Synthetic studies on N-alkoxyamines: A mild and broadly applicable route starting from nitroxide radicals and aldehydes

Article abstract of DOI:10.1021/jo802403j

A broad variety of 2,2,6,6-tetramethylpiperidine-based N-alkoxyamines were prepared in a newly found reaction. By means of a copper-catalyzed fragmentation reaction of aldehyde peroxides in the presence of TEMPO or TEMPO derivatives, N-alkoxyamines were o

Full text of DOI:10.1021/jo802403j

Synthetic Studies on N-Alkoxyamines: A Mild and Broadly
Applicable Route Starting from Nitroxide Radicals and Aldehydes
Kai-Uwe Schoening,* Walter Fischer, Stefan Hauck, Alexander Dichtl, and
Michael Kuepfert
Ciba Inc., WRO-1059, 4002 Basel, Switzerland
kai-uwe.schoening@ciba.com
ReceiVed October 28, 2008
A broad variety of 2,2,6,6-tetramethylpiperidine-based N-alkoxyamines were prepared in a newly found
reaction. By means of a copper-catalyzed fragmentation reaction of aldehyde peroxides in the presence
of TEMPO or TEMPO derivatives, N-alkoxyamines were obtained in moderate to good yields.
Introduction
metal salts,5 or via oxidation of organometallic compounds,6
boronates,7 or boranes.8 Other well-known methods start from
reactive esters such as malonates9 or R-haloesters10 or from
haloalkanes,11 hydrazides,12 diazonium salts,13 or haloalkyl-
N-Alkoxyamines (also termed alkoxyamines) derived from
persistent sterically hindered aminoxyl radicals represent an
important and rapidly developing class of organic compounds.
They can be used not only as initiators for controlled radical
polymerizations1 but also as polymer light stabilizers, peroxide
substitutes (rheology modifiers), or fireproofing agents.2 There
has been an ongoing interest in developing simple, selective,
scalable, and cost-efficient methods for synthesizing diverse and
functionalized analogues of this structural class starting from
readily available precursors. However, most procedures con-
ceived so far have not been able to fulfill these particular
requirements for various reasons. The vast majority of syntheses
known start from readily available nitroxide radicals, which are
then reacted with carbon radicals, while only a few other
approaches start from hydroxyl amines or oxoammonium salts.
Quite naturally, the main focus of most investigations was to
develop cheap and highly efficient methods for the generation
of carbon radicals. These species can for instance be formed
via treatment of alkanes with strong oxidizing agents3 or
iodides,4 by reacting organo-peroxides with selected transition
(3) (a) Galbo, J. P.; Detlefsen, R. E. Hydrogen peroxide catalyzed alkoxylation
of nitroxyl compounds to sterically hindered N-hydrocarbyloxyamines, especially
N-hydrocarbyloxy-2,2,6,6-piperidines. PCT Patent Appl. WO 2005005388, 2005;
CAN 142:155822. (b) Kirner, H.-J.; Schwarzenbach, F.; Van Der Schaaf, P. A.;
Hafner, A.; Rast, V.; Frey, M.; Nesvadba, P.; Rist, G. AdV. Synth. Catal. 2004,
346, 554–560. (c) Winter, R. A. E.; Galbo, J. P.; Seltzer, R.; Behrens, R. A.;
Mar, A.; Schirmann,P. J.; Malherbe, R. F. N-Substituted hindered amine
stabilizers for coatings. Eur. Patent Appl. EP 309402,1998; CAN 112:79514.
(4) Frey, M.; Rast, V.; Martinez, F.; Alvisi, D. Process for the synthesis of
sterically hindered N-alkoxyamines. PCT Patent Appl. WO 2006048389, 2006;
CAN 144:468916.
(5) Sugimoto, N.; Narumi, A.; Satoh, T.; Kaga, H.; Kakuchi, T. Polym. Bull.
2003, 49, 337–340.
