Tin-free radical alkoxyamine addition and isomerization reactions by using the persistent radical effect: Variation of the alkoxyamine structure

Article abstract of DOI:10.1002/chem.200400936

Various C-centered radicals can efficiently be generated through thermal C-O-bond homolysis of alkoxyamines. This method is used to perform environmentally benign radical cyclization and intermolecular addition reactions. These alkoxyamine isomerizations and intermolecular carboaminoxylations are mediated by the persistent radical effect (PRE). In the paper, the effect of the variation of the alkoxyamine structure - in particular steric effects in the nitroxide moiety - on the outcome of the PRE mediated radical reactions will be discussed. Fourteen different nitroxides were used in the studies. It will be shown that reaction times can be shortened about 100 times upon careful tuning of the alkoxyamine structure. Activation energies for the C-O-bond homolysis of the various alkoxyamines are provided. The kinetic data are used to explain the reaction outcome of the PRE-mediated processes.

Full text of DOI:10.1002/chem.200400936

FULL PAPER
Tin-Free Radical Alkoxyamine Addition and Isomerization Reactions by
Using the Persistent Radical Effect: Variation of the Alkoxyamine Structure
Kian Molawi, Tobias Schulte, Kai Oliver Siegenthaler, Christian Wetter, and
Armido Studer*[a]
Abstract: Various C-centered radicals
can efficiently be generated through
paper, the effect of the variation of the
alkoxyamine structure—in particular
steric effects in the nitroxide moiety—
on the outcome of the PRE mediated
radical reactions will be discussed.
Fourteen different nitroxides were used
in the studies. It will be shown that re-
action times can be shortened about
100 times upon careful tuning of the al-
koxyamine structure. Activation ener-
ꢀ
thermal C O-bond homolysis of al-
koxyamines. This method is used to
perform environmentally benign radi-
cal cyclization and intermolecular addi-
tion reactions. These alkoxyamine iso-
merizations and intermolecular carboa-
minoxylations are mediated by the per-
sistent radical effect (PRE). In the
ꢀ
gies for the C O-bond homolysis of
the various alkoxyamines are provided.
The kinetic data are used to explain
the reaction outcome of the PRE-
mediated processes.
ꢀ
Keywords: C C coupling · kinetics ·
persistent radical effect · radical
reactions · synthetic methods
Introduction
The reason behind this reactivity lies in the reluctance of
the persistent radicals to undergo homo-coupling. Therefore,
the persistent radicals can only be consumed through cross-
reaction with a transient radical. The transient species, how-
ever, can also react in a homo-coupling process to form R2–
R2 and the corresponding disproportionation products. This
leads to a build up of the persistent radical and eventually
to the highly selective cross-coupling reaction.
Recently, we communicated first results on environmen-
tally benign radical alkoxyamine isomerization reactions
using the PRE.[4] For example, alkoxyamine 1 was isomer-
ized to the corresponding cyclized alkoxyamines 2 (70%)
and 3 (13%, Scheme 1). Heating of alkoxyamine 1 reversi-
bly generates a transient C-radical 4 and the persistent
TEMPO radical. 5-exo or 6-endo cyclization leads to the
transients 5 and 6 which upon trapping with TEMPO finally
provide the alkoxyamine isomerization products 2 and 3.
The coupling of the transient species 4, 5 and 6 with the per-
sistent TEMPO is a highly selective process steered by the
PRE.[5]
Organotin compounds have found widespread application
for conducting various types of radical reactions.[1] However,
there are drawbacks associated with tin-based radical
chemistry, namely toxicity, hazardous handling, and prob-
lems with product purification. Therefore, many research
groups have initiated programs towards tin-free radical
chemistry.[2] Herein we report on environmentally benign
radical cyclization and addition reactions using the so-called
persistent radical effect (PRE).
The PRE is a general principle that explains the highly
specific formation of the cross-coupling product R1–R2 be-
tween two radicals R1 and R2 when one species is persistent
(R1) and the other transient (R2) and the two radicals are
formed at equal rates.[3] Nonselective statistical reaction be-
tween the two different radical intermediates is suppressed.
We have also shown that these reactions can be conducted
under microwave conditions.[6] Herein we report in full de-
tails on alkoxyamine isomerization and addition reactions.
Structure/reactivity profiles of various new alkoxyamines
[a] Dipl.-Chem. K. Molawi, Dipl.-Chem. T. Schulte,
Dipl.-Chem. K. O. Siegenthaler, Dr. C. Wetter, Prof. Dr. A. Studer
Organisch Chemisches-Institut
Westfꢀlische Wilhelms-Universitꢀt, Corrensstrasse 40
48149 Mꢁnster (Germany)
Fax : (+49)251-833-6523
ꢀ
will be discussed. In addition, C O-bond dissociation ener-
E-mail: studer@uni-muenster.de
gies of the new alkoxyamines are provided.
Chem. Eur. J. 2005, 11, 2335 – 2350
DOI: 10.1002/chem.200400936
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2335

TEMPO with the corresponding transient C-radical or from
a direct ionic elimination of TEMPOH.[10] The products 8b
and 9b were isolated in 54% combined yield (8b:9b 2.8:1,
run 2). Clean reactions were observed for heteroarenes 7c
and 7d (runs 3 and 4). The reaction with nitrile 7e afforded
61% of the 5-exo product 8e and 7% of 9e (run 5). With
7 f, no 6-endo product was formed and 8 f was isolated in
67% (dr 1:1, run 6) along with 10% of 10 (R=CO2tBu). No
isomerization occurred with 7g, h, and i (runs 7–9).
ꢀ
In Table 1 the activation energies (Ea) of the C O-bond
homolysis of the alkoxyamines 7a–i are listed. One can
readily see that the success of the reaction depends on the
ꢀ
activation energy of the C O-bond homolysis. For alkoxya-
mines with Ea <140 kJmolꢀ1 isomerization readily occurred
(runs 1–6, Ea(1) = 131.9 kJmolꢀ1) whereas for alkoxya-
ꢀ
mines 7g–i the C O bonds are too strong and homolysis
cannot be accomplished under the applied conditions (Ea
values are above 160 kJmolꢀ1, runs 7–9).
It would be important to know the upper limit for alkoxy-
amine Ea for which isomerization is still feasible. The 140–
Scheme 1. Alkoxyamine isomerization using the PRE.
Results and Discussion
Table 1. Isomerization of 7a–i (tBuOH (0.02m), 10% CSA, 130–1328C, 24 h, sealed tube) and activation ener-
ꢀ
gies for the C O-bond homolysis of alkoxyamines 7a–i.
Intramolecular
processes—
[b]
Run
Compd
R
8 [%]
dr (8)
9
10
[%]
Ea
(trans/cis)
[%][a]
[kJmolꢀ1
]
Radical alkoxyamine isomeri-
zations: The synthesis of the
alkoxyamines 1 and 7a–h has
previously been described.[7]
All the radical isomerizations
were conducted in sealed
tubes at 130–1328C under an
argon atmosphere. Optimiza-
tions were performed by using
alkoxyamine 1. Various sol-
vents were tested. Best results
were obtained in tBuOH
(0.02m) in the presence of
10% camphor sulfonic acid
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7 f
7g
7h
7i
4-BrC6H4
4-CH3OC6H4
2-thienyl
2-pyridyl
NC
tBuO2C
H
CH3
71
46
67
57
61
2.7:1
2.8:1
2.1:1
1.6:1
1.1:1[c]
1:1
–
–
–
8
8
11
12
7
<2
<2
<2
<2
<2
10
5
5
<2
10
<2
<2
<2
127.2
132.8
112.4
129.7
137.9
67
139.0[d]
<2
<2
<2
>165.3
>165.3[d]
PhS
162.7[b,e]
[a] The 6-endo product was formed as a 1:1 mixture of the diastereoisomers. [b] Ref. [7]. [c] The relative con-
figuration of the two isomers was not assigned. [d] Estimated from data on similar compounds published in
ref. [11]. [e] 4-Hydroxy-TEMPO was used instead of TEMPO for the preparation of the alkoxyamine.
(CSA) for 24 h (2: 70%, trans:cis 2.5:1; 3: 13%, trans/cis
1:1). CSA is used to decrease the concentration of TEMPO.
If the TEMPO concentration is too high, the desired cycliza-
tion reaction of radical 4 cannot efficiently compete with
TEMPO trapping.[8] In fact, isomerization without CSA was
not completed after 36 h. The relative configuration of the
major isomer was assigned after N–O cleavage in 2 by using
standard conditions (Zn, AcOH, H2O, THF) to form the
corresponding known alcohol.[9]
160 kJmolꢀ1 range extracted from Table 1 is certainly too
large for synthetic planning. Therefore, we looked for other
substrates for which the Ea lies in between this range. We
found that isomerization of alkoxyamine 11, for which an Ea
of 144.0 kJmolꢀ1 was measured,[7] did not work under the
standard conditions (Scheme 2). Even at 1508C reaction
In DMF isomerization occurred faster (16 h), however,
slightly lower yields were obtained (2: 56%; 3: 10%). Reac-
tions in tert-butylbenzene, N,N’-dimethyl-N,N’-propylene
urea (DMPU) and water did not work.
Scheme 2. Attempted isomerization of 11.
Under the optimized conditions alkoxyamines 7a–f were
successfully isomerized. The results are summarized in
Table 1. Isomerization of bromide 7a afforded 8a (71%,
trans:cis 2.7:1) and 9a in 8% yield (run 1). Reaction of 7b
led to 10% of the side product 10 (R=Ph-4-OMe). The side
product either derives from a disproportionation reaction of
could not be performed. Since the statistical error in the ki-
netic experiments lies between 2 and 3 kJmolꢀ1, we assume
that isomerizations should work for alkoxyamines with Ea
values below 142 kJmolꢀ1.
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Persistent Radical Effect
FULL PAPER
ꢀ
The activation energy for the C O-bond homolysis of an
alkoxyamine depends on the stability of the released radical
and on the structure of the corresponding nitroxide.[7,11,12]
Steric and polar effects in the nitroxide moiety play an im-
portant role.[12] In order to improve the efficiency of the
PRE-mediated isomerizations, we decided to test other ni-
troxides. As a model reaction the cyclization of the 1-
phenyl-5-hexenyl radical 4 was investigated. The nitroxide
moiety was systematically varied. The synthesis of the al-
koxyamines 13a, 15a and 16a has previously been de-
scribed.[7] The alkoxyamines 12a, 14a and 17–24a were pre-
pared from the corresponding nitroxides[12–16] and 1-bromo-
1-phenyl-5-hexene as described in the Experimental Section.
In sealed tubes the alkoxyamines 12–24a were heated
under standard conditions (tBuOH, 0.02m, with or without
CSA, 1308C) and the time necessary to get complete con-
version was determined. Samples were taken after appropri-
OH groups appropriately positioned for intramolecular H-
bonding, a further decrease of the isomerization time was
obtained (4 h, run 6). However, at the same time the yield is
steadily decreasing from 97 to 73 to 69%. This is due to the
instability of the nitroxides capable of forming intramolecu-
lar H-bonds.[14]
We have recently shown that substitution of the tert-butyl
group in Hawker–Braslau-type alkoxyamines of type 15a by
the larger triethylmethyl group provides effective shielding
of the nitroxide moiety and this in turn leads to reactive al-
koxyamines.[16] To our delight, a highly efficient isomeriza-
tion was observed for alkoxyamine 18a: Reaction was com-
pleted in less than 15 minutes and CSA addition did not
show any effect (Table 2, run 7).
Encouraged by these results we decided to prepare other
sterically highly hindered alkoxyamines (see Scheme 3,
Table 2). On the basis of experimental results and on calcu-
lations, it has been predicted that in cyclic nitroxides the
1
ate time intervals and were analyzed by H NMR spectro-
ꢀ
scopy. The 5-exo (12–24b, trans:cis mixture of isomers) and
6-endo products (12–24c) were obtained in moderate to
good yields. The endo/exo isomers were not separated. The
isomer ratio for the compounds 12 and 13 was determined
ring size influences the C O-bond dissociation energy
(BDE) of the corresponding alkoxyamines.[13,21] The BDE
increases from seven- to six- to five-membered cyclic nitro-
xides. Therefore, alkoxyamines prepared from seven-mem-
bered cyclic nitroxides were tested in the model isomeriza-
tion reaction. Disappointingly, alkoxyamine 19a isomerized
sluggishly (entry 8). A slightly better result was obtained for
the seven-membered ketone 20a (entry 9). A further im-
provement was observed upon reduction of the keto func-
tionality. Isomerization of alcohol 21a was completed in 3 h
(entry 9). The switching of the hybridization from sp2 to sp3
in the nitroxide ring at position 4 probably leads to a confor-
mational change which eventually provides better shielding
and hence faster homolysis.
1
by using H NMR spectroscopy. The relative configuration
of the major isomer of the exo-cyclization products 12b and
13b was assigned in analogy to alkoxyamine 2. Due to the
complexity of the 1H NMR spectra of the isomerization
products 14–24 their isomer ratio was not determined. The
results are summarized in Table 2. In addition, we also in-
ꢀ
cluded the activation energies for the alkoxyamine C O-
bond homolysis into Table 2. Most of the kinetic data have
ꢀ
previously been published. The Ea for C O-bond homolysis
for alkoxyamine 19a and for the other new alkoxyamines
described herein (see below) was determined by kinetic
EPR experiments (see Experimental Section).[7]
Finally, we tested TEMPO analogues in which the four
methyl substituents are replaced by larger ethyl and silylox-
ymethyl groups, respectively. A highly efficient isomeriza-
tion was observed for alkoxyamine 22a (<0.25 h, entry 11).
As with the seven-membered ring systems, the correspond-
ing ketone 23a isomerized far less efficiently (entry 12). We
believe that the decreased stability of the ketoalkoxyamine
due to a possible b-elimination may be the reason for the
different reactivity. In fact, decomposition products were
identified in the crude 1H NMR spectrum. A very good
result was also obtained for the bissilyl ether 24a for which
reaction was completed in 20 minutes (entry 13).
From these structure–activity studies we can state that 6-
membered cyclic nitroxides with bulky a-substituents per-
form very well in the PRE-mediated test reaction. Steric ef-
fects seem to play a major role for increasing the reactivity
of a given alkoxyamine. For efficient alkoxyamines CSA ad-
dition is not necessary.
