Organic Letters
Letter
a
Scheme 3. Chemoselective Functionalization of 3-
Fluoropiperidine Imines
Scheme 4. Synthesis of 3-SCF3-Substituted Piperidines
a
a
Reagents and conditions: (a) NaBH(OAc)3 (1.5 equiv), AcOH, rt,
18 h (90%); (b) Boc2O (2.0 equiv), Et3N (2.0 equiv), THF, rt, 18 h
(88%); (c) LiAlH4 (2.0 equiv), THF, rt, 3.5 h (50%); (d) aq. HCl (15
equiv), 100 °C, 1 h (quant.); (e) NaBH4 (2.0 equiv), MeOH, 0 °C to
rt, 18 h (77%); (f) Hoveyda−Grubbs second Gen. (5 mol %), pent-4-
en-1-yl acetate (3 equiv), DCM, 25 °C 18 h then reflux, 3 h (54%).
a
Reagents and conditions: 11 (0.7 mmol), 2 (0.47 mmol), Pd(dba)2
(23 μmol, 5 mol %), L1 (70 μmol, 15 mol %), CH2Cl2 (0.1 M), RT,
18 h under N2. Heated at 40 °C.
b
decarboxylation using aq. HCl and heating afforded
fluoropiperidine 8, which could then be reduced using
NaBH4 to provide saturated piperidine 9 in 77% yield as a
single diastereoisomer following column chromatography.17
Notably, this decarboxylation circumvents the limitation
associated with the poor reactivity of α-fluoroketones in the
allylation/condensation cascade. Selective functionalization of
the exocyclic alkene is also possible; cross-metathesis produced
10 as a mixture of geometric isomers. The ability to selectively
functionalize each functional handle in piperidine imines 4
demonstrates their utility as synthetic intermediates.
The suitability of our method for accessing useful fluorinated
heterocycles suggested that it might be adapted to allow the
incorporation of trifluoromethylthio (SCF3) groups. In this
regard, and to the best of our knowledge, only two examples of
3-SCF3-substituted piperidines have been reported.18 Due to
its electron-withdrawing nature and high lipophilicity, the
SCF3 moiety can significantly modulate the pharmacological
properties of bioactive compounds.19 Nevertheless, the
availability of synthetic methods that deliver saturated N-
trifluoromethyl-thiolated six-membered heterocycles is scarce,
and those that are documented suffer from limited substrate
scope.20
Our efforts to employ the [4 + 2] annelation sequence to α-
SCF3-ketones is summarized in Scheme 4. Aryl substituted
ketones proved to be excellent substrates for this trans-
formation, generating a range of 3-SCF3-substituted piper-
idines under mild conditions. Unfortunately, these products
proved to be unstable to chromatography, and so we used a
borohydride reduction step prior to isolation. Accordingly, 2-
aryl 3-trifluoromethylthio-piperidines 13a−g were isolated in
excellent yields over three steps, and with very high cis-
stereocontrol. X-ray crystal structure analysis of aryl substituted
confirmed the relative stereochemistry of the major diaster-
eomer in these cases, and the stereochemistry of all other aryl-
substituted products was assigned by inference. Unfortunately,
however, 2-aryl-substituted ketones containing electron-with-
drawing groups (4-nitrophenyl and 4-trifluoromethylphenyl)
were found to decompose during the TFA-mediated
deprotection−condensation step. Finally, α-SCF3-propiophe-
none led to a more substituted analog 13h, while the potential
to access 2-alkyl piperidine products was confirmed in one
case, albeit in low yield.
In conclusion, we report that 3-fluoropiperidines bearing
orthogonal imine, ester, and alkene functionality can be readily
prepared and chemoselectively derivatized, providing a power-
ful approach to these important substructures. Moreover, this
method can be extended to provide the first general means to
incorporate the 3-trifluoromethylthio-group into piperidines,
offering a new and efficient entry into these important
scaffolds.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
Details of experimental procedures and spectroscopic
data. NMR spectral data included (PDF)
Accession Codes
supplementary crystallographic data for this paper. These
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
2813
Org. Lett. 2021, 23, 2811−2815