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26, 4725–4730. (b) Thiessen, W.; Wolff, T. Des. Monomers Polym. 2005, 8,
397–407. (c) Stipa, P.; Greci, L.; Carloni, P.; Damiani, E. Polym. Degrad. Stab.
1997, 55, 323–327. (d) Braslau, R.; Burrill, L. C.; Siano, M.; Naik, N.; Howden,
R. K.; Mahal, L. K. Macromolecules 1997, 30, 6445–6450.
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(10) Matyjaszewski, K.; Spanswick, J. Process for preparation of alkoxyamines
via a coupling reaction using a transition metal catalyst, an atom transfer radical
polymerization (ATRP) initiator and a nitroxide or nitroxide precursor. PCT
Patent Appl. WO 2007059350, 2007; CAN 147:9806.
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nitroxides. PCT Patent Appl. WO 2002012149, 2002; CAN 136:169419. (c)
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10.1021/jo802403j CCC: $40.75
Published on Web 01/12/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1567–1573 1567

Schoening et al.
SCHEME 1. Plausible Reaction Mechanism for the
Alkoxyamine Formation
that byproducts were formed in the reaction of R-oxo radicals
with nitroxide radicals, which impaired the overall yield. We
reasoned that these problems might be overcome by employing
aliphatic aldehydes under the same reaction conditions (Scheme
1, R′ ) H).
The known fact that aldehydes are less prone to oxidation in
the presence of stable nitroxide radicals24 was one important
factor for this reaction to occur in a reliable fashion. Also, the
reaction rate of the radical scavenging process by nitroxide
radicals was so favorable that no homocoupling products were
obtained in significant amounts. Thus, we were able to
demonstrate that aldehydes are a superb source for the generation
of intermediate alkyl radical species and eventually alkoxyamines.
benzenes.14 Further methods involve ene-like additions of
oxoammonium cations15 or nitroxide radicals16 to alkenes, the
use of dithianes,17 photolysis reactions,18 SN2-type reactions of
alkoxides,19 the reaction of nitrosoarenes with nitrogen oxides,20
and even Meisenheimer-type rearrangements.21 A comprehen-
sive overview on state-of-the-art methods is given in a number
of excellent reviews and monographs.22
Recently, we reported on the use of ketones and hydrogen
peroxide to efficiently create alkyl radical precursors.23 The
copper(I) chloride-catalyzed decomposition of these peroxide
intermediates in the presence of tetramethylpiperidine N-oxyl
radicals represents a straightforward way to obtaining the desired
alkoxyamines (Scheme 1).
Results and Discussion
During our investigation into the formation of alkoxyamines
we used 4-hydroxy-TEMPO (Prostab 5198)25 as nitroxide
radical, since this building block provided auspicious opportuni-
ties for subsequent chemical modifications.26 When reacting
mixtures of 4-hydroxy-TEMPO, catalytic amounts of copper(I)
chloride, and various aldehydes with 30-50% aqueous hydrogen
peroxide solution, we observed smooth conversions into the
respective N-alkoxyamines. As depicted in Table 1, primary,
secondary, and even tertiary aldehydes resulted in the anticipated
products, whereby secondary and tertiary aldehydes seemed to
give marginally smoother reactions. In most cases only small
excesses (∼1.3 equiv) of aldehyde in relation to the nitroxyl
radical were required to achieve satisfactory yields. However,
in the case of acetaldehyde and longer chain aldehydes (>6
carbon atoms), higher amounts were necessary to obtain
adequate yields. We attribute this behavior to the slightly higher
sensitivity of these aldehydes toward oxidation. Also, the heat
of formation in the case of S-1 was significantly higher than
with most other aldehydes. A larger aldehyde quantity was also
required for the dimeric compound S-7 in order to obtain a
homogeneous product in a high yield.