Isomerization of the hydroxy-TEMPO-derivative 12 was
completed in 14 h in the presence of CSA. The exo/endo-iso-
mers 12b,c were isolated in 73% combined yield (run 1). A
faster cyclization was obtained for the di-tert-butyl nitroxide
derived alkoxyamine 13a. Isomerization for 3 h afforded the
alkoxyamines 13b,c in 87% yield (run 2). Since the addition
of CSA led to decomposition of the starting alkoxyamine
13a, the reaction had to be conducted without CSA. A
short reaction time was also observed for the phosphonate
14a (4.5 h, run 3).[17,18] Hydrogen bonding in nitroxides has
been shown to lead to a stabilization of the nitroxides and
hence to decreased reactivity towards C-centered radicals.[19]
Moreover, we have shown that intramolecular H-bonding in
ꢀ
alkoxyamines influences the C O-bond homolysis. Faster
homolysis was obtained for alkoxyamines capable of form-
ing intramolecular hydrogen bonds.[7] Thus, H-bonding in al-
koxyamines and nitroxides should lead to a shift of the equi-
The isomerization results correlate fairly well with the ac-
ꢀ
ꢀ
librium of the reversible alkoxyamine C O-bond homolysis
tivation energies for the C O-bond homolysis of the corre-
towards the radical pair. This eventually should lead to
faster isomerization reactions. In fact, upon going from the
parent Hawker–Braslau-type[20] alkoxyamine 15a to the H-
bonding system 16a a small decrease of the reaction time
was noticed (runs 4,5). With alkoxyamine 17a, bearing three
sponding alkoxyamines. Slow isomerizations were observed
for alkoxyamines with Ea values above 133 kJmolꢀ1 (12a,
19a and 20a). For alkoxyamines with Ea values between
124–127 kJmolꢀ1 reaction took 3–8 h for completion. For
systems with Ea values below 123 kJmolꢀ1 efficient isomeri-
Chem. Eur. J. 2005, 11, 2335 – 2350
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2337

A. Studer et al.
merized in 3 h, whereas for the slower homolysing alkoxy-
amines 22a and 24a less than 20 minutes is necessary to get
complete conversion. It is important to note that the trap-
ping of the nitroxide with the C-centered radical is as impor-
ꢀ
tant as the C O-bond homolysis. It is the equilibrium con-
stant which is important and which should provide a better
correlation. Unfortunately, the equilibrium constants for our
alkoxyamines are not known. We assume that the trapping
reaction of radical 4 with the nitroxides derived from 22a
and 24a is slower than the analogous reaction with the di-
tert-butyl-nitroxide. This leads to a higher life time of the in-
termediate radicals in systems 22 and 24 and eventually to
faster isomerizations.
Intermolecular processes—Radical alkoxyamine additions:
We next decided to study nitroxide-mediated intermolecular
alkoxyamine additions, so-called carboaminoxylations.[22]
ꢀ
Along with the strength of the C O bond, the reactivity of
the C-centered radical in the intermolecular addition has to
be considered. As a model reaction the addition onto 1-
octene was investigated. It is obvious that the attempted in-
termolecular carboaminoxylation will only work for stabi-
lized radicals which at the same time are reactive in inter-
molecular additions. Malonyl radicals, which have success-
fully been used in atom transfer reactions,[23] fulfill these cri-
teria. Indeed, we have already shown that intermolecular
carboaminoxylation
of TEMPO-malonate
25[24] in
ClCH2CH2Cl onto 1-octene provided carboaminoxylation
product 26 in 66% yield (Table 3, run 1).[22] To study the
scope and the limitations we decided to look at other
TEMPO-alkoxyamines derived from stabilized radicals
which are reactive in intermolecular additions. The alkoxya-
mines 27–32 were prepared via deprotonation of the corre-
sponding C–H acidic compounds with subsequent oxidation
(CuCl2) in the presence of TEMPO. The compounds were
obtained as racemates. Alkoxyamine additions were studied
by using 1-octene as acceptor under the optimized condi-
tions (ClCH2CH2Cl, 1m, 1358C, 3 d, Table 3). Products de-
rived from 27, 30 and 31 were obtained as 1:1 mixture of di-
astereoisomers. Reaction of Weinreb amide 27 with 1-
octene afforded addition product 33 in 33% yield (run 2).
Alkoxyamine addition by using 28, derived from methyl ace-
tylacetate, failed (run 3). The starting alkoxyamine was not
stable under the applied conditions. The same behavior was
observed for alkoxyamine 29 (run 4). Probably, the a-H-
atoms at C(4) of the b-ketoester are the reason for the fail-
ure. Intramolecular 1,5-proton transfer to the alkoxyamine
N atom may initiate the decomposition, as suggested by a
referee.[25] Indeed, the pivaloylated alkoxyamine 30 lacking
a-H-atoms at C(4) delivered the desired carboaminoxylation
product 36 in 51% yield. The Horner-type alkoxyamine 31
was successfully added onto 1-octene (37, 56%, run 6).[26]
Moreover, we showed that functionalized geminal bis-
phosphonates can be prepared using our methodology (38,
57%, run 7).[27] Thus, various functional groups, which are
highly useful for further synthetic manipulations, can be in-
troduced using our method.
Scheme 3. Various alkoxyamines tested in the alkoxyamine isomerization.
Table 2. Effect of the nitroxide structure on the isomerization; activation
ꢀ
energies for the alkoxyamine C O-bond homolysis.
Run Cpd Yield [%]
(exo + endo)
t [h] Ea [kJmolꢀ1
]
Ref.
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
19
20
21
22
23
24
73[a]
14[b] 133.6
[13]
[7]
[11]
[7]
[7]
[7]
[16]
this work
[13]
[13]
[15]
[15]
[14]
87[c]
80
97
73
69
90
61
74
75
95
38
84
3
119.1
4.5[b] 124.5
8[b] 127.1
7.5[b] 126.5
4[b] 124.1
<0.25 121.7
>36[b,d,e] 133.0
20[b] 133.1
3[b] 124.4
<0.25 122.8
>24[d] 123.7
0.33 122.2
9
10
11
12
13
[a] exo/endo 2.2:1; trans/cis (12b) 2.2:1. [b] 10% CSA was added. [c] exo/
endo 13.5:1; trans/cis (13b) 2.2:1. [d] Reaction was not completed.
[e] Yield determined by 1H NMR spectroscopy. Remaining material is
unreacted 19a (39%).
zations were obtained. However, the correlation is not per-
fect. The di-tert-butyl-nitroxide derived alkoxyamine 13a,
for which the lowest activation energy was determined, iso-
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Persistent Radical Effect
FULL PAPER
We also measured the Ea values for alkoxyamines 25, 27,
30–32 (see Table 3). As expected for successful PRE-mediat-
ed processes, all values lie below 142 kJmolꢀ1. The change
of the ester functionality by an amide, such as the Weinreb
amide, does not alter the Ea to a large extent (compare runs
1 and 2, 140.0 vs 137.7 kJmolꢀ1). The introduction of a di-
alkylphosphonyl group leads to
a
lowering of Ea
(135.3 kJmolꢀ1, run 6). This is probably due to steric factors.
For the bisphosphonate 32 the lowest activation energy was
measured (123.8 kJmolꢀ1, run 7). The replacement of the
methoxycarbonyl group by a pivaloyl group also leads to a
decrease of the Ea (compare run 1 and 5, 140.0 versus
132.1 kJmolꢀ1). Electronic as well as steric factors are con-
tributing in this case.
We have to admit that a disadvantage of our method is
the long reaction times necessary to get high conversions
(three days!). We thought that the change of the TEMPO
moiety by sterically more hindered nitroxides should lead to
decreased reaction times, as already observed for the alk-
oxyamine isomerizations described above. To this end, alk-
oxyamines 39–43 were prepared and tested in the 1-octene
carboaminoxylation reaction (44–48, Scheme 4). The experi-
ments were conducted in sealed tubes at 1258C in
ClCH2CH2Cl (1m) by using 5 equiv of 1-octene. The time
necessary to get complete conversion was determined. The
results are summarized in Scheme 4. With malonate 39 reac-
tion was completed after 7 h and alkoxyamine 44 was isolat-
ed in 77% yield. With the more bulky triethylmethyl conge-
ner 40 an even faster addition was obtained. Reaction was
finished in just 1.5 h and 45 was isolated in 78% yield. Simi-
lar results were obtained for the alkoxyamines 41 and 42. In-
Scheme 4. Carboaminoxylation of 1-octene by using alkoxyamines 39–43.
We also measured the acti-
Table 3. Intermolecular carboaminoxylations of various TEMPO-derived alkoxyamines onto 1-octene. Ea for
the starting alkoxyamines.
ꢀ
vation energies for the C O-
bond homolysis of malonates
39–43. The kinetic data corre-
late well with the reaction
times. For TEMPO-malonate
25 with an Ea of 140.0 kJmolꢀ1
three days were necessary for
the carboaminoxylation at
1358C. The alkoxyamines 39,
cis-43 and trans-43 with Ea
values in the range of
131 kJmolꢀ1 reacted in 5–7 h
at 1258C. For malonates 40–42
(Ea =124.9 kJmolꢀ1 for each)
addition was completed in just
1.5 h. Hence, the reaction time
could be shortened from 3 d to
Run
Compd
R1
R2
Product
Yield [%]
Ea [kJmolꢀ1
]
1
2
3
4
5
6
7
25
27
28
29
30
31
32
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Me
CON(Me)OMe
COMe
COEt
COtBu
26
33
34
35
36
37
38
66
33
–
140.0
137.7
n.d.
–
n.d.
51
56
57
132.1
135.3
123.8
CO2Et
PO(OMe)2
PO(OEt)2
PO(OMe)2
terestingly, although the ketonitroxide derived from 42 did
not perform well in the cyclization reaction described above,
highly efficient intermolecular addition was obtained by
using 42. The alkoxyamines 43 (cis and trans-isomer) under-
went intermolecular addition onto 1-octene in 5 and 6 h, re-
spectively, providing the corresponding carboaminoxylation
products trans and cis-48 in high yields.
1.5 h upon simply switching the nitroxide moiety, clearly
showing the benefits of our nitroxide design.
With highly efficient nitroxides in hand we also attempted
intermolecular addition of tertiary alkyl radicals. The tert-
butyl alkoxyamines 49 and 51 were readily prepared from
tBuLi oxidation in the presence of the corresponding nitro-
xide. The intermolecular carboaminoxylations were per-
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2339

A. Studer et al.
formed in tBuOH at 1308C by using 1-octene as radical ac-
ceptor (Scheme 5). A 40% yield was obtained using alkoxy-
amine 49 (dr 1:1). The reaction with 51 provided adduct 52
in a moderate yield (24%). Increasing the reaction time did
switching the nitroxide moiety. For the intermolecular addi-
tion of TEMPO-malonate 25 to 1-octene three days were
necessary for high conversions, whereas for alkoxyamines 40
and 41, deriving from sterically highly hindered nitroxides,
only 1.5 h were necessary for the same reaction. Important-
ly, reactions which cannot be conducted by using TEMPO-
derived alkoxyamines can be performed in moderate to
good yields using alkoxyamines derived from sterically
highly hindered alkoxyamines. Various functional groups,
such as the Weinreb amide, Horner-phosphonates or gemi-
nal bisphosphonates can be introduced using our methodol-
ogy. The environmentally benign reactions are easy to per-
form. No special equipment is necessary.
ꢀ
not improve the result. Surprisingly, the Ea for C O-bond
homolysis of alkoxyamine 51 is smaller than the Ea for 49,
although with the latter a better result was obtained in the
1-octene addition. Alkoxyamine stability may be the reason
for the improved yield using 49.
We could also show that the reaction times correlate
ꢀ
fairly well with the activation energies for the C O-bond
homolysis of the starting alkoxyamines. Hence, upon simply
looking at the kinetics of the homolysis process, the success
of the reaction can be predicted. Of course this is important
for careful reaction planning.
Finally, it is worth mentioning that alkoxyamines are also
used as regulators for the nitroxide mediated stable free rad-
ical polymerization.[28] The results presented herein will lead
to new ideas for the design of alkoxyamine polymerization
regulators.
Experimental Section
General: All reactions involving air- or moisture-sensitive reagents or in-
termediates were carried out in dried glassware under an argon atmos-
phere. THF was freshly distilled from potassium under argon. Et2O was
freshly distilled from K/Na under argon. CH2Cl2 was freshly distilled
from P2O5. All other solvents and reagents were purified according to
standard procedures or were used as received from Aldrich or Fluka. 1H
and 13C NMR spectra were recorded on a Bruker AMX 500, AMX 400,
AC 300, ARX 300, ARX 200, a Varian-Gemini 300 or a Varian-Gemini
200. Chemical shifts d in ppm relative to CHCl3 at 7.26 ppm as external
standard. TLC was performed by using Merck silica gel coated 60 F254
glass plates; detection with UV or dipping into a solution of KMnO4
(1.5 g in 400 mL H2O, 5 g NaHCO3) or a solution of Ce(SO4)2·H2O
(10 g), phosphormolybdic acid hydrate (25 g), concentrated H2SO4
(60 mL), and H2O (940 mL), followed by heating. Flash column chroma-
tography (FC) was performed using Merck or Fluka silica gel 60 (40–
63 mm) applying a pressure of about 0.4 bar. Melting points were deter-
mined with a Bꢁchi 510 or a Bꢁchi SMP-20 apparatus and are uncorrect-
ed. IR spectra were recorded on a Perkin Elmer 1600, a Perkin Elmer
782, a Bruker IFS-200 or a Nicolet Magna-IR 750 spectrophotometer.
Mass spectra were recorded on a VG Tribid, a CG Tribid, Varian CH7
(EI); IonSpec Ultima, QStarPulsar i, Finnigan MAT TSQ 700 or a Finni-
gan MAT 95S (ESI) and peaks are given in m/z (% of basis peak). Kinet-
ic EPR experiments were performed on a Bruker ESP 300 E at 1308C.
The temperature of the probe was regulated in a gas flow (92% N2, 8%
H2) by a Bruker Variable Temperature Unit BVT 2000. The nitroxide
concentrations were determined by double integration of the EPR spec-
Scheme 5. Intermolecular carboaminoxylation by using the PRE.
We could also show that with efficient nitroxides, addi-
tions of a-methoxycarbonyl alkyl radicals are feasible. Addi-
tion of 53 onto 1-octene provided ester 55 as a 1:1 mixture
of diastereoisomers in 75% yield (24 h). A slower reaction
was observed using alkoxyamine 54. The carboaminoxyla-
tion was stopped after four days. Product 56 was isolated in
57% yield along with 14% of unreacted starting alkoxy-
amine.
