydrofluorination
and ethers (1r−s), or tosylate (1t) could also be used. In those
cases, the tertiary fluorides 2r−t were obtained in moderate
yields (54−68%). A phthalimide protected substrate (1u)
reacted slowly under the reaction conditions and provided the
corresponding fluorinated product 2u in 37% yield. Citronellol,
protected as a benzoate, could also be used, and the
corresponding fluoride 2v was obtained in 54% yield. This
result demonstrated that a trisubsituted alkene could also be
used in the hydrofluorination reaction. Reaction of substrates
1v−w showed that more methylene unit could be inserted
between the ester group and the alkene group. Finally, tertiary
fluoride 2x was obtained in 59% yield from 1x indicating that a
basic group (ester, ether, etc.) is not required for the reaction
to proceed. Unfortunately, a pyridine-containing substrate (1y)
or methallyl benzoate (1z) provided the fluorinated products
in very low yield (<5% by NMR). We hypothesized that, in the
former case, the basic nitrogen, through protonation, perturbed
the acid/fluorine source ratio (cf. Table 1), while, in the latter
case, the alkene was less nucleophilic, thus affecting the
protonation step, because of the electron-withdrawing
inductive effect of the ester.
In numerous cases, the NMR yield is somewhat higher than
the isolated one. This can be explained by the difficulty in
separating, by flash chromatography on silica gel, the residual
starting material from the fluorinated product, compounds
with similar polarity. In a few cases, a small amount (<5%) of
unidentified nonfluorinated side products also had to be
removed.
Finally, we investigated the possibility of running the
hydrofluorination reaction under continuous flow conditions16
since only a single example of such transformation, using an
ion-exchange resin-supported hydrogen fluoride, has been
reported to date.7 As shown in Scheme 3, a promising 36%
yield (NMR) could be obtained for a 91% conversion.
Notably, the reaction time could be reduced from 4 h in
batch to 16.7 min.
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Olivier Gosselin and Dr. Jean-Denys Hamel
■
́
(Universite Laval) for some initial experiments and Dr.
́
Myriam Drouin (Universite Laval) for the synthesis of a few
substrates. This work was supported by the Natural Sciences
and Engineering Research Council of Canada (NSERC), the
Fonds de recherche du Quebec−Nature et technologies (FRQ-
́
NT), and the Universite Laval. The NSERC CREATE
program in Continuous Flow Science is also acknowledged.
REFERENCES
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̈
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