The transformations presented were mostly executed between
room temperature and 35 °C but may also be conducted at
temperatures up to 45 °C (or even higher) to speed up the
progress of the reactions. At higher temperatures the decom-
position of hydrogen peroxide became rampant and necessitated
higher dosages of the oxidant. In general, the reactions can be
conducted with or without solvents. We learned that basically
any solvent may be employed as long as it tolerates the presence
of the oxidant. Among the solvents effectively tested were
hexane, toluene, methyl tert-butyl ether, methylene chloride,
alcohols, and water. Biphasic mixtures showed reaction rates
comparable to those of homogeneous ones, though the use of
phase-transfer catalysts proved to be advantageous in some
cases. We also approached the question as to how much copper
catalyst is required and which is the best one. Evidently, all
copper sources catalyze the formation of alkoxyamines in this
setup. In addition to the mentioned copper(I) chloride, other
copper(I) salts promote the reaction equally well, independent
of the solvent system used. By contrast, when the activity of
copper(II) salts was evaluated, a clear solvent dependence was
Notwithstanding the fact that this reaction was successfully
applied to synthesize a broad range of alkoxyamines, an element
of limitation was the moderate selectivity in the radical transfer
process (R vs R′). The problem was exacerbated by the fact
(12) Braslau, R.; Anderson, M. O.; Rivera, F.; Jimenez, A.; Haddad, T.; Axon,
J. R. Tetrahedron 2002, 58, 5513–5523.
(13) (a) Judd, D.; Shum, S. P.; Pastor, S. D. Polyoxometalate catalysts
for the preparation of sterically hindered N-substituted aryloxyamines. US
Patent 2003208071, 2003; CAN 139:350640. (b) Pastor, S. D.; Shum, S. P.
Transition-metal-catalyzed preparation of sterically hindered N-substituted
alkoxyamines and compositions. PCT Patent Appl. WO 2002079182, 2002;
CAN 137:295596.
(14) Grubbs, R. B.; Wegrzyn, J. K.; Xia, Q. Chem. Commun. 2005, 1, 80–
82.
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5485–5487. (b) Schaemann, M.; Chaefer, H. J. Synlett 2004, 9, 1601–1603.
(16) (a) Dufils, P.-E.; Chagneux, N.; Gigmes, D.; Trimaille, T.; Marque,
S. R. A.; Bertin, D.; Tordo, P. Polymer 2007, 48, 5219–5225. (b) Schulte, B.;
Studer, A. Synthesis 2006, 13, 2129–2138. (c) Wetter, C.; Studer, A. Chem.
Commun. 2004, 2, 174–175.
(17) Herrera, A. J.; Studer, A. Synthesis 2005, 9, 1389–1396.
(18) Bertin, D.; Couturier, J. L.; Gigmes, D.; Guerret, O.; Guillaneuf, Y.
Process for preparation of alkoxyamines by photolysis of dithiocarbamates. Fr.
Patent FR 2884517, 2006; CAN 145:421104.
(19) Moon, B.; Kang, M. Macromol. Res. 2005, 13, 229–235.
(20) Astolfi, P.; Carloni, P.; Damiani, E.; Greci, L.; Marini, M.; Rizzoli, C.;
Stipa, P. Eur. J. Org. Chem. 2008, 19, 3279–3285.
(21) (a) Zedda, A.; Ferri, G.; Sala, M. Production of steric hindered cyclic
amine ethers for stabilizers for polymers. Ger. Patent DE 19907945, 1999; CAN
131:185784. (b) Bergbreiter, D. E.; Walchuk, B. Macromolecules 1998, 31, 6380–
6382. (c) Tabushi, I.; Hamuro, J.; Oda, R. Tetrahedron Lett. 1968, 53, 5581–
5584.