Conclusion
We reported radical alkoxyamine isomerization and inter-
molecular addition reaction using the PRE. We showed that
the nitroxide structure effects the reaction outcome to a
large extent. In particular steric effects play a major role.
For the alkoxyamine isomerization investigated comprising
the ubiquitous 5-hexenyl radical cyclization, reaction time
could be shortened from 24 h to 15 minutes upon simply
tra and calibration with
a TEMPO solution in tert-butylbenzene
(0.1 mm).
General procedure 1 (GP 1)—Isomerization of alkoxyamines: The al-
koxyamine and in some cases CSA (10%) were dissolved in degassed
tBuOH (0.02m solution) under argon. The mixture was heated to 130–
1328C in a sealed tube for 0.25–40 h. After removal of the solvent in
vacuo the residue was purified by FC.
2340
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2335 – 2350

Persistent Radical Effect
FULL PAPER
General procedure 2 (GP 2)—Synthesis of alkoxyamines according to
the method of Matyjaszewski:[29] The bromide, nitroxide, copper powder,
Cu(OTf)2 and 4,4’-di-tert-butyl-[2,2’]bipyridine were dissolved in benzene
under argon. The reaction mixture was heated to 65–758C in a sealed
tube for 6–20 h. Afterwards the mixture was filtered through silica gel
and the solvents were removed in vacuo. FC finally yielded the desired
alkoxyamine. For highly efficient nitroxides the alkoxyamine synthesis
should be performed at lower temperatures (< 408C).
=5.83–5.73 (m, 1H, H2C=CH), 5.03–4.93 (m, 2H, H2C=CH), 4.14–4.10
(m, 1H, HCO), 2.17–2.00 (m, 2H), 1.87–1.79 (m, 2H), 1.60–1.20 (m, 8H),
1.46 (s, 9H, C(CH3)3), 1.16 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.11 (s, 6H,
CH3); 13C NMR (100 MHz, CDCl3): d=172.9 (C), 138.4 (CH), 114.7
(CH2), 85.8 (CH), 80.8 (C), 59.9 (C), 59.5 (C), 40.3 (CH2), 33.7 (CH3),
33.5 (CH2, CH3), 31.9 (CH2), 28.1 (CH3), 23.7 (CH2), 20.2 (CH3), 17.1
(CH2); IR (CHCl3): n˜ = 2979s, 2935s, 2871s, 1732s, 1640w, 1457m, 1368s,
1153s, 915s, 843s cmꢀ1; MS (EI): m/z: 339 (2) [M]+, 156 (100); elemental
analysis calcd (%) for C20H37NO3 (339.52): C 70.75, H 10.98, N 4.13;
found: C 70.84, H 10.75, N 4.28.
General procedure 3 (GP 3)—Oxidative coupling of 1,3-dicarbonyl-com-
pounds and phosphonates with nitroxides: LDA was prepared from diiso-
propylamine (DIPA) and n-butyl lithium (nBuLi) in dimethoxyethane
(DME) at ꢀ608C. The 1,3-dicarbonyl-compound or the phosphonate, re-
spectively, was added and the mixture was stirred for 30 min at ꢀ608C.
Then the nitroxide and anhydrous CuCl2 were added followed by stirring
for 90 min at 08C and 2–20 h at room temperature. The reaction was
stopped upon addition of NH4Cl (aq. sat.) and the aqueous layer was ex-
tracted (3ꢃ) with Et2O. The combined organic layers were dried over
MgSO4 and the solvents were removed in vacuo. FC finally yielded the
desired alkoxyamine.
2,2,6,6-Tetramethyl-1-(1-methyl-hex-5-enoyloxy)-piperidine (7h):
A so-
lution of 6-iodo-hept-1-ene (224 mg, 1.0 mmol) and TEMPO (941 mg,
6.0 mmol) in benzene (10 mL) was heated under reflux under argon.
Tris(trimethylsilyl)silane (TTMSH) (1.23 mL, 4.0 mmol) was added in
three portions every 60 min. After the last addition of TTMSH the mix-
ture was heated under reflux for another 30 min. The solvent was re-
moved in vacuo and the residue was purified by FC (Et2O/pentane 1:100)
to yield 7h (246 mg, 97%). 1H NMR (400 MHz, CDCl3): d=5.88–5.78
(m, 1H, H2C=CH), 5.04–4.93 (m, 2H, H2C=CH), 3.91–3.83 (m, 1H,
HCO), 2.09–2.03 (m, 2H), 1.69–1.27 (m, 10H), 1.16–1.07 (m, 15H);
13C NMR (100 MHz, CDCl3): d=139.1 (CH), 114.3 (CH2), 78.2 (CH),
60.1 (C), 59.1 (C), 40.3 (CH2), 35.9 (CH2), 34.4 (2ꢃCH3), 34.1 (CH2), 25.3
(CH2), 20.4 (2 CH3), 19.9 (CH3), 17.4 (CH2); IR (CHCl3): n˜ = 2973s,
2933s, 2871w, 1639w, 1457m, 1376s, 1361s, 1132s, 915m cmꢀ1; MS (EI): m/
z: 253 (< 1) [M]+, 157 (11), 142 (100); elemental analysis calcd (%) for
C16H31NO (253.43): C 75.83, H 12.33, N 5.53; found: C 75.97, H 12.44, N
5.27.
General procedure 4 (GP 4)—Intermolecular additions of alkoxyamines
to alkenes: The alkoxyamine was dissolved under argon in degassed 1,2-
dichloroethane (DCE, 1m solution) and the alkene was added (5 equiv).
The mixture was heated in a sealed tube to 125–1358C for 1.5–72 h.
After evaporation of the solvent in vacuo the residue was purified by FC
to yield the desired products.
2,2,6,6-Tetramethyl-1-(2-phenyl-cyclopentylmethoxy)-piperidine
(2),
2,2,6,6-tetramethyl-1-(2-phenyl-cyclohexyloxy)-piperidine (3): The iso-
merization was performed according to GP 1 by using alkoxyamine 1
(210 mg, 0.67 mmol), CSA (15.6 mg, 0.067 mmol) and tBuOH (33.5 mL)
2,2,6,6-Tetramethyl-1-(1-phenylsulfanyl-hex-5-enoyloxy)-piperidine (7i):
Calcium ascorbate dihydrate (1.50 g, 3.80 mmol) was added to a suspen-
sion of TEMPO (468 mg, 3.00 mmol) in H2O (26 mL) and the mixture
was stirred at room temperature for 15 min. H2O was added and the re-
action mixture was extracted with Et2O (3ꢃ). The combined organic
layers were dried over MgSO4 and the solvent was removed in vacuo.
The resulting hydroxylamine was dissolved in THF (2 mL) under argon
at 130–1328C for 24 h. FC (Et2O/pentane 1:100) yielded
a mixture
(174 mg, 83%) of 2 and 3 (2/3 5.4:1, cis/trans (2) 1:2.5, cis/trans (3) 1:1;
1
all ratios determined by analysis of H NMR spectra).
Compound 2: 1H NMR (400 MHz, CDCl3): d=7.31–7.11 (m, 5H, Ph-H),
3.72–3.63 (m, 2H, CH2O, trans), 3.38–3.29 (m, 2H, CH2O, cis), 3.27–3.21
(m, 1H, CHPh, cis), 2.78–2.72 (m, 1H, CHPh, trans), 2.55–0.99 (m, 25H,
both isomers); 13C NMR (100 MHz, CDCl3): cis-2: d=143.2 (C), 128.4
(CH), 128.0 (CH), 125.7 (CH), 77.5 (CH2), 59.6 (C), 47.3 (CH), 43.6
(CH), 39.6 (CH2), 32.8 (CH3), 32.7 (CH3), 30.8 (CH2), 29.1 (CH2), 23.7
(CH2), 20.1 (CH3); trans-2: d=145.9 (C), 128.2 (CH), 127.5 (CH), 125.7
(CH), 79.3 (CH2), 59.7 (C), 49.2 (CH), 47.2 (CH), 39.6 (CH2), 35.9 (CH2),
33.2 (CH3), 32.9 (CH3), 24.8 (CH2), 20.1 (CH3), 17.1 (CH3).
Compound 3: 1H NMR (400 MHz, CDCl3): d=7.31–7.15 (m, 5H, Ph-H,
both isomers), 4.07–4.04 (m, 1H, HCO, single isomer), 3.79–3.70 (m, 1H,
HCO, single isomer), 3.00–2.92 (m, 1H, CHPh, single isomer), 2.60–2.40
(m, 1H, CHPh, single isomer), 2.40–1.00 (m, 26H, both isomers);
13C NMR (100 MHz, CDCl3): both isomers: d=147.7 (C), 146.9 (C),
128.3 (2ꢃCH), 126.9 (2ꢃCH), 125.9 (CH), 125.8 (CH), 82.2 (CH), 78.5
(CH), 59.8 (C), 59.7 (C), 43.5 (CH), 40.4 (CH2), 40.3 (2ꢃCH2), 38.7
(CH), 38.5 (CH2), 34.6 (CH3), 34.0 (CH2), 33.9 (CH2), 32.7 (CH2), 30.4
(CH2), 25.0 (CH2), 21.6 (CH2), 20.3 (CH3), 17.3 (CH2), 17.2 (CH2);
and then added dropwise to
a suspension of NaH (148 mg, 60%,
3.70 mmol) in THF (5 mL). The mixture was stirred for 30 min at room
temperature. Afterwards a solution of 1-Chlor-1-phenylsulfanyl-5-hexene
(566 mg, 2.50 mmol)[30] in THF (2 mL) was added and the reaction mix-
ture was heated under reflux for 20 h. The reaction was stopped upon the
addition of H2O followed by extraction of the aqueous layer with Et2O
(2ꢃ). The combined organic layers were dried over MgSO4 and the sol-
vents were removed in vacuo. FC (pentane/CHCl3 20:1!2:1) yielded 7i
(174 mg, 20%). 1H NMR (400 MHz, CDCl3): d=7.62–7.52 (m, 2H, Ph-
H), 7.39–7.17 (m, 3H, Ph-H), 5.80–5.70 (m, 1H, H2C=CH), 5.19 (dd, J1
=9.0, J2 =3.9 Hz, 1H, HCO), 4.99–4.90 (m, 2H, H2C=CH), 2.10–1.95 (m,
3H), 1.82–1.72 (m, 1H), 1.70–1.13 (m, 20H); 13C NMR (100 MHz,
CDCl3): d=138.6 (CH), 135.8 (C), 132.1 (CH), 128.5 (CH), 126.5 (CH2),
114.6 (CH2), 93.9 (CH), 60.7 (C), 59.8 (C), 40.4 (CH2), 34.7 (CH3), 34.0
(CH2), 33.5 (CH3), 33.4 (CH2), 25.5 (CH2), 20.6 (2ꢃCH3), 17.2 (CH2); IR
(CHCl3): n˜ = 2933s, 1639w, 1583w, 1377m, 1362m, 1132m, 973m, 914s
cmꢀ1; MS (EI): m/z: 347 (< 1) [M+H]+, 234 (10), 218 (25), 191 (33), 157
(22), 142 (24), 140 (48), 126 (85), 110 (100); elemental analysis calcd (%)
for C21H33NOS (347.56): C 72.57, H 9.57, N 4.03; found: C 72.51, H 9.53,
N 3.93.
IR(CHCl3): n˜
= 2933s, 2871s, 1601w, 1492m, 1470m, 1452m, 1374m,
1360m, 1260w, 1132m, 1046m, 994w, 957w cmꢀ1; MS (EI): m/z: 315 (5)
[M]+, 300 (35), 159 (13), 157 (18), 142 (100), 91 (35); elemental analysis
calcd (%) for C21H33NO (315.50): C 79.95 H 10.54, N 4.44; found: C
80.05, H 10.78, N 4.67.
Isomerization of 7a: Applying GP 1 7a[7] (250 mg, 0.63 mmol), CSA
(14.6 mg, 0.063 mmol) and tBuOH (31.5 mL) were heated for 24 h. FC
(Et2O/pentane 1:100) yielded a mixture (201 mg, 80%) of 8a (71%) and
9a (8%). The trans/cis ratios (2.8:1 for 8a, 1:1 for 9a) were determined
The syntheses of the alkoxyamines 7a–e have previously been publish-
ed.[7]
2-(2,2,6,6-Tetramethyl-piperidin-1-yloxy)-hept-6-enoic acid tert-butylester
(7 f): A solution of hept-6-enoic acid tert-butyl ester (200 mg, 1.09 mmol)
in THF (1.8 mL) was added to a solution of LDA (1.20 mmol) in THF
(5 mL) at ꢀ788C. After stirring for 30 min at ꢀ788C a suspension of
TEMPO (157 mg, 1.00 mmol) and CuCl2 (161 mg, 1.20 mmol) in THF
(4 mL) was added. The mixture was allowed to warm to room tempera-
ture (over 5 h) and was stirred over night. The reaction was stopped by
addition of NH4Cl (aq. sat.) followed by extraction (3ꢃ) of the aqueous
layer with Et2O. The combined organic layers were washed with brine,
dried over MgSO4 and the solvents were removed in vacuo. FC (Et2O/
pentane 1:45) yielded 7 f (200 mg, 59%). 1H NMR (400 MHz, CDCl3): d
1
by H NMR spectroscopy.
