Job/Unit: O42225
/KAP1
Date: 26-03-14 17:09:48
Pages: 7
O-Trifluoromethylation of N,N-Disubstituted Hydroxylamines
anol slush). In a separate flask, the hydroxylamine substrate was
dissolved in dry CH2Cl2 to give a 0.5 m solution. The substrate
solution was rapidly injected to the precooled CF3 reagent solution,
and the resulting mixture was immediately taken out of the cooling
bath and allowed to reach room temperature.
As shown in Scheme 3, competitive trifluoromethylation of
the excess amount of TEMPO completely suppressed the
formation of 4a. We consider this result as a strong indica-
tion for a radical pathway with a CF3 radical as the key
intermediate. Unfortunately, trifluoromethylation of the po-
tential radical clock 1-allyl-3,4-dihydroisoquinolin-2(1H)-ol
failed to provide a single product.
GP 2: A dry Schlenk flask under an atmosphere of Ar was charged
with CF3 reagent 2 (244 mg, 0.737 mmol, 1.1 equiv.) and cooled to
–78 °C in an ethanol/dry ice bath. A solution of trimethylsilyl trifl-
ate (0.5579 m in CH2Cl2, 1.32 mL, 0.737 mmol, 1.1 equiv.) was then
injected within 10 s along the precooled wall whilst stirring. The
resulting solution was stirred at this temperature for 5 min. Mean-
while, a solution of the hydroxylamine substrate (0.67 mmol,
1 equiv.) and tetramethylguanidine (92 μL, 84.8 mg, 0.737 mmol,
1.1 equiv.) in CH2Cl2 (1 mL) was prepared. After a period of 5 min
for the TMSOTf-mediated activation of the CF3 reagent, the sub-
strate solution was added within 10 s to the solution of the acti-
vated CF3 reagent along the precooled wall of the Schlenk flask.
The resulting mixture was stirred at –78 °C for 1 min, and then
taken out of the cooling bath and allowed to reach room tempera-
ture.
GP 3: In a dry Schlenk flask under an atmosphere of Ar, CF3 rea-
gent 1 (1.5 equiv.) was suspended in CH2Cl2 (0.3 mL of CH2Cl2
per mmol of CF3 reagent) and cooled in an ice bath (0 °C). In a
separate flask, the hydroxylamine substrate (1 equiv.) was dissolved
in CH2Cl2 to give a 0.5 m solution, and it was added dropwise with
a Pasteur pipette to the well-stirred suspension of the reagent. Fi-
nally, triethylamine (1 equiv.) was injected with a syringe. The ice
bath was removed, and the mixture was stirred several minutes at
room temperature.
Scheme 3. CF3 radical quenching experiment with TEMPO.
As shown in Scheme 4, a plausible mechanism for the
reaction would thus involve a proton transfer pre-equilib-
rium between the hydroxylamine and 2 followed by a SET
step. This affords a pair of radicals leading to the desired
product upon recombination (see the Supporting Infor-
mation for a detailed discussion).
GP 2 was always superior to GP 1 and GP 3, which were used in
the early stages of this project. Further details are included in the
Supporting Information.
CCDC-978124 (for 4o) and -978125 (for 4r) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and copies of the 1H NMR,
13C NMR, and 19F NMR spectra.
Scheme 4. Proposed reaction mechanism.
Acknowledgments
The ETH Zürich is acknowledged for financial support. Dr. Nico
Santschi is acknowledged for providing helpful suggestions regard-
ing mechanistic issues. Julie Charpentier and Joël Egloff are ac-
knowledged for their assistance in preparing this manuscript.
Conclusions
In summary, we developed a method for the chemoselec-
tive O-trifluoromethylation of N,N-disubstituted hydroxyl-
amines. Mechanistic and screening experiments indicated
that the reaction follows a radical pathway with nitroxyl
and CF3 radicals as relevant intermediates. The method was
shown to be suited for a wide variety of substrates, includ-
ing more complex molecular targets with potential applica-
tion in medicinal chemistry.
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Experimental Section
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Org. Chem. 2014, 10, 1–6; for our previous work on O-trifluor-
GP 1: In a dry Schlenk flask under an atmosphere of Ar, CF3 rea-
gent 2 (1.5 equiv.) was dissolved in dry CH2Cl2 to give a 1 m solu-
tion that was precooled to –20 °C in a cooling bath (water/ice/eth-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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