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L. J. Tilley et al.
PRACTICAL SYNTHETIC PROCEDURES
2,2,6,6-Tetramethylpiperidin-4-amine was obtained in bulk (500
mL) from TCI America (Portland, OR). HBF4 and NaBF4 were ob-
tained in bulk (2.5 kg) from Alfa-Aesar (Ward Hill, MA). Sodium
tungstate, EDTA, and H2O2 were obtained from various supply
houses. Bleach (Chlorox) was purchased fresh for each experiment
from a local supermarket.
The reaction is colorimetric in that the salt 6 is bright yel-
low and its reduced form 5 is white. During an oxidation,
the color changes from bright yellow to white. Finally, the
oxidation is environmentally friendly, as no metals are in-
volved. The solubilities of the nitroxide in water, diethyl
ether, and dichloromethane permit the removal of the ni-
troxide from diethyl ether by extraction with water and the
removal of the nitroxide from water by extraction with di-
chloromethane, although more than one extraction may be
needed.
The costs of the chemicals used to prepare 4 and 6 were about $0.55
and $0.53 per gram, respectively. Procedures are available for re-
covering nitroxide from spent oxidant,6,12,29 but in the case of small-
scale reactions, this might not be worth the trouble.
The approximate solubilities in Table 1 were measured as follows.
For Et2O and CH2Cl2, portions of solvent (100 mL) were stirred for
one day with an excess of the solid solute. The solutions were fil-
tered and the solvent was evaporated to dryness to determine the
solubility. For H2O, the solvent (100 mL) was stirred with a known
amount of solute for one day and then the mixture was filtered. The
weight of residual solid was subtracted from the total original
weight of solute to obtain the solubility.
The oxidant 6 and its reduction product 5 have very low
solubilities in dichloromethane, and they are also ionic.
The low solubility of 6 means that a constant low concen-
tration of oxidant is present during the reaction, which
may lead to functional-group selectivity. In a dichloro-
methane oxidation mixture, optionally containing silica
gel, 6 and 5 can be completely removed by simple filtra-
tion through a 3- to 5-mm-thick pad of silica gel. This
gives a solution of pure product in an essentially quantita-
tive manner. The product can be isolated by evaporation
of the solvent, or the dichloromethane solution can be
used in subsequent tandem reactions. The disproportion
reaction with 4-toluenesulfonic acid is similar, in that the
oxoammonium tosylate 11 precipitates and the reaction
gives good yields; however, the products sometimes re-
quire further purification.12
(4-Acetamido-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4)
Amine 1 (78.1 g, 0.5 mol) was dissolved in H2O (100 mL) in a 2-L
beaker (because some of the reactions generate large amounts of
foam) equipped with a large magnetic stirring bar (at least 3-in
long). The stirred mixture was cooled to 0 °C in an ice bath, and ice
(400 g) was added to the mixture. Ac2O (61.2 g, 0.60 mol) was then
added dropwise over about 0.5 h at such a rate that the temperature
remained near 0 °C. The mixture was then allowed to warm to r.t.
and stirred for 1 h. Solid Na2CO3 (74.2 g, 0.7 mol) or K2CO3 (96.7
g, 0.7 mol) was then added slowly to the mixture. Some foaming oc-
curred, and a white solid precipitate of amide 3 formed.
Catalysts Na2WO4 (9 g, 0.03 mol) and EDTA (9 g, 0.03 mol) were
added to the mixture, followed by dropwise addition over 1 h of
30% H2O2 (223.0 g, 2.0 mol). The suspension turned yellow then
orange, and a dense orange precipitate eventually formed. Because
some heat was given off, the beaker was cooled by placed it in a pan
of water at r.t. The mixture was stirred for 24–48 h or until foaming
ceased. (This foaming is presumably caused by O2 from the H2O2.)
The mixture was then vacuum filtered and the residue was dried
over CaCl2 in vacuum at 50 °C; yield: 99–101 g, (93–95%); mp
145–147 °C (Lit.6 145–147 °C).
We have previously published descriptions of several
methods for the preparation of 4 and 6 (Scheme 1).6,12,27–29
These preparations are handicapped by the fact that the
oxidizing agents, hydrogen peroxide and commercial
bleach, although inexpensive, are available only as dilute
solutions. Both the nitroxide 4 and the oxoammonium salt
6 have appreciable solubilities in water (Table 1), which
reduce the yields. The previous preparations and our re-
vised preparation are summarized in Scheme 1.
The product appears to be stable indefinitely and is resistant to air
and moisture. It can be recrystallized from H2O (2.5 parts) with
about a 15% loss, but this is not normally necessary.
In the original preparations, the first step, acylation of 1 to
give the acetate salt 2, was carried out in dry diethyl ether,
and 2 was isolated as such; this is an expensive operation.
Salt 2 was then basified in a separate step and oxidized to
give the nitroxide 4, which was also isolated. The nitrox-
ide was then disproportionated with aqueous commercial
tetrafluoroboric acid to give 5 and 6 by the Golubev reac-
tion,11 and further oxidized by treatment with 0.5 equiva-
lents of commercial bleach (6% aqueous sodium
hypochlorite) to complete the preparation of 6.
4-Acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium Tetrafluo-
roborate (6)
CAUTION: Tetrafluoroboric acid is extremely destructive to the
skin, eyes, and respiratory tract.
Oxyl 4 (106.5 g, 0.5 mol) was slurried in H2O (200 mL) in a 2-L
beaker containing a large stirring bar, and 50% aq HBF4 (100.0 g,
0.57 mol) was added dropwise over about 1 h. The orange slurry ini-
tially became brown–black and then turned yellow as a mixture of
10 and 6 formed by a disproportionation reaction. Commercial
bleach [Chlorox (6% aq NaOCl); 308.0 g, 0.25 mol] was added
dropwise over about 3 h to convert the mixture of 10 and 6 entirely
into 6. NaBF4 (55.0 g, 0.5 mol) was added to salt out the product,
and the mixture was stirred for 30 min, cooled in an ice bath for
about 2 h, and vacuum filtered. The precipitate was washed with
CH2Cl2 (200 mL) and air dried; yield: 136–139 g (91–93%); mp
190-195 °C (dec.; browned at ≥180 °C) (Lit.29 190–195 °C).
In our revised procedure, 1 is acylated in ice water and
converted, in a one-pot reaction, directly into 4, which can
be isolated by filtration in 90–95% yield. In the last step
(the conversion of 4 into 6), by using the common-ion ef-
fect and salting out with sodium tetrafluoroborate, 6 can
obtained in 90–92% yield.
Anal. Calcd for C11H21N2O2BF4: C, 44.03; H, 4.04; N, 9.33. Found:
C, 44.11; H, 6.91; N, 9.37.
All of the reactions were carried out with distilled H2O. For the sake
of convenience, each of the two procedures was performed with 0.5
moles of starting material; the reactions were not contiguous. The
procedures can be scaled up to one or more moles with the appro-
priate equipment. Melting points were measured on a Kofler Hot-
Stage apparatus.
Drying over CaCl2 under a vacuum at about 60 °C and 60–80 mm
removed only about 0.2 g of additional H2O. The material appears
to be stable indefinitely and is resistant to air and moisture.
This material is suitable for most oxidations. For special uses, it can
be recrystallized but, because the salt reacts slowly with hot H2O,30
Synthesis 2013, 45, 326–329
© Georg Thieme Verlag Stuttgart · New York
Tilley, Leon J.