1-[2-(4-Bromophenyl)-cyclopentylmethoxy]-2,2,6,6-tetramethyl-piperi-
dine (8a): 1H NMR (400 MHz, CDCl3): trans-8a: d=7.38 (d, J=8.4 Hz,
2H, Ph-H), 7.10 (d, J=8.3 Hz, 2H, Ph-H), 3.70–3.62 (m, 2H, H2CO),
2.75–2.69 (m, 1H, HCPh), 2.40–0.90 (m, 25H); cis-8a: d=7.36 (d, J
=8.3 Hz, 2H, Ph-H), 7.06 (d, J=8.1 Hz, 2H, Ph-H), 3.37–3.28 (m, 2H,
H2CO), 3.22–3.16 (m, 1H, HCPh), 2.47–2.42 (m, 1H), 2.20–1.00 (m,
21H), 0.86 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): trans-8a:
d
=145.0 (C), 131.2 (CH), 129.2 (CH), 119.3 (C), 79.2 (CH2), 59.7 (C), 48.8
(CH), 47.2 (CH), 39.6 (CH2), 39.6 (CH2), 36.0 (CH2), 33.1 (CH3), 33.0
Chem. Eur. J. 2005, 11, 2335 – 2350
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2341

A. Studer et al.
(CH3), 30.1 (CH2), 24.7 (CH3), 20.1 (CH3), 17.1 (CH2); cis-8a: d=142.3
(C), 131.0 (CH), 130.1 (CH), 119.4 (C), 77.4 (CH2), 59.6 (C), 59.5 (C),
46.7 (CH), 43.5 (CH), 32.8 (CH3), 32.8 (CH3), 30.9 (CH2), 29.1 (CH2),
136.0 (CH), 122.6 (CH), 120.9 (CH), 79.7 (CH2), 59.7 (C), 51.6 (CH),
46.1 (CH), 39.6 (CH2), 34.7 (CH2), 33.0 (CH3), 33.0 (CH3), 30.1 (CH2),
25.0 (CH2), 20.0 (CH3), 20.0 (CH3), 17.1 (CH2); IR (CHCl3): n˜ = 2935s,
2870s, 1592s, 1474s, 1435s, 1374m, 1360m, 1132m, 1047m cmꢀ1; MS (EI):
m/z: 317 (< 1) [M+H]+, 301 (< 1) [MꢀCH3]+, 160 (100); elemental
analysis calcd (%) for C20H32N2O (316.49): C 75.90, H 10.19, N 8.85;
found: C 75.85, H 9.98, N 8.84.
23.7 (CH2), 20.1 (CH2); IR (CHCl3): n˜
= 2933s, 2872s, 1488s, 1374s,
1360s, 1260w, 1131s, 1074s, 1046s, 1010s cmꢀ1; MS (EI): m/z: 395 (4)
[M]+, 380 (38) [MꢀCH3]+, 171 (25), 156 (24), 142 (100); elemental analy-
sis calcd (%) for C21H32NOBr (394.39): C 63.95, H 8.18, N 3.55; found:
C 64.07, H 8.04, N 3.23.
Isomerization of 7e: Applying GP 1 7e[7] (200 mg, 0.76 mmol), CSA
(17.6 mg, 0.076 mmol) and tBuOH (38 mL) were heated for 24 h. FC
Isomerization of 7b: Applying GP 1 7b[7] (37 mg, 0.11 mmol), CSA
(2.5 mg, 0.011 mmol) and tBuOH (5.5 mL) were heated for 24 h. FC
(Et2O/pentane 1:60) yielded a mixture (21 mg, 54%) of 8b (46%) and
9b (8%). The trans/cis ratios (2.8:1 for 8b, 1:1 for 9b) were determined
(Et2O/pentane 1:40!1:20) yielded
a mixture (135 mg, 68%) of 8e
(61%) and 9e (7%). The trans/cis ratios (1.1:1 for 8e, 1:1 for 9e) were
1
determined by H NMR spectroscopy.
1
by H NMR spectroscopy. 10c (10%) was isolated as a by-product.
2-(2,2,6,6-Tetramethyl-piperidin-1-yloxymethyl)-cyclopentane-1-nitrile
(8e): 1H NMR (400 MHz, CDCl3): isomer A: d=3.87–3.83 (m, 1H,
H2CO), 3.72 (dd, J1 =9.0, J2 =6.6 Hz, 1H, H2CO), 2.70–2.64 (m, 1H,
HCCN), 2.35–2.25 (m, 1H), 2.15–1.40 (m, 12H), 1.40–1.00 (m, 12H,
CH3); isomer B: d=3.96 (dd, J1 =9.2, J2 =8.5 Hz, 1H, H2CO), 3.87–3.83
(m, 1H, H2CO), 3.05–3.01 (m, 1H, HCCN), 2.47–2.38 (m, 1H), 2.15–1.40
(m, 12H), 1.40–1.00 (m, 12H, CH3); 13C NMR (100 MHz, CDCl3): isomer
A: d=123.0 (C), 77.1 (CH2), 60.0 (C), 44.8 (CH), 39.6 (CH2), 33.3 (CH3),
32.3 (CH), 31.2 (CH2), 27.4 (CH2), 22.8 (CH2), 20.2 (2ꢃCH3), 20.2 (CH3),
17.0 (CH2); isomer B: d=121.3 (C), 77.1 (CH2), 59.9 (C), 42.4 (CH), 39.6
(CH2), 33.1 (CH3), 31.2 (CH2), 30.8 (CH), 28.5 (CH2), 24.6 (CH2), 20.1
(CH3), 20.0 (CH3), 17.1 (CH2); IR (CHCl3): n˜ = 2974s, 2935s, 2875s,
2238m, 1470m, 1453m, 1375m, 1360m, 1132s, 1049s cmꢀ1; MS (EI): m/z:
264 (6) [M]+, 249 (100) [MꢀCH3]+, 156 (25), 142 (14); elemental analysis
calcd (%) for C16H28N2O (264.41): C 72.68, H 10.67, N 10.59; found: C
72.51, H 10.89, N 10.59.
1-[2-(4-Methoxyphenyl)-cyclopentylmethoxy]-2,2,6,6-tetramethyl-piperi-
dine (8b): 1H NMR (400 MHz, CDCl3): trans-8b: d=7.14 (d, J=8.5 Hz,
2H, Ph-H), 6.82 (d, J=8.8 Hz, 2H, Ph-H), 3.78 (s, 3H, OCH3), 3.69 (dd,
J1 =8.5, J2 =5.0 Hz, 1H, H2CO), 3.63 (dd, J1 =8.4, J2 =7.0 Hz, 1H,
H2CO), 2.73–2.67 (m, 1H, HCPh), 2.20–1.00 (m, 25H). cis-8b: d=7.09
(d, J=8.3 Hz, 2H, Ph-H), 6.79 (d, J=8.8 Hz, 2H, Ph-H), 3.78 (s, 3H,
OCH3), 3.37 (dd, J1 =8.8, J2 =5.7 Hz, 1H, H2CO), 3.30 (dd, J1 =8.6, J2
=8.6 Hz, 1H, H2CO), 3.22–3.16 (m, 1H, HCPh), 2.20–1.00 (m, 22H),
0.88 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): trans-8b: d=157.7 (C),
137.9 (C), 128.3 (CH), 113.6 (CH), 79.3 (CH2), 59.7 (C), 55.3 (CH3), 48.3
(CH), 47.3 (CH), 39.6 (CH2), 35.9 (CH2), 33.2 (CH3), 33.0 (CH3), 30.2
(CH2), 24.6 (CH2), 20.1 (CH3), 17.1 (CH2); cis-8b: d=157.6 (C), 135.3
(C), 129.2 (CH), 113.4 (CH), 77.6 (CH2), 59.8 (C), 55.3 (CH3), 46.4 (CH),
43.6 (CH), 40.2 (CH2), 32.8 (CH3), 32.6 (CH3), 31.0 (CH2), 29.1 (CH2),
23.7 (CH2), 20.1 (CH3); IR (CHCl3): n˜ = 2938s, 2871s, 1611m, 1512s,
1467s, 1374m, 1359m, 1132s, 1037s, 828s cmꢀ1; MS (EI): m/z: 345 (5)
[M]+, 330 (22) [MꢀCH3]+, 189 (76), 142 (46), 121 (100); elemental analy-
sis calcd (%) for C22H35NO2 (345.52): C 76.48, H 10.21, N 4.05; found: C
76.64, H 10.35, N 4.23.
Isomerization of 7 f: Applying GP 1 7 f (200 mg, 0.59 mmol), CSA
(13.7 mg, 0.059 mmol) and tBuOH (29.5 mL) were heated for 24 h. FC
(Et2O/pentane 1:60) yielded 8 f (134 mg, 67%). The trans/cis ratio (1:1)
was determined by 1H NMR spectroscopy. 10 f (10%) was isolated as a
by-product.
Isomerization of 7c: Applying GP 1 7c[7] (200 mg, 0.62 mmol), CSA
(14.4 mg, 0.062 mmol) and tBuOH (31 mL) were heated for 24 h. FC
(Et2O/pentane 1:100) yielded a mixture (156 mg, 78%) of 8c (67%) and
9c (11%). The trans/cis ratios (2.1:1 for 8c, 1:1 for 9c) were determined
by 1H NMR spectroscopy. 10c (5%) was isolated as a by-product.
2-(2,2,6,6-Tetramethyl-piperidin-1-yloxymethyl)-cyclopentanoic acid tert-
butylester (8 f): 1H NMR (400 MHz, CDCl3): Isomer A: d=3.81 (dd, J1
=8.6, J2 =5.3 Hz, 1H, H2CO), 3.61 (dd, J1 =9.6, J2 =8.6 Hz, 1H, H2CO),
2.87–2.71 or 2.52–2.46 (m, 1H, HCCO2R), 2.38–2.28 (m, 1H,
HCCH2ON), 2.00–1.30 (m, 12H), 1.44 (s, 9H, C(CH3)3), 1.16–1.09 (m,
12H, CH3); isomer B: d=3.77 (dd, J1 =8.4, J2 =5.8 Hz, 1H, H2CO), 3.73
(dd, J1 =8.4, J2 =6.4 Hz, 1H, H2CO), 2.87–2.71 or 2.52–2.46 (m, 1H,
HCCO2R), 2.38–2.28 (m, 1H, HCCH2ON), 2.00–1.30 (m, 12H), 1.44 (s,
9H, C(CH3)3), 1.16–1.09 (m, 12H, CH3); 13C NMR (100 MHz, CDCl3):
isomer A: d=175.9 (C), 79.7 (C), 79.0 (CH2), 59.9 (C), 47.8 (CH), 43.4
(CH), 39.6 (CH2), 33.1 (CH3), 30.0 (CH2), 28.2 (CH2), 28.1 (CH3), 25.4
(CH2), 20.1 (CH3), 17.1 (CH2); isomer B: d=174.2 (C), 79.9 (C), 76.9
(CH2), 59.9 (C), 47.3 (CH), 42.4 (CH), 39.6 (CH2), 33.1 (CH3), 30.5
(CH2), 29.1 (CH2), 28.2 (CH3), 23.3 (CH2), 20.2 (CH3), 17.2 (CH2); IR
(CHCl3): n˜ = 2975s, 2934s, 2872s, 1715s, 1471s, 1454s, 1368s, 1151s, 1047m
cmꢀ1; MS (EI): m/z: 339 (1) [M]+, 324 (9) [MꢀCH3]+, 157 (20), 142
(100), 127 (33); elemental analysis calcd (%) for C20H37NO3 (339.52): C
70.75, H 10.98, N 4.13; found: C 70.67, H 10.79, N 4.16.
2,2,6,6-Tetramethyl-1-(2-thiophene-2-yl-cyclopentyl-methoxy)-piperidine
(8c): 1H NMR (400 MHz, CDCl3): trans-8c: d=7.10–7.08 (m, 1H, arom.
H), 6.90–6.88 (m, 1H, arom. H), 6.83–6.80 (m, 1H, arom. H), 3.79 (dd, J1
=8.5, J2 =5.2 Hz, 1H, H2CO), 3.72 (dd, J1 =8.5, J2 =6.7 Hz, 1H, H2CO),
3.15–3.09 (m, 1H, HCAryl), 2.30–1.20 (m, 13H), 1.20–1.00 (m, 12H, CH3);
cis-8c: d=7.12–7.08 (m, 1H, arom. H), 6.94–6.88 (m, 1H, arom. H),
6.78–6.76 (m, 1H, arom. H), 3.53–3.47 (m, 2H, H2CO), 3.42–3.38 (m, 1H,
HCAryl), 2.43–2.34 (m, 1H), 2.30–1.20 (m, 12H), 1.20–1.00 (m, 9H, CH3),
0.93 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): trans-8c: d=150.2 (C),
126.4 (CH), 123.0 (CH), 122.4 (CH), 79.0 (CH2), 59.8 (C), 48.1 (CH),
43.8 (CH), 40.0 (CH2), 36.6 (CH2), 33.2 (CH3), 33.1 (CH3), 29.9 (CH2),
24.6 (CH2), 20.2 (CH3), 17.1 (CH2); cis-8c: d=146.6 (C), 126.3 (CH),
124.2 (CH), 122.9 (CH), 77.3 (CH2), 59.6 (C), 44.1 (CH), 42.9 (CH), 39.6
(CH2), 32.9 (CH3), 32.7 (CH2), 32.4 (CH3), 28.5 (CH2), 23.0 (CH2), 20.2
(CH3), 17.1 (CH2); IR (CHCl3): n˜ = 2934s, 2871s, 1468s, 1375m, 1360m,
1132m, 1045m cmꢀ1; MS (EI): m/z: 321 (4) [M]+, 306 (42) [MꢀCH3]+,
165 (70), 156 (22), 142 (100); elemental analysis calcd (%) for
C19H31NOS (321.53): C 70.98, H 9.72, N 4.36; found: C 71.21, H 9.58, N
4.34.
2,2,6,6-Tetramethyl-1-(1-phenyl-hex-5-enyloxy)-piperidin-4-ol (12a): Cal-
cium ascorbate dihydrate (2.77 g, 6.50 mmol) was added to a suspension
of 4-tert-butyldimethylsilyloxy-TEMPO (1.72 mg, 6.0 mmol) in H2O
(25 mL) and the mixture was stirred at room temperature for 15 min.
H2O was added and the reaction mixture was extracted with Et2O (3ꢃ).
The combined organic layers were dried over MgSO4 and the solvent was
removed in vacuo. The resulting hydroxylamine was dissolved in THF
under argon and then added dropwise to a suspension of NaH (240 mg,
60%, 6.00 mmol) in THF (10 mL). The mixture was stirred for 30 min at
room temperature. Afterwards a solution of 1-bromo-1-phenyl-5-hexene
(703 mg, 3.00 mmol) in THF (2 mL) was added and the reaction mixture
was heated under reflux for 14 h. The reaction was stopped by the addi-
tion of H2O followed by extraction of the aqueous layer with Et2O (2ꢃ).
The combined organic layers were dried over MgSO4 and the solvents
were removed in vacuo. FC (Et2O/pentane 1:130) yielded silylated-12a
(493 mg, 37%). Desilylation was achieved by dissolving silylated-12a
(490 mg, 1.10 mmol) in THF (13 mL) and adding TBAF·3H2O (868 mg,
Isomerization of 7d: Applying GP 1 7d[7] (76 mg, 0.24 mmol), CSA
(5.6 mg, 0.024 mmol) and tBuOH (12 mL) were heated for 24 h. FC
(Et2O/pentane 1:6!1:4) yielded a mixture (55 mg, 72%) of 8d (57%)
and 9d (15%). The trans/cis ratios (1.6:1 for 8d, 1:1 for 9d) were deter-
1
mined by H NMR spectroscopy. 10d (5%) was isolated as a by-product.