(22) (a) Sciannamea, V.; Jerome, R.; Detrembleur, C. Chem. ReV. 2008, 108,
1104–1126. (b) Nesvadba, P. Chimia 2006, 12, 832–840. (c) Bertin, D.; Gigmes,
D.; Marque, S. R. A. Recent Res. DeV. Org. Chem. 2006, 10, 63–121. (d) Studer,
A.; Schulte, T. Chem. Rec. 2005, 5, 27–35. (e) Studer, A. Chem. Soc. ReV. 2004,
33, 267–273. (f) Togo, H. AdVanced Free Radical Reactions for Organic
Synthesis, 1st ed.; Elsevier: Amsterdam, 2004. (g) Tirrell, D. A. J. Polym. Sci.,
Part A: Polym. Chem. 1998, 36, 2667–2668. (h) Volodarsky, L. B.; Reznikov,
V. A.; Ovcharenko, V. I. Synthetic Chemistry of Stable Nitroxides; CRC Press:
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(25) Commercial Product of Ciba Inc.
(26) The same reactions were also conducted with TEMPO, but because of
limited options for further chemical transformations this nitroxide radical is of
little use in industrial applications.
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Synthetic Studies on N-Alkoxyamines
TABLE 1. Reaction of Aliphatic Aldehydes with 4-Hydroxy TEMPO
a Isolated yield. b Reaction performed in H2O. c Reaction performed in 1-BuOH/H2O (4:1). d Reaction performed in 2-PrOH/H2O (1:5). e Reaction
performed in EtOH/H2O (1:1). f Reaction performed in t-BuOH/H2O (2:1). g Reaction performed in heptane/t-BuOH (4:1).
found: in polar systems the counterion had essentially no effect
on the conversion rate, but in apolar systems most copper(II)
catalysts showed an inferior performance. The same held true
for elementary copper, which was successfully used in systems
where it was allowed to gradually dissolve. Optimal catalyst
amounts were determined to be between 1 and 3 mol % in
relation to the amount of nitroxide radical employed.
substrates were less reactive than their acyclic counterparts.
From C-4 toward C-8 carbaldehydes we observed increasing
yields, and the optimum seemed to be at C-6. The below average
yield of S-8 may be explained by increased concomitant
carboxylic acid formation or decomposition of the aldehyde.
The reaction of cyclopropyl carbaldehyde and related aldehydes
was also investigated, but we were unable to isolate the
corresponding products; traces of the compounds were detectable
by mass spectrometry only. During the investigation of the ring
Next, we investigated the transformation of cycloaliphatic
aldehydes (entries 8-10, Table 2), and apparently these
J. Org. Chem. Vol. 74, No. 4, 2009 1569

Schoening et al.
TABLE 2. Reaction of Cycloaliphatic and Unsaturated Aldehydes with 4-Hydroxy TEMPO
a Isolated yield. b Reaction performed in t-BuOH/H2O (2:1). c Reaction performed in EtOH. d Reaction performed in t-BuOH. e Reaction performed in
H2O. f CuCl2 used as catalyst.
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Synthetic Studies on N-Alkoxyamines
TABLE 3. Synthesis of Functionalized Alkoxyamines
a Isolated yield. b Reaction performed in toluene. c Reaction performed in HOAc/H2O (3:1).
J. Org. Chem. Vol. 74, No. 4, 2009 1571

Schoening et al.
systems, we also employed 3-cyclohexene-1-carboxaldehyde,
which was found to react without accompanying side reactions
at the olefinic position (S-11). A deeper evaluation of the scope
and limitation of olefins revealed that many unsaturated alde-
hydes may be used in this coupling reaction. Except for R, ꢀ
and R, ꢀ, γ, δ unsaturated aldehydes, most aldehydes tested
yielded the envisioned products irrespective of the position or
the substitution pattern of the double bonds (entries 11-14).
Alkoxyamines bearing benzylic substituents are of particular
interest as polymerization initiators. The relevant phenethyl-
substituted product (entry 15) was accordingly prepared,27 as
well as the CH2-elongated homo product (entry 16), both without
formation of noteworthy byproduct. However, the presumption
that benzaldehyde(s) would react likewise proved to be wrong,
as we were not able to prepare the corresponding phenoxy
tetramethylpiperidines. We ascribe this result to the insufficient
electrophilicity of many aromatic aldehydes so that the hydrogen
peroxide does not readily add to the carbonyl group. Neverthe-
less, it may be possible, by choosing appropriate aryl substi-
tutents, to form benzyl hydroperoxides28 and, ultimately, phenyl
radicals.