2-[2-(2,2,6,6-Tetramethyl-piperidin-1-yloxymethyl)-cyclopentyl]-pyridine
(8d): 1H NMR (400 MHz, CDCl3): trans-8d: d=8.55–8.53 (m, 1H, arom.
H), 7.57–7.53 (m, 1H, arom. H), 7.18–7.16 (m, 1H, arom. H), 7.08–7.04
(m, 1H, arom. H), 3.74–3.68 (m, 2H, H2CO), 2.97–2.91 (m, 1H, HCAryl),
2.54–2.45 (m, 1H), 2.13–1.97 (m, 2H), 1.96–1.68 (m, 4H), 1.61–1.14 (m,
6H), 1.08 (s, 3H, CH3), 1.04 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.93 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3): trans-8d: d=165.0 (C), 149.2 (CH),
2342
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2335 – 2350

Persistent Radical Effect
FULL PAPER
2.75 mmol) at room temperature. The mixture was stirred for 6 h. The re-
action was stopped upon the addition of NH4Cl (aq. sat.) followed by ex-
traction (3ꢃ) of the aqueous layer with Et2O. The combined organic
layers were washed with brine, dried over MgSO4 and the solvents were
removed in vacuo. FC (Et2O/pentane 2:3) yielded 12a (336 mg, 92%).
1H NMR (400 MHz, CDCl3): d=7.32–7.21 (m, 5H, Ph-H), 5.76–5.66 (m,
1H, H2C=CH), 4.96–4.87 (m, 2H, H2C=CH), 4.57 (dd, J1 =9.9, J2
=4.1 Hz, 1H, HCO), 3.96–3.88 (m, 1H, HCOH), 2.13–1.91 (m, 3H),
1.84–1.74 (m, 2H), 1.70–1.51 (m, 1H), 1.51–1.46 (m, 1H), 1.33 (s, 3H,
CH3), 1.22 (s, 3H, CH3), 1.33–1.00 (m, 3H), 1.04 (s, 3H, CH3), 0.53 (s,
3H, CH3); 13C NMR (100 MHz, CDCl3): d=143.4 (C), 138.7 (CH), 127.9
(CH), 127.9 (CH), 127.1 (CH), 114.5 (CH2), 87.5 (CH), 63.3 (CH), 60.5
(C), 59.8 (C), 48.9 (CH2), 48.9 (CH2), 35.3 (CH2), 34.3 (CH3), 34.1 (CH3),
33.7 (CH2), 24.7 (CH2), 21.3 (2CH3); IR (CHCl3): n˜ = 3604m, 3440br,
2975s, 2940s, 1639m, 1456s, 1363s, 1046s, 1027m, 996m, 913m cmꢀ1; MS
(EI): m/z: 316 (< 1) [MꢀCH3]+, 173 (29), 158 (100), 117 (35); elemental
analysis calcd (%) for C21H33NO2 (331.50): C 76.09, H 10.03, N 4.23;
found: C 76.17, H 9.89, N 4.26.
in tBuOH (10 mL) at 130–1328C in 3 h. The crude product was purified
by FC (Et2O/pentane 1:120) and the isomerization product was isolated
in an overall yield of 87% (exo/endo 13.5:1, trans/cis (13b) 2.2:1).
1H NMR (400 MHz, CDCl3): trans-13b: d=7.30–7.10 (m, 5H, Ph-H),
3.69–3.62 (m, 2H, OCH2), 2.70–2.64 (m, 1H, HC-Ph), 2.25–2.15 (m, 1H,
OCH2CH), 2.12–1.50 (m, 6H, CH2), 1.16 (s, 9H, C(CH3)3), 1.10 (s, 9H,
C(CH3)3); cis-13b: d=7.30–7.10 (m, 5H, Ph-H), 3.36–3.19 (m, 3H,
OCH2, HCPh), 2.12–1.50 (m, 7H, OCH2CH,CH2), 1.15 (s, 9H, C(CH3)3),
1.05 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3): trans-13b: d=145.8
(C), 128.2 (CH), 127.4 (CH), 125.7 (CH), 79.7 (CH2), 62.4 (C), 62.2 (C),
49.5 (CH), 47.0 (CH), 35.7 (CH2), 30.7 (CH2), 29.9 (CH3), 29.8 (CH3),
24.7 (CH2); cis-13b: d=128.3 (CH), 128.0 (CH), 126.9 (CH), 77.2 (CH2),
62.3 (C), 62.2 (C), 47.3 (CH), 43.3 (CH), 30.7 (CH2), 29.9 (CH3), 29.7
(CH3), 29.3 (CH2), 23.6 (CH2); IR (CHCl3): n˜ = 3008m, 2940s, 2868m,
1703s, 1450m, 1361m, 1312m, 1120m, 1053w, 1018m, 913m cmꢀ1; MS
(FAB): m/z: 303 (100) [M]+, 248 (91) [MꢀC4H7]+, 232 (94), 159 (93)
[MꢀONC8H18]+, 145 (87) [MꢀC12H14]+, 90 (98), 71 (96); elemental anal-
ysis calcd (%) for C20H33NO (303.49): C 79.15, H 10.96, N 4.62; found: C
79.11, H 10.97, N 4.41.
2,2,6,6-Tetramethyl-1-(2-phenyl-cyclopentylmethyl)-piperidin-4-ol (12b):
GP 1 was applied by using alkoxyamine 12a (200 mg, 0.60 mmol) and
CSA (13.0 mg, 0.06 mmol) in tBuOH (30 mL) at 1308C for 14 h. The de-
sired isomerization product could be isolated after FC (Et2O/pentane
1:2) in an overall yield of 73% (exo/endo 12.2:1, trans/cis (12b) 2.2:1).
M.p. 94–958C. 1H NMR (400 MHz, CDCl3): trans-12b: d=7.31–7.12 (m,
5H, Ph-H), 3.92–3.87 (m, 1H, HCOH), 3.70 (dd, J1 =8.6, J2 =5.4 Hz, 1H,
HCON), 3.65 (dd, J1 =8.5, J2 =6.8 Hz, 1H, HCON), 2.77–2.70 (m, 1H,
HC-Ph), 2.50–1.00 (m, 23H, CH, CH2, CH3); cis-12b: d=7.31–7.12 (m,
5H, Ph-H), 3.92–3.87 (m, 1H, HCOH), 3.37 (dd, J1 =8.8, J2 =5.9 Hz, 1H,
HCON), 3.65 (dd, J1 =8.7, J2 =8.7 Hz, 1H, HCON), 3.27–3.21 (m, 1H,
HC-Ph), 2.50–1.00 (m, 22H, CH, CH2, CH3), 0.87 (s, 1H, CH3); 13C NMR
(100 MHz, CDCl3): trans-12b: d=145.7 (C), 128.2 (CH), 127.4 (CH),
125.8 (CH), 79.5 (CH2), 63.3 (CH), 60.1 (C), 60.0 (C), 49.3 (CH), 48.3
(CH2), 47.1 (CH), 35.9 (CH2), 33.2 (CH3), 33.0 (CH3), 30.2 (CH2), 24.7
(CH2), 21.0 (CH3); cis-12b: d=143.1 (C), 128.4 (CH), 127.4 (CH), 125.7
(CH), 77.6 (CH2), 63.3 (CH), 59.9 (C), 59.8 (C), 48.3 (CH2), 47.2 (CH),
35.9 (CH2), 32.8 (CH3), 32.6 (CH3), 30.9 (CH2), 29.2 (CH2), 23.7 (CH2),
{1-[tert-Butyl-(1-phenyl-hex-5-enyloxy)-amino]-2,2-dimethyl-propyl}-
phosphonic acid dimethylester (14a): GP 2 was applied by using (1-
bromo-hex-5-enyl)-benzene (235 mg, 1.00 mmol), corresponding nitro-
xide[17] (303 mg, 1.20 mmol), Cu (67 mg, 1.05 mmol), Cu(OTf)2 (3.5 mg,
10 mmol) and 4,4’-di-tert-butyl-[2,2’]bispyridine (1 mg, 40 mmol) in ben-
zene (1.5 mL) for 22 h at 708C. FC (Et2O/pentane 1:2) yielded 14a
(77 mg, 19%) as a mixture of diastereoisomers. 1H NMR (400 MHz,
CDCl3): isomer A: d=7.45–7.43 (m, 2H, Ph-H), 7.33–7.20 (m, 3H, Ph-
H), 5.76–5.64 (m, 1H, H2C=CH), 5.00–4.82 (m, 3H, H2C=CH, HCO),
3.51 (d, JHP =11.1 Hz, 3H, OCH3), 3.41 (d, JHP =26.1 Hz, 1H, HCP), 2.97
(d, JHP =11.4 Hz, 3H, OCH3), 2.65–2.57 (m, 1H), 2.10–1.95 (m, 2H),
1.75–1.50 (m, 2H), 1.10–0.90 (m, 1H), 1.20 (s, 9H, C(CH3)3), 1.18 (s, 9H,
C(CH3)3); isomer B: d=7.33–7.20 (m, 5H, Ph-H), 5.76–5.64 (m, 1H,
H2C=CH), 5.00–4.82 (m, 2H, H2C=CH), 4.74 (dd, J1 =11.9, J2 =3.3 Hz,
1H, HCO), 3.86 (d, JHP =11.2 Hz, 3H, OCH3), 3.64 (d, JHP =11.0 Hz, 3H,
OCH3), 3.35 (d, JHP =26.0 Hz, 1H, HCP), 2.76–2.67 (m, 1H), 2.00–1.80
(m, 2H), 1.75–1.50 (m, 2H), 1.10–0.90 (m, 1H), 1.22 (s, 9H, C(CH3)3),
0.82 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3): isomer A: d=141.7
(C), 138.8 (CH), 128.8 (CH), 127.9 (CH), 114.4 (CH2), 83.5 (CH), 70.2 (d,
J=139.2 Hz, CH), 61.4 (C), 52.9 (d, J=6.2 Hz, CH3), 49.1 (d, J=7.5 Hz,
CH3), 35.2 (d, J=5.1 Hz, C), 34.0 (CH2), 33.0 (CH2), 28.5 (CH3), 28.1
(CH3), 24.7 (CH2); isomer B: d=143.5 (C), 138.9 (CH), 128.0 (CH),
127.7 (CH), 127.2 (CH), 114.2 (CH2), 90.5 (CH), 70.0 (d, J=138.1 Hz,
CH), 61.2 (C), 53.0 (d, J=7.4 Hz, CH3), 36.1 (CH2), 35.7 (d, J=6.1 Hz,
C), 33.6 (CH2), 30.6 (CH2), 30.5 (CH3), 29.9 (CH3), 25.4 (CH2); IR
(CHCl3): n˜ = 2979s, 1639w, 1454m, 1394m, 1365s, 1070s, 1035s, 914m
cmꢀ1; MS (FAB): m/z: 426 (89) [M+H]+, 316 (36), 267 (56), 210 (44),
158 (100), 154 (30); elemental analysis calcd (%) for C23H40NO4P
(425.55): C 64.92, H 9.47, N 3.29; found: C 65.08, H 9.61, N 3.26.
21.0 (CH3); IR (CHCl3): n˜
= 3606m, 3428br, 2941s, 2872m, 1601w,
1492w, 1453m, 1375s, 1364s, 1044s, 1027s, 952m, 897w cmꢀ1; MS (EI): m/z:
331 (8) [M]+, 316 (42) [MꢀCH3]+, 173 (41) [MꢀC12H14]+, 158 (100)
[MꢀONC9H18OH]+, 91 (68); elemental analysis calcd (%) for C21H33NO2
(331.50): C 76.09, H 10.03, N 4.32; found: C 76.02, H 10.24, N 4.27.
N,N-Di-tert-butyl-O-(1-phenyl-hex-5-enyl)-hydroxylamine (13a): Calcium
ascorbate dihydrate (1.194 g, 2.80 mmol) was added to a suspension of
N,N-di-tert-butylnitroxide (403 mg, 2.80 mmol) in water (10 mL). The
mixture was stirred at room temperature for 15 min. After the addition
of water and extraction with Et2O (2ꢃ) evaporation of the solvent led to
the corresponding hydroxylamine which was then dissolved in THF
under argon. The solution was added slowly to a suspension of NaH
(112 mg, 60%, 2.80 mmol) in THF (5 mL) prior to the addition of a so-
lution of 1-bromo-1-phenyl-5-hexene (300 mg, 1.28 mmol) in THF
(1 mL). The reaction mixture was heated to reflux for 44 h. After the ad-
dition of water the mixture was extracted with Et2O twice and the com-
bined organic layers was dried over MgSO4. Evaporation of the solvent
in vacuo and purification with FC (Et2O/pentane 1:120) yielded alkoxy-
{1-[tert-Butyl-(2-phenyl-cyclopentylmethoxy)-amino]-2,2-dimethyl-
propyl}-phosphonic acid dimethyl ester (14b): Applying a variation of
GP 2 a solution of alkoxyamine 14a in tBuOH (6.3 mL, 0.05m) was
heated to 1308C for 4.5 h. FC (Et2O/pentane 1:2) yielded the desired cyc-
lization product as a mixture of 14b and 14c (102 mg, 80%). 1H NMR
(400 MHz, CDCl3) (4 isomers): d=7.27–7.22 (m, 5H, Ph-H), 4.23–4.04
(m, 1H, OCH2), 3.81–3.35 (m, 7H, OCH2, OCH3), 3.21–3.10 (m, 1H,
PCH), 2.64–1.35 (m, 8H, CH, CH2), 1.19–0.94 (m, 18H, CH3); due to its
complexity (4 isomers) the 13C NMR spectrum was not interpreted; IR
(CHCl3): n˜ = 3400br, 2956s, 2873w, 1601w, 1468s, 1392m, 1365s, 1070s,
1032s cmꢀ1; MS (FAB): m/z: 426 (11) [M+H]+, 368 (18) [MꢀC4H9]+, 316
(100) [MꢀC2H6O3P]+, 260 (81), 210 (20); elemental analysis calcd (%)
for C23H40NO4P (425.55): C 64.92, H 9.47, N 3.29; found: C 64.86, H 9.50,
N 3.22.
1
amine 13a (185 mg, 24%). H NMR (400 MHz, CDCl3): d=7.35–7.20 (m,
5H, Ph-H), 5.76–5.66 (m, 1H, CH=CH2), 4.96–4.87 (m, 2H, CH=CH2),
4.60 (dd, J1 =3.9, J2 =10.3 Hz, 1H, HCO), 2.21–2.12 (m, 1H), 2.07–1.91
(m, 2H), 1.83–1.73 (m, 1H), 1.31 (s, 9H, C(CH3)3), 1.20–1.00 (m, 2H),
0.97 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3): d=143.10 (C),
138.79 (CH), 128.29 (CH), 127.82 (CH), 127.13 (CH), 114.39 (CH2), 87.44
(CH), 62.07 (C), 61.68 (C), 34.47 (CH2), 33.79 (CH2), 30.70 (CH3), 30.62
(CH3), 25.13 (CH2); IR (CHCl3): n˜ = 2971s, 2931s, 2861w, 1639w, 1494m,
1453m, 1386m, 1362s, 976m, 912s cmꢀ1; MS (FAB): m/z: 304.3 (25)
[M+H]+, 248.3 (26), 159.2 (83), 145.2 (100), 128.1 (40), 117.0 (28); ele-
mental analysis calcd (%) for C20H33NO (303.49): C 79.15, H 10.96, N
4.62; found: C 79.24, H 11.02, N 4.51.
The syntheses of alkoxyamines 15a, 16a and 17a have previously been
published.[7]
N-tert-Butyl-N-(2-methyl-1-phenyl-propyl)-O-(2-phenyl-cyclopentyl-
methyl)-hydroxylamine (15b): Applying a variation of GP 1 a solution of
alkoxyamine 15a (350 mg, 0.92 mmol) and CSA (20.1 mg, 0.092 mmol) in
tBuOH (1.75 mL, 0.05m) was heated in a sealed tube to 1308C for 8 h.
N,N-Di-tert-butyl-O-(2-phenyl-cyclopentylmethyl)-hydroxylamine (13b):
According to GP 1 alkoxyamine 13a (60 mg, 0.198 mmol) was isomerized
Chem. Eur. J. 2005, 11, 2335 – 2350
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2343

A. Studer et al.
FC (pentane/MTBE 20:1) yielded 15b as a colourless oil (338 mg, 97%).
15b was isolated as an unseparable mixture of diastereoisomers. Due to
the complexity of the 1H NMR spectrum the diastereomeric ratio could
not be determined. 1H NMR (300 MHz, CDCl3): d=7.20–7.10 (m, 10H,
Ph-H), 3.89–3.12 (m, 4H, CH2ON, PhCH), 2.74–0.28 (m, 23H); 13C NMR
(75 MHz, CDCl3): d=145.6, 142.8, 131.1, 130.9, 129.4, 128.3, 127.4, 126.9,
126.2, 125.8, 79.5, 72.3, 72.1, 60.0, 49.2, 47.1, 35.9, 31.4, 30.9, 28.4, 27.6,
126.2 (CH), 125.9 (CH), 79.2 (CH2), 78.9 (CH2), 71.1 (CH), 71.0 (CH),
67.1 (C), 66.9 (C), 49.1 (CH), 47.5 (CH), 47.1 (CH), 35.7 (CH), 35.6
(CH), 32.2 (CH2), 32.0 (CH2), 31.1 (CH2), 30.8 (CH2), 27.3 (CH2), 27.1
(CH2), 24.6 (CH3), 24.5 (CH3), 22.2 (CH3), 22.1 (CH3), 21.4 (CH2), 8.7
(CH3); IR (neat): n˜ = 3026w, 2955s, 2872s, 1644s, 1492m, 1452s, 1382m,
1029m cmꢀ1; MS (ESI): m/z: 481 (100), 444 (14) [M+Na]+, 437 (78);
HRMS (ESI): m/z: calcd for C29H43NNaO: 444.3242; found: 444.3249
[M+Na]+.
24.7, 21.9, 21.1; IR (neat): n˜
= 3061w, 2954s, 2869m, 1491w, 1452m,
1384m, 1359m, 1213w, 1040w, 756m, 701s cmꢀ1; MS (ESI): m/z: 411 (100),
380 (47) [M+H]+, 325 (54), 222(82); HRMS (ESI): m/z: calcd for
C26H38NO: 380.2953; found: 380.2953 [M+H]+.
2,2,7,7-Tetramethyl-1-(1-phenylhex-5-enyloxyl)[1,4]diazepane-5-one
(19a): GP 2 was applied by using (1-bromo-hex-5-enyl)-benzene (253 mg,
1.06 mmol), the corresponding nitroxide (150 mg, 0.57 mmol), Cu (72 mg,
1.12 mmol), Cu(OTf)2 (4.0 mg, 10.6 mmol) and 4,4’-di-tert-butyl-[2,2’]bi-
pyridine (7.0 mg, 42.4 mmol) in benzene (4.0 mL) for 14 h at 758C. FC
(ethyl acetate/MeOH 30:1) yielded 19a (169 mg, 39%). 1H NMR
(300 MHz, CDCl3): d=7.33–7.23 (m, 5H, Ph-H), 6.94 (1H, NH), 5.75–
5.63 (m, 1H, H2C=CH), 4.96–4.88 (m, 2H, H2C=CH), 4.60 (dd, J1 =10.6,
J2 =3.9 Hz, 1H, OCH), 3.40–3.18 (m, 1H, NCH2), 2.96–2.67 (m, 2H,
NCH2, OCCH2), 2.44–2.05 (m, 1H, OCH2), 2.31–1.80 (m, 4H, CH2),
1.44–1.03 (m, 12H, CH2, CH3), 0.70 (brs, 1H, CH3), 0.60 (brs, 1H, CH3);
13C NMR (75 MHz, CDCl3): d=175.7 (C), 143.8 (C), 138.5 (CH), 128.0
(CH), 127.4 (CH), 114.6 (CH2), 87.9 (CH), 63.5 (C), 61.8 (C), 51.0 (CH2),
47.2 (CH2), 34.8 (CH2), 34.2 (CH3), 33.6 (CH2), 30.1 (CH3), 24.7 (CH2),
22.8 (CH3), 20.4 (CH3); IR (neat): n˜ = 3426br, 3214m, 3081w, 2078w,
2949m, 1676s, 1493w, 1434w, 1381m, 1247m cmꢀ1; MS (ESI): m/z: 367
(33) [M+Na]+, 345 (100) [M+H]+, 255 (17), 227 (21), 195 (28); HRMS
(ESI): m/z: calcd for C21H33N2O2: 345.2542; found: 345.2540 [M+H]+.
2-Methyl-2-[(1-methyl-1-phenyl-ethyl)-(2-phenyl-cyclopentylmethoxy)-
amino]-propane-1-ol (16b): A solution of alkoxyamine 16a (102 mg,
0.258 mmol) and CSA (6 mg, 0.026 mmol) in tBuOH (13 mL) was heated
under argon in a sealed tube to 1308C for 7.5 h. Evaporation of the sol-
vent and purification by FC (Et2O/pentane 1:20!1:10) yielded the iso-
merization product (74 mg, 73%). Due to their complexity (4 isomers)
the 1H NMR spectrum and the 13C NMR spectrum were not interpreted.
IR (CHCl3): n˜
= 3482br, 3007w, 2957s, 2871m, 1601w, 1492m, 1452s,
1409m, 1383s, 1365m, 1322w, 1162m, 1042s cmꢀ1; MS (MALDI): m/z: 418
(23) [M+Na]+, 264 (42), 200 (100); HRMS (MALDI): m/z: calcd for
C26H37NO2Na: 418.2716; found: 418.2712 [M+Na]+; elemental analysis
calcd (%) for C26H37NO2 (395.58): C 78.94, H 9.43, N 3.54; found: C
78.78, H 9.49, N 3.55.
2-Hydroxymethyl-2-[(1-methyl-1-phenyl-ethyl)-(2-phenyl-cyclopentylme-
thoxy)-amino]-propane-1,3-diol (17b): The isomerization was performed
according to GP 1 by using alkoxyamine 17a, CSA and tBuOH. FC
(Et2O/pentane 1:2) yielded the cyclization product 17b. Due to their
complexity (4 isomers) the 1H NMR spectrum and the 13C NMR spec-
2,2,7,7-Tetramethyl-1-(-2-phenyl-cyclopentylmethyloxy)-[1,4]diazepan-5-
one (19b), 2,2,7,7-tetramethyl-1-(-2-phenyl-cyclohexyloxy)-[1,4]diazepan-
5-one (19c): According to GP 1 a solution of alkoxyamine 19a (25 mg,
0.073 mmol) and CSA (1.8 mg, 0.0073 mmol) in tBuOH (3.65 mL, 0.02m)
was heated to 1308C for 36 h. The reaction was not yet completed and
the products could not be separated from the starting material. Due to
the complexity of the NMR spectra (starting material 19a, 2 isomers of
19b, 2 isomers of 19c) the reaction product was not analyzed.
trum were not interpreted. IR (CHCl3): n˜
= 3503br, 2960s, 2872m,
1601m, 1496w, 1452m, 1385m, 1111m, 1045s, 881w cmꢀ1; MS (FAB): m/z:
450 (8) [M+Na]+, 428 (88) [M+H]+, 396 (31) [MꢀCH2OH]+, 384 (63)
[MꢀC3H7]+, 296 (32) [MꢀC10H11]+, 264 (35), 133 (100)
[MꢀC12H15ONC4H9O3]+, 90 (75).
N-(1,1-Diethylpropyl)-N-(2-methyl-1-phenylpropyl)-O-(1-phenylhex-5-
enyl)hydroxylamine (18a): GP 2 was applied by using (1-bromo-hex-5-
enyl)-benzene (137 mg, 0.57 mmol), the corresponding nitroxide[16]
(150 mg, 0.57 mmol), Cu (36 mg, 0.57 mmol), Cu(OTf)2 (10.0 mg,
29 mmol) and 4,4’-di-tert-butyl-[2,2’]bipyridine (15.0 mg, 0.114 mmol) in
benzene (2.0 mL) for 14 h at 758C. FC (Et2O/pentane 1:250) yielded 18a
(162 mg, 67%) as a mixture of diastereoisomers (dr 1:1, determined by
1H NMR analysis). 1H NMR (400 MHz, CDCl3): isomer A: d=7.41–7.14
(m, 10H, CH), 5.79–5.68 (m, 1H, CH), 5.01–4.90 (m, 2H, CH2), 4.68 (dd,
J1 =10.8, J2 =3.7 Hz, 1H, CH), 3.88 (d, J=7.0 Hz, 1H, CH), 2.42–1.04
(m, 13H), 0.94–0.17 (m, 15H); isomer B: d=7.41–7.14 (m, 10H, CH),
5.79–5.68 (m, 1H, CH), 5.01–4.90 (m, 2H, CH2), 4.63 (dd, J1 =10.8, J2
=3.7 Hz, 1H, CH), 3.42 (d, J=7.0 Hz, 1H, CH), 2.42–1.04 (m, 13H),
2,2,7,7-Tetramethyl-1-(1-phenyl-hex-5-enyloxy)-azepane-4-one
GP 2 was applied by using the corresponding nitroxide[13] (527 mg,
2.86 mmol), (1-bromo-hex-5-enyl)-benzene (570 mg, 2.38 mmol),
(20a):
Cu(OTf)2 (8.6 mg, 0.024 mmol), Cu (159 mg, 2.50 mmol) and 4,4’-di-tert-
butyl-[2,2’]bipyridine (12.8 mg, 0.095 mmol). FC (pentane/MTBE 4:1)
yielded alkoxyamine 20a as a yellowish oil (204 mg, 25%). 1H NMR
(300 MHz, CDCl3): both isomers: d=7.23–7.19 (m, 5H, Ph-H), 5.70–5.57
(m, 1H, CH2=CH), 4.90–4.82 (m, 2H, CH2=CH), 4.51 (dd, J1 =3.6, J2
=9.9, 1H, CHON), 2.86 (d, J=11.6 Hz, 1H, CHC=O, single isomer),
2.72 (d, J=11.6 Hz, 1H, CHC=O, single isomer), 2.39 (d, J=11.6 Hz,
1H, CHC=O, single isomer), 2.24 (d, J=11.6 Hz, 1H, CHC=O, single
isomer), 2.13–1.60 (m, 8H, CH2), 1.42–1.06 (m, 11H, CH2, CH3), 0.69,
0.55 (2s, 3H, CH3, both isomers); 13C NMR (75 MHz, CDCl3): both iso-
mers: d=211.4, 211.2, 142.1, 138.3, 128.2, 127.7, 127.2, 125.7, 114.4, 87.1,
63.4, 62.2, 37.7, 36.3, 36.0, 33.9, 33.4, 32.5, 32.3, 25.1, 24.7, 24.3; IR (film):
n˜ = 2974s, 2937s, 1714s, 1454m, 1363m, 911m, 700s cmꢀ1; MS (ESI): m/z:
366 (33) [M+Na]+, 207 (100); HRMS (ESI): m/z: calcd for
C22H33NNaO2: 366.2409; found: 366.2396 [M+Na]+.
0.94–0.17 (m, 15H); 13C NMR (100 MHz, CDCl3): both isomers:
d
=145.4 (C), 143.7 (C), 143.2 (C), 138.6 (C), 128.7 (CH), 128.5 (CH),
128.1 (CH), 127.9 (CH), 127.2 (CH), 126.9 (CH), 126.0 (CH), 125.8
(CH), 114.5 (CH2), 114.4 (CH2), 87.8 (CH), 87.3 (CH), 71.2 (CH), 70.8
(CH), 67.2 (C), 67.0 (C), 36.4 (CH2), 36.3 (CH2), 35.4 (CH), 35.3 (CH),
27.2 (CH2), 27.1 (CH2), 25.2 (CH2), 25.0 (CH2), 24.6 (CH3), 24.5 (CH3),
22.2 (CH3), 22.1 (CH3), 9.0 (CH3), 8.9 (CH3); IR (neat): n˜ = 3442br,
2,2,7,7-Tetramethyl-1-(2-phenyl-cyclopentylmethoxy)-azepan-4-one (20b),
2,2,7,7-tetramethyl-1-(3-phenyl-cyclohexyloxy)-azepan-4-one (20c): Ac-
cording to GP 1 a solution of alkoxyamine 20b (90.0 mg, 0.26 mmol) and
CSA (5.70 mg, 0.026 mmol) in tBuOH (0.02m) was heated in a sealed
tube to 1308C for 20 h. FC (pentane/MTBE 4:1) yielded the desired
product as a yellow oil (66.0 mg, 0.19 mmol, 74%). The isomerization
product was isolated as an unseparable mixture of 20b (two diaster-
eoisomers) and 20c (due to the complexity of the NMR spectra the prod-
uct ratios could not be determined). 1H NMR (200 MHz, CDCl3): d
=7.22–7.07 (m, 5H, Ph-H), 3.68–3.46 (m, 2H, CH2ON), 3.25–3.07 (m,
1H, CHPh), 2.79–0.82 (m, 25H, CH2, CH, CH3); IR (neat): n˜ = 2946s,
2873s, 1710s, 1493m, 1451m, 1363m, 1222m, 1031s, 759m, 703s cmꢀ1; MS
(ESI): m/z: 366 (100) [M+Na]+, 344 (21) [M+H]+, 288 (10), 242 (31),
232 (11); HRMS (ESI): m/z: calcd for C22H34NO2: 344.2590; found:
344.2588 [M+H]+.