As discussed earlier, this coupling protocol appears quite mild
compared to other alkoxyamine-forming reactions, and so far
we have gathered mounting evidence that a much broader range
of aldehydes (and in particular functionalized ones) ought to
be applicable in this reaction. First, we investigated the use of
ester-substituted aldehydes (Table 3, entries 17 and 18). Again,
neither the presence of a substituent in R-position nor the
presence of a nitro group interfered with the reaction,29 and
even carbonates were formed quite smoothly (entry 19). The
next challenge was to form acetal-containing alkoxyamines
(entries 20 and 21), because the required precursors as well as
the products are more labile than esters and prone to peroxide
attack.30 We were pleased to find that the conjectured products
formed equally well. Furthermore, carbamate protecting groups
(entry 22) were tolerated as well as nitriles (entry 23). The latter
one was particularly surprising since nitriles are known to readily
interact with hydrogen peroxide to form transient peroxyimidates
or peroxycarboximidic acids. The fact that ꢀ-fluoro aldehydes
(entry 24) were decent substrates (in contrast to R-substituted
ones, cf. ref 23) did not take us by surprise. Finally, we
investigated the behavior of hydroxy-substituted aldehydes. We
envisioned that sterically hindered alcohols would work best
(entry 25) because the possibility of concomitant side reactions
would be limited, and we were surprised to discover that even
hydroxy aldehydes that prevail as hemiacetals (entry 26) formed
the anticipated products in modest yields. However, more
complex sugars such as glucose did not give any conversion,
presumably due to copper complexation.
range of functional groups is tolerated. Also, the method allows
all reactions to be performed in wet solvents and under an
aerobic atmosphere, thus offering a high operational simplicity.
Although reactive carbon radicals are evidently generated in
this process, the number and amount of isolatable byproduct is
almost negligible.31 This is particularly important if an industrial
large-scale application is considered. It appears that the radicals
are somewhat tamed so as to not display their full reaction
potential, e.g., in terms of H-radical abstraction or homocou-
pling. The relatively small excesses of aldehyde and H2O2
necessary to achieve a full nitroxide radical conversion point
into the same direction. We speculate that this reduced reactivity
might be the result of intermediary Cu-complexes of the type
[CuI-OOC(OH)R]32 or connatural intermediates that do not
decompose until coming into contact with the nitroxide radical.
As the successful usage of more complex aldehydes pointed
out, this method may also be adoptable in natural product
synthesis and redundantize or allow the use of particular
protecting groups, or may be applicable to the preparation of
new spin-label precursors. In addition, this method could open
up new opportunities in the field of living radical polymerization,
as entirely new initiators may be accessible by the use of
accordingly substituted aldehydes. In particular in combination
with the complementary ketone option this reaction has an
enormous potential.
The method presented is not fully optimized yet, and we are
convinced that by carefully choosing the parameters temperature,
amounts of aldehyde and hydrogen peroxide, and solvent higher
yields and/or conversion rates can be achieved. Moreover, the
full potential in terms of synthetic applications has not been
discovered yet. So it may well be possible to synthesize
alkoxyamines with a predictable temperature stability by an
accurate choice of the type of nitroxyl radical and the aldehyde.
A final comment should be made with regard to the safety of
this process: as the combination of hydrogen peroxide and
organic matter always poses the risk of uncontrollable decom-
position reactions, adequate safety measures should be applied
when conducting this reaction. In particular, a peroxide test
should be carried out after the workup process (before solvent
removal) and before conducting distillations.
Experimental Section
Representative Procedures for the Synthesis of Alkoxy-
amines. 1-Methoxy-2,2,6,6-tetramethylpiperidin-4-ol (S-1). To
a solution of 5.0 g (29.0 mmol) of 4-hydroxy-TEMPO in 20 mL
of water was added CuCl (57 mg, 2 mol %) and acetaldehyde (6.6
mL, 116 mmol). Next, 8.9 mL (87 mmol) of 30% H2O2 was added
(27) Alkoxyamines based on the 2,6-diethyl-4-hydroxy-2,3,6-trimethylpip-
eridine-1-N-oxyl core were also prepared. As a result of the higher sterical
hindrance, prolonged reaction times were observed.
(28) (a) Rakhimov, A. I.; Chapurkin, V. V. Zh. Org. Khim. 1981, 17, 1546–
7. (b) Rakhimov, A. I.; Chapurkin, V. V. Zh. Org. Khim. 1978, 14, 204.
(29) Zelentsov, S. V.; Simdyanov, I. V. Russ. Chem. Bull. 2006, 55, 207–
211.
A particularly interesting product was S-27, which was
formed in a formal reduction reaction under oxidative conditions.
Evidently, formaldehyde was capable of following the same
reaction pathway as most other aldehydes and correspondingly
provided the free hydroxylamine in a straightforward fashion.
To the best of our knowledge, this is the first time that a radical-
induced reduction using formaldehyde is reported.
(30) Rieche, A. Chem. Ber. 1961, 94, 2457–61.
(31) Typical byproducts of this process were 4-oxo-alkoxyamines and C-1-
shortened carbon chain homologues of the respective products in small amounts.
The former ones can be transformed into the desired product by means of a
sodium borohydride treatment during the workup process; the latter ones usually
do not have a negative impact on subsequent chemistry. In addition, 1-hydroxy-
2,2,6,6-tetramethyl-4-piperidinol and 2-methyl-2-penten-4-one were formed and
were removed during the workup process. Among the gaseous byproducts carbon
dioxide and, in some cases, olefins (generated via ꢀ-H radical elimination of the
respective alkyl radicals) were identified by GC-MS.
Conclusions
We have presented a broadly applicable and extraordinary
mild reaction for the formation of N-alkoxyamines. It stands
out from the mass of methods available because cheap or readily
available nontoxic precursors are used and particularly, a broad
(32) Hong, S.; Huber, S. M.; Gagliardi, L.; Cramer, C. C.; Tolman, W. B.
J. Am. Chem. Soc. 2007, 129, 14190–14192.
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Synthetic Studies on N-Alkoxyamines
over a period of 30 min while keeping the temperature at 65-70
°C. After 4 h of stirring at this temperature, the mixture was slowly
cooled to room temperature while the product started to precipitate.
The pH of the reaction mixture was adjusted to ∼8 using 10%
K2CO3 solution, and the mixture was cooled to 5 °C. The product
was collected by filtration. The filter cake was washed successively
with cold 10% ascorbic acid solution and water. The filtrate was
extracted with toluene, and the organic phase was washed with
brine. Upon drying over Na2SO4, the organic phase was removed
in vacuo to yield a tan residue. The combined crude product
fractions were purified by distillation (0.04 mbar, 120 °C oil bath
temp, bp ∼90 °C) to give S-1 as a white solid (3.9 g, 20.8 mmol,
72%). 1H NMR (400 MHz, CDCl3): δ 3.94 (m, 1H), 3.61 (s, 3H),
1.79 (dd, J ) 12.0, 4.0 Hz, 2H), 1.64 (br s, 1H), 1.46 (ps t, J )
12.0 Hz, 2H), 1.21 (2s, 6H), 1.26 (2s, 6H). 13C NMR (100 MHz,
CDCl3): δ 65.4 (t), 63.2 (2q), 60.0 (p), 48.2 (2s), 33.1 (2p), 20.9
(m, 4H), 1.24 (2s, 6H), 1.15 (2s, 6H), 0.95 (t, J ) 10.4 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 78.4 (s), 63.3 (t), 60.0 (2q), 48.3
(2s), 33.2 (2p), 21.9 (s), 21.0 (2p), 10.9 (p). IR (neat): νmax 3264,
2965, 1451, 1363, 1173, 1040 cm-1. MS: m/z ) 216 [M + H]+.