3061w, 3026w, 2956s, 2873m, 1601w, 1492w, 1453m, 1382w, 1029m cmꢀ1
;
MS (ESI): m/z: 422 (27) [M+H]+, 409 (100); HRMS (ESI): m/z: calcd
for C29H44NO: 422.3423; found: 422.3414 [M+H]+.
N-(1,1-Diethylpropyl)-N-(2-methyl-1-phenylpropyl)-O-(2-phenylcyclo-
pentylmethyl)hydroxylamin (18b): Applying GP 1 a solution of alkoxya-
mine 18a (71.5 mg, 0.170 mol) in tBuOH (8.5 mL) was heated for 20 min.
FC (Et2O/pentane 1:200) yielded the cyclization product (64.1 mg, 90%).
1H NMR (200 MHz, CDCl3): trans-18b: d=7.39–7.17 (m, 10H, Ph-H),
3.90–3.87 (m, 1H, CH), 3.78–3.67 (m, 2H, CH2), 3.51–3.40 (m, 1H, CH),
2.35–1.12 (m, 14H), 0.93–0.35 (m, 15H, CH3); cis-18b: d=7.39–7.17 (m,
10H, Ph-H), 3.90–3.87 (m, 1H, CH), 3.51–3.40 (m, 2H, CH2), 3.34–3.11
(m, 1H, CH), 2.35–1.12 (m, 14H), 0.93–0.35 (m, 15H, CH3); 13C NMR
(50 MHz, CDCl3): mixture of isomers: d=145.4 (C), 143.8 (C), 130.4
(CH), 128.3 (CH), 128.2 (CH), 127.4 (CH), 127.3 (CH), 127.2 (CH),
2344
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2335 – 2350

Persistent Radical Effect
FULL PAPER
2,2,7,7-Tetramethyl-1-(1-phenyl-5-hexenyloxy)-azepan-4-ol (21a): A so-
lution of alkoxyamine 20a (500 mg, 1.46 mmol) in MeOH (50 mL) with
molecular sieves (3) ꢄ) was cooled to 08C and NaBH4 (275 mg,
7.28 mmol) was added portionwise. After gas development ceased
MeOH (70 mL) was added to dissolve the solid formed. The solution was
stirred at room temperature for 24 h prior to the addition of NH4Cl (aq.
sat., 30 mL). The resulting suspension was filtered, washed with Et2O
(3ꢃ30 mL) and the combined organic layers were dried over MgSO4.
Evaporation of the solvent and purification by FC (pentane/MTBE 4:1)
yielded 21a as a yellow oil (450 mg, 89%). Alkoxyamine 21a was isolat-
ed as an unseparable mixture of diastereoisomers. Due to the complexity
of the NMR spectra the diastereomeric ratios could not be determined.
1H NMR (300 MHz, CDCl3): d=7.33–7.19 (m, 5H, Ph-H), 5.77–5.62 (m,
1H, CH2=CH), 5.47–5.26 (m, 1H, OH, both isomers), 4.96–4.88 (m, 2H,
CH2=CH), 4.62–4.53 (m, 1H, CHON), 4.08–3.93 (m, 1H, CHOH), 2.36–
1.01 (m, 21H, CH2, CH3), 0.72, 0.64, 0.53 (3s, 3H, CH, both isomers); IR
MS (ESI): m/z: 389 (27), 388 (100) [M+H]+, 320 (10), 260 (11), 192 (11),
184 (13); HRMS (ESI): m/z: calcd for C25H42NO2: 388.3216; found:
388.3216 [M+H]+.
2,2,6,6-Tetraethyl-1-(1-phenylhex-5-enyloxy)-piperidin-4-one (23a): GP 2
was applied by using (1-bromo-hex-5-enyl)benzene (191 mg, 0.80 mmol),
corresponding nitroxide[15] (200 mg, 0.88 mmol), Cu (53 mg, 0.84 mmol),
Cu(OTf)2 (3.0 mg, 8.4 mmol) and 4,4’-di-tert-butyl-[2,2’]bipyridine (4.5 mg,
0.034 mmol) in benzene (2.6 mL) for 14 h at 758C. FC (Et2O/pentane
1:20) yielded alkoxyamine 23a (86 mg, 28%). 1H NMR (300 MHz,
CDCl3): d=7.23–7.19 (m, 5H, Ph-H), 5.68–5.59 (m, 1H, CH), 4.90–4.82
(m, 2H, CH2), 4.44 (dd, J1 =10.0, J2 =3.9 Hz, 1H, CH), 2.24 (brs, 4H,
CH2), 1.98–1.89 (m, 4H, CH2), 1.69–1.62 (m, 6H, CH2), 1.10–0.49 (m,
4H, CH2), 0.99 (brs, 3H, CH3), 0.86 (brs, 3H, CH3), 0.65 (brs, 3H, CH3),
0.52 (brs, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=211.0 (C), 142.8
(C), 138.4 (CH), 127.8 (CH), 127.6 (2 CH), 127.4 (CH), 114.5 (CH2), 87.0
(CH), 66.2 (C), 66.1 (C), 46.5 (CH2), 35.3 (CH2), 33.5 (CH2), 30.9 (CH2),
30.0 (CH2), 29.5 (CH2), 28.6 (2ꢃCH2), 24.7 (CH2), 9.7 (CH3), 9.5 (CH3),
8.6 (CH3), 8.3 (CH3); IR (CCl4): n˜ = 3444w, 3065w, 2971s, 2940s, 2881m,
1718s, 1463m, 1329m cmꢀ1; MS (ESI): m/z: 408 (83) [M+Na]+, 386 (4)
[M+H]+, 281 (65), 249 (100); HRMS (ESI): m/z: calcd for
C25H39NNaO2: 408.2879; found: 408.2879 [M+Na]+.
(neat): n˜
= 3352m, 2936s, 1478m, 1454m, 1361s, 1160m, 911m, 700m
cmꢀ1; MS (ESI): m/z: 346 (100) [M+H]+, 188 (34), 171 (30).
2,2,7,7-Tetramethyl-1-(2-phenyl-cyclopentylmethoxy)-azepan-4-ol (21b),
2,2,7,7-tetramethyl-1-(2-phenyl-cyclohexyloxy)-azepan-4-ol (21c): Ac-
cording to GP 1 a solution of alkoxyamine 21a (79.0 mg, 0.23 mmol) and
CSA (5.00 mg, 0.023 mmol) in tBuOH (0.02m) was heated to 1308C for
3 h. FC (pentane/MTBE 4:1) yielded the isomerization product as a
yellow oil (60.0 mg, 75%). Both 21b (cis and trans isomers) and 21c
were observed. Due to the complexity of the NMR spectra the product
ratios could not be determined. 1H NMR (200 MHz, CDCl3): d=7.24–
7.09 (m, 5H, Ph-H), 4.92 (brs, 1H, OH), 3.99–3.60 (brm, 3H, CHOH,
CH2ON), 3.42–3.17 (m, 1H, PhCH), 2.76–0.93 (m, 25H); IR (neat): n˜ =
3359brm, 2936s, 2871s, 1474m, 1451m, 1359m, 1238w, 1161m, 1036s,
755m, 699s cmꢀ1; MS (ESI): m/z: 368 (18) [M+Na]+, 346 (100) [M+H]+,
328 (13), 290 (7), 242 (25), 192 (10), 171 (8).
2,2,6,6-Tetraethyl-1-(2-cyclopentylmethyloxy)-piperidin-4-one
2,2,6,6-tetraethyl-1-(2-cyclohexyloxy)-piperidin-4-one (23c): According to
GP 1 solution of alkoxyamine 23a (10 mg, 26.0 mmol) and CSA
(23b),
a
(0.6 mg, 2.6 mmol) in tBuOH (1.3 mL) was heated to 1308C for 24 h. The
reaction was not yet completed and the products could not be separated
from the starting material. Due to the complexity of the NMR spectra
(starting material 23a, 2 isomers of 23b, 2 isomers of 23c) the reaction
product was not analyzed.
trans-2,6-Bis(tert-butyldimethylsilyloxymethyl)-2,6-diethyl-1-(1-phenyl-
hex-5-enyloxy)-piperidin (24a): GP 2 was applied by using (1-bromohex-
5-enyl)benzene (76 mg, 0.319 mmol), the corresponding nitroxide[14]
(142 mg, 0.319 mmol), Cu (20 mg, 0.319 mmol), Cu(OTf)2 (5.8 mg,
0.016 mmol), 4,4’-di-tert-butyl-[2,2’]bipyridine (8.6 mg, 0.064 mmol) in
benzene (2.0 mL) for 16 h at 758C. FC (pentane) yielded alkoxyamine
24a (183 mg, 93%) as a mixture of diastereoisomers (dr 1:1). Isomer A:
1H NMR (400 MHz, CDCl3): d=7.34–7.13 (m, 5H, Ph-H), 5.74–5.64 (m,
1H, CH), 4.95–4.87 (m, 2H, CH2), 4.77–4.73 (m, 1H, CH), 4.00–3.92 (m,
4H, CH2), 2.14–0.50 (m, 40H), 0.10–(ꢀ0.07) (m, 12H, CH3); 13C NMR
(100 MHz, CDCl3): d=144.2 (C), 138.7 (CH), 128.2 (CH), 127.6 (2ꢃCH),
127.1 (2ꢃCH), 114.4 (CH2), 86.8 (CH), 78.0 (CH2), 76.3 (CH2), 65.7 (C),
65.0 (C), 36.7 (CH2), 33.9 (CH2), 31.0 (CH2), 30.4 (CH2), 28.9 (CH2), 28.7
(CH2), 25.9 (6ꢃCH3), 24.8 (CH2), 18.2 (2ꢃC), 15.8 (CH2), 10.1 (CH3), 7.9
(CH3), ꢀ5.5 (CH3); isomer B: 1H NMR (400 MHz, CDCl3): d=7.34–7.13
(m, 5H, CH), 5.74–5.64 (m, 1H, CH), 4.95–4.87 (m, 2H, CH2), 4.57 (dd,
J1 =10.2, J2 =3.3 Hz, 1H, CH), 4.00–3.92 (m, 4H, CH2), 2.14–0.50 (m,
40H), 0.10–(ꢀ0.01) (m, 12H, CH3); 13C NMR (100 MHz, CDCl3): d
=144.2 (C), 138.7 (CH), 128.3 (CH), 127.3 (2ꢃCH), 126.8 (2ꢃCH), 114.4
(CH2), 86.8 (CH), 78.0 (CH2), 76.3 (CH2), 68.7 (C), 68.0 (C), 36.7 (CH2),
33.9 (CH2), 31.7 (CH2), 31.2 (CH2), 30.4 (CH2), 28.9 (CH2), 25.9 (6ꢃ
CH3), 24.8 (CH2), 18.2 (2ꢃC), 15.8 (CH2), 10.3 (CH3), 8.0 (CH3), ꢀ5.5
2,2,6,6-Tetraethyl-1-(1-phenylhex-5-enyloxy)-piperidin-4-ol (22a): GP 2
was applied by using (1-bromo-hex-5-enyl)-benzene (281 mg, 1.17 mmol),
corresponding nitroxide[15] (295 mg, 1.29 mmol), Cu (78 mg, 1.23 mmol),
Cu(OTf)2 (9.4 mg, 0.026 mmol) and 4,4’-di-tert-butyl-[2,2’]bipyridine
(13.8 mg, 0.103 mmol) in benzene (4.0 mL) for 14 h at 758C. FC (Et2O/
pentane 1:3) yielded 22a (146 mg, 32%). 1H NMR (200 MHz, CDCl3): d
=7.30–7.11 (m, 5H, Ph-H), 5.76–5.62 (m, 1H, H2C=CH), 4.97–4.87 (m,
2H, H2C=CH), 4.73 (s, 1H, OH), 4.49 (dd, J1 =10.1, J2 =3.4 Hz, 1H,
NOCH), 4.01–3.79 (m, 1H, HOCH), 2.14–0.58 (m, 30H, CH2, CH3);
13C NMR (50 MHz, CDCl3): d=138.6 (C), 128.2 (CH), 127.3 (CH), 127.0
(CH), 125.7 (CH), 114.4 (CH2), 86.0 (CH), 65.4 (C), 65.0 (C), 62.5 (CH),
39.9 (CH2), 39.6 (CH2), 35.7 (CH2), 33.6 (CH2), 30.3 (CH2), 30.1 (CH2),
29.5 (CH2), 29.1 (CH2), 24.6 (CH2), 10.2 (CH3), 10.0 (CH3), 8.2 (CH3), 8.0
(CH3); IR (neat): n˜ = 3325br, 3027w, 2959s, 2877s, 1942w, 1803w, 1640w,
1603w, 1493m, 1464s, 1377m cmꢀ1; MS (ESI): m/z: 410 (27) [M+Na]+,
388 (82) [M+H]+, 372 (77), 260 (41), 242 (72), 184 (100); HRMS (ESI):
m/z: calcd for C25H42NO2: 388.3216; found: 388.3209 [M+H]+.