Anal. Calcd for C12H25NO2: C, 66.93; H, 11.70; N, 6.50. Found:
C, 66.73; H, 11.59; N, 6.38.
4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-yl Carbonic Acid
Methyl Ester (S-19). To a solution of 2.5 g (14.5 mmol) of
4-hydroxy-TEMPO in 8 g (90.8 mmol) of methyl glyoxylate was
added CuCl (28.7 mg, 2 mol%). Next, 2.0 g (19.6 mmol) of 30%
H2O2 was added over a period of 60 min. After 12 h of stirring at
room temperature, the mixture was diluted with MTBE. The organic
phase was washed with 10% ascorbic acid solution, 1 N NaOH,
water, and brine. After drying over MgSO4, the organic phase was
concentrated under vaccum to leave a white solid. The crude product
was filtered over silica gel using hexane/acetone (2:1) as the eluent
to yield S-19 as a white solid (2.55 g, 11.0 mmol, 76%). 1H NMR
(300 MHz, CDCl3): δ 4.01 (m, 1H), 3.82 (s, 3H), 1.89 (dd, J )
11.2, 4.2 Hz, 2H), 1.82 (br s, 1H), 1.67 (ps t, J ) 11.2 Hz, 2H),
1.21 (2s, 6H), 1.15 (2s, 6H). 13C NMR (75 MHz, CDCl3): δ 157.6
(q), 63.1 (t), 61.1 (2q), 55.5 (p), 48.1 (2s), 32.0 (2p), 21.6 (2p). IR
(2p). IR (neat): νmax 3265, 2960, 1450, 1358, 1173, 1026 cm-1
.
MS: m/z ) 188 [M + H]+. Anal. Calcd for C10H21NO2: C, 64.13;
H, 11.30; N, 7.48. Found: C, 63.94; H, 11.22; N, 7.45.
1-Propoxy-2,2,6,6-tetramethylpiperidin-4-ol (S-2). To a mix-
ture of 150.0 g (870.8 mmol) of 4-hydroxy-TEMPO in 620 mL of
1-butanol/water (1:4) were added CuCl (861 mg, 1 mol%) and
butanal (94.2 g, 1.31 mol). Next, 120 mL (1.18 mol) of 30% H2O2
was added over a period of 30 min while keeping the temperature
between 30 and 35 °C. Stirring was continued at 35 °C for 8 h,
whereupon another 12 mL (118.0 mmol) of H2O2 was added. After
6 h the reaction mixture was extracted with MTBE. The combined
organic phases were washed with 2 N NaOH, water, 5% Na2EDTA,
10% ascorbic acid solution, and brine. After drying over Na2SO4,
the organic phase was concentrated in vacuo to provide an off-
white solid. Pure S-2 was obtained after column chromatography
(neat): νmax 3234, 2966, 1773, 1440, 1365, 1225, 1183, 1047 cm-1
.
MS: m/z ) 232 [M + H]+. Anal. Calcd for C11H21NO4: C, 57.12;
H, 9.15; N, 6.06. Found: C, 57.34; H, 8.97; N, 5.83.
Acknowledgment. The authors thank the Ciba Research
Analytics group (Coating Effects Segment) and the Ciba Expert
Services Group, Switzerland for their support.
Supporting Information Available: Experimental proce-
dures and 1H, 13C NMR spectra of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
(silica gel, hexane/acetone 9:1) (157.5 g, 731.5 mmol, 84%). H
NMR (400 MHz, CDCl3): δ 3.95 (m, 1H), 3.70 (q, J ) 9.2 Hz,
2H), 1.80 (dd, J ) 14.4, 3.2 Hz, 2H), 1.70 (br s, 1H, OH), 1.50
JO802403J
J. Org. Chem. Vol. 74, No. 4, 2009 1573