2,2,6,6-Tetraethyl-1-(2-phenylcyclopentylmethoxy)-piperidin-4-ol (22b),
2,2,6,6-tetraethyl-1-(3-phenylcyclohexyloxy)-piperidin-4-ol (22c): GP 1
was applied by using alkoxyamine 22a (49.0 mg, 0.133 mmol) in tBuOH
(6.6 mL) for 15 min. FC (Et2O/pentane 1:3) yielded the products 22b and
22c (48.1 mg, 95%) as mixture of isomers (22b/22c 12.5:1; 22b: trans/cis
2.7:1). 1H NMR (500 MHz, CDCl3): trans-22b: d=7.37–7.17 (m, 5H, Ph-
H), 4.02–3.84 (m, 1H, CH), 3.64–3.59 (m, 2H, CH2), 2.69 (dt, J1 =8.3, J2
=8.3 Hz, 1H, CH), 2.18–1.07 (m, 20H, CH2, CH, OH), 1.10–0.81 (m,
12H, CH3); cis-22b: d=7.37–7.17 (m, 5H, Ph-H), 4.02–3.84 (m, 1H,
CH), 3.27–3.22 (m, 2H, CH2), 2.43–2.35 (m, 1H), 2.18–1.07 (m, 20H,
CH2, OH), 1.06–0.68 (m, 12H, CH3); 13C NMR (125 MHz, CDCl3): mix-
ture of isomers: d=145.5 (C), 138.4 (C), 128.4 (CH), 128.3 (CH), 128.2
(CH), 128.1 (CH), 127.9 (CH), 127.3 (CH), 126.8 (CH), 125.8 (CH),
127.7 (CH), 76.5 (CH), 75.4 (CH), 65.4 (C), 65.3 (C), 65.0 (C), 64.8 (C),
64.7 (C), 62.9 (C H), 49.1 (CH), 47.5 (CH), 47.3 (CH), 43.6 (CH), 40.1
(CH2), 40.0 (CH2), 39.9 (CH2), 39.6 (CH2), 35.7 (CH2), 30.9 (CH2), 30.3
(CH2), 29.5 (CH2), 29.3 (CH2), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 27.4
(CH2), 27.1 (CH2), 24.6 (CH2), 23.8 (CH2), 10.2 (CH3), 10.1 (CH3), 8.3
(CH3), 8.2 (CH3), 8.1 (CH3), 8.0 (CH3), 7.9 (CH3); IR (neat): n˜ = 3338br,
(CH3); IR (neat): n˜
= 2954s, 2930s, 2881m, 2857m, 1641br, 1471m,
1254m, 1089s cmꢀ1; MS (ESI): m/z: 604 (100) [M+H]+, 569 (79); HRMS
(ESI): m/z: calcd for C35H66NO3Si2: 604.4581; found: 604.4583 [M+H]+.
trans-2,6-Bis(tert-butyldimethylsilyloxymethyl)-2,6-diethyl-1-(2-phenylcy-
clopentylmethoxy)-piperidine (24b), trans-2,6-bis(tert-butyldimethylsily-
loxymethyl)-2,6-diethyl-1-(3-phenylcyclohexyloxy)-piperidine (24c): GP 1
was applied by using alkoxyamine 24a (46.0 mg, 76.2 mmol) in tBuOH
(3.8 mL, 0.02m) for 20 min. FC (Et2O/pentane 1:250) yielded the prod-
ucts 24b and 24c (39.2 mg, 84%) as a mixture of isomers (24b/24c
10.6:1; 24b: trans/cis 2.9:1; 24c: dr 1.1:1; the diastereoisomers due to the
stereogenic centre of the nitroxide moiety are formed in a 1:1 ratio).
1H NMR (500 MHz, CDCl3): trans-24b: d=7.33–7.13 (m, 5H, CH), 4.00–
3.24 (m, 6H, CH2), 2.70–2.59 (m, 1H, CH), 2.15–1.15 (m, 23H), 0.90–0.77
(m, 18H, CH3), 0.07–(ꢀ0.13) (m, 12H, CH3); cis-24b: d=7.33–7.13 (m,
5H, CH), 4.00–3.24 (m, 4H, CH2), 3.23–3.17 (m, 3H), 2.15–1.15 (m,
23H), 0.90–0.77 (m, 18H, CH3), 0.07–(ꢀ0.13) (m, 12H, CH3); 24c
(isomer A): d=7.33–7.13 (m, 5H, CH), 4.00–3.24 (m, 5H), 2.90–2.84 (m,
3062w, 3027w, 2959s, 2877m, 1603w, 1493w, 1466m, 1378m, 1038s cmꢀ1
;
Chem. Eur. J. 2005, 11, 2335 – 2350
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2345

A. Studer et al.
1H, CH), 2.15–1.15 (m, 24H), 0.90–0.77 (m, 18H, CH3), 0.07–(ꢀ0.13) (m,
12H, CH3); 24c (isomer B): d=7.33–7.13 (m, 5H, CH), 4.00–3.24 (m,
5H), 2.49–2.46 (m, 1H, CH), 2.15–1.15 (m, 24H), 0.90–0.77 (m, 18H,
CH3), 0.07–(ꢀ0.13) (m, 12H, CH3); 13C NMR (125 MHz, CDCl3): mixture
of isomers: d=145.8 (C), 145.6 (C), 128.3 (CH), 128.2 (CH), 127.4 (CH),
127.3 (CH), 125.8 (CH), 125.7 (CH), 78.0 (CH2), 77.9 (CH2), 68.1 (CH2),
65.8 (C), 65.6 (C), 65.5 (C), 65.0 (C), 63.6 (CH2), 49.5 (CH), 49.1 (CH),
47.3 (CH), 35.9 (CH2), 35.8 (CH2), 31.7 (CH2), 31.5 (CH2), 30.4 (CH2),
30.2 (CH2), 28.7 (CH2), 28.1 (CH2), 26.0 (CH3), 24.9 (CH2), 24.8 (CH2),
24.6 (CH2), 18.2 (C), 15.8 (CH2), 10.3 (CH3), 10.2 (CH3), 7.9 (CH3), 7.7
(CH3), ꢀ5.5 (CH3); IR (neat): n˜ = 3063w, 3027w, 2955s, 2880s, 2857s,
1939w, 1603w, 1471m, 1462m, 1254s, 1089s cmꢀ1; MS (ESI): m/z: 605 (43),
604 (100) [M+H]+, 569 (78); HRMS (ESI): m/z: calcd for C35H66NO3Si2:
406.4582; found: 406.4559 [M+H]+.
nBuLi (2.35m in hexane, 0.91 mL, 2.13 mmol), TEMPO (333 mg,
2.13 mmol) and CuCl2 (782 g, 5.82 mmol) in DME (12 mL) and stirring
at room temperature for 17 h. FC (Et2O/pentane 1:10) yielded alkoxy-
amine 30 (447 mg, 1.37 mmol, 48%). 1H NMR (300 MHz, CDCl3): d
=5.30 (s, 1H, CH), 4.20 (q, J=7.1 Hz, 2H, OCH2), 1.69–1.39 (m, 6H, 3ꢃ
CH2), 1.28 (t, J=7.1 Hz, 3H, CH2CH3), 1.23–1.11 (m, 15H, C(CH3)3,
CH3), 0.97 (s, 3H, CH3), 0.93 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d=208.1 ((H3C)3CCO), 167.7 (COOEt), 89.5 (CH), 61.4 (OCH2), 60.5
(NC), 59.8 (NC), 44.2 ((CH3)3C), 40.1 (CH2), 33.0 (CH3), 27.1 ((CH3)3C),
20.3 (CH3), 20.1 (CH3), 17.0 (CH2), 14.0 (CH3); IR (neat): n˜ = 2987s,
2936s, 2872w, 1750s, 1716s, 1472m, 1362m, 1325m, 1271w, 1242m, 1174m,
1093s, 1048w, 1016m, 986m cmꢀ1; MS (ESI): m/z: 328 (100) [M+H]+, 158
(53), 156 (16), 142 (15), 126 (35); HRMS (ESI): m/z: calcd for
C18H34NO4: 328.2488; found: 328.2461 [M+H]+.
N-Methoxy-N-methyl-2-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-malonam-
ic acid methylester (27): GP 3 was applied by using N-methoxy-N-methyl
malonamic acid methylester (483 mg, 3.00 mmol), DIPA (0.47 mL,
3.30 mmol), nBuLi (2.35m in hexane, 1.40 mL, 3.30 mmol), TEMPO
(516 mg, 3.30 mmol) and CuCl2 (1.210 g, 9.00 mmol) in DME (18 mL)
and stirring for 5 h at room temperature. FC (Et2O/pentane 1:5) yielded
alkoxyamine 27 (746 mg, 2.36 mmol, 79%) as a colourless oil. 1H NMR
(500 MHz, CDCl3): d=5.27 (s, 1H, CCH3), 3.74 (s, 3H, NOCH3), 3.73 (s,
3H, COCH3), 3.16 (s, 3H, NCH3), 1.57–1.25 (m, 6H, CH2), 1.22 (s, 3H,
CCH3), 1.16 (s, 3H, CCH3), 1.11 (s, 3H, CCH3), 1.05 (s, 3H, CCH3);
13C NMR (125 MHz, CDCl3): d=168.8 ((CO)O), 167.8 ((CO)N), 84.3
(CH), 61.5 (NOCH3), 60.5 (NC(CH3)2), 59.9 (NC(CH3)2), 52.1 (OCH3),
40.1 (CH2), 32.6 (NCH3), 32.4 (CH3), 20.3 (CH3), 20.0 (CH3), 16.9 (CH2);
IR (neat): n˜ = 3501m, 2958s, 2922w, 1761s, 1670s, 1473m, 1428m, 1384m,
1361w, 1307w, 1264s, 1199s, 1176w, 1136w, 1080s, 1018w, 999w, 944w,
931w, 652m, 588m cmꢀ1; MS (ESI): m/z: 317 (100) [M+H]+, 183 (6), 156
(33), 140 (8), 126 (7); HRMS (ESI): m/z: calcd for C15H29N2O5: 317.2076;
found: 317.2074 [M+H]+.
Diethoxyphosphoryl-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-acetic
acid
ethyl ester (31): GP 3 was applied by using diethoxyphosphoryl-acetic
acid ethyl ester (0.68 mL, 3.46 mmol), DIPA (0.54 mL, 3.84 mmol),
nBuLi (1.6m in hexane, 2.4 mL, 3.84 mmol), TEMPO (600 mg,
3.84 mmol) and CuCl2 (4.66 g, 34.6 mmol) in DME (60 mL). FC (ace-
1
tone/pentane 1:4) yielded 31 (1.1 g, 83%). H NMR (200 MHz, CDCl3): d
=4.81 (d, J=18.0 Hz, 1H, CH), 4.32–4.10 (m, 6H, OCH2), 1.43–1.05 (m,
27H, 3ꢃCH3CH2, TEMPO); 13C NMR (75 MHz, CDCl3): d=168.6 (C),
83.6 (d, J=147.6 Hz, CHP), 63.4–62.9 (m, CH2-O-P), 61.2 (CH2), 60.0
(C), 40.7 (CH2), 16.9 (CH2), 16.4 (CH2), 16.3 (CH3), 16.3 (CH3), 13.9
(CH3); IR (neat): n˜ = 2978s, 2934s, 1788s, 1468m, 1379m, 1366m, 1263s,
1213m, 1150m, 1097m, 1024s, 975m, 902w, 875s, 789m, 599m, 540m cmꢀ1
;
MS (EI): m/z: 379 (75) [M]+, 364 (100), 296 (66), 156 (71) [TEMPO]+;
HRMS (EI): m/z: calcd for C17H34NO6P: 379.2124; found: 379.2124 [M]+.
[(Dimethoxyphosphoryl)-(2,2,6,6-tetramethylpiperidin-1-yloxy)-methyl]-
phosphonic acid dimethylester (32): GP 3 was applied by using DIPA
(0.72 mL, 5.19 mmol), nBuLi (1.62m in hexane, 3.2 mL, 5.19 mmol), (di-
methoxyphosphorylmethyl)-phosphonic acid dimethylester (803 mg,
3.46 mmol), TEMPO (600 mg, 3.81 mmol) and CuCl2 (4.66 g,
34.60 mmol) in DME (40 mL) and stirring at ꢀ608C for 90 min before al-
lowing to warm up and stirring at room temperature for another 3 h. FC
(acetone) yielded alkoxyamine 32 (526 mg, 39%). 1H NMR (300 MHz,
CDCl3): d=4.85 (t, J=26.3 Hz, 1H, CH), 3.87–3.81 (m, 12H, OCH3),
1.61–1.22 (m, 18H, TEMPO); 13C NMR (75 MHz, CDCl3): d=76.3 (t, JCP
=148.9 Hz, CH), 61.7 (CH2), 53.3 (CH3), 40.9 (CH2), 33.5 (CH3), 20.5
(CH3), 16.9 (CH2); IR (neat): n˜ = 2955s, 2853s, 1467s, 1369m, 1365m,
1260s, 1183m, 1132m, 1039s, 862m, 832m, 784m, 603m, 529m cmꢀ1; MS
(EI): m/z: 387 (61) [M]+, 304 (80), 323 (91), 157 (74) [TEMPOꢀH]+, 156
(100) [TEMPO], 124 (77); HRMS (EI): m/z: calcd for C14H31NO7P2:
387.1576; found: 387.1576 [M]+.
3-Oxo-2-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-methylbutanoate
(28):
GP 3 was applied by using 3-oxo butyric acid methylester (1.858 g,
16.00 mmol), DIPA (2.49 mL, 17.60 mmol), nBuLi (2.19m in hexane,
8.05 mL, 17.60 mmol), TEMPO (2.750 g, 17.60 mmol) and CuCl2 (2.366 g,
17.60 mmol) in DME (64 mL) and stirring at room temperature for 2 h.
FC (Et2O/pentane 1:20) yielded alkoxyamine 28 (2.065 g, 7.61 mmol,
48%). 1H NMR (300 MHz, CDCl3): d=4.83 (s, 1H, CH), 3.76 (s, 3H,
OCH3), 2.32 (s, 3H, OCCH3), 1.60–1.26 (m, 6H, CH2), 1.20 (s, 6H, CH3),
1.04 (s, 3H, CH3), 1.00 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d
=202.3 (H3CCO), 167.8 (OCO), 92.9 (CH), 59.8 (NC), 59.5 (NC), 51.9
(OCH3), 39.6 (CH2), 32.5 (CH3), 32.0 (CH3), 26.0 (CH3), 19.7 (CH3), 16.4
(CH2); IR (KBr): n˜ = 3004m, 2986m, 2931s, 1749s, 1717s, 1455m, 1435m,
1376w, 1362m, 1315m, 1236m, 1198s, 1172s, 1133w, 1085s, 993w, 975w,
958w, 925m, 523m cmꢀ1; MS (ESI): m/z: 272 (55) [M+H]+, 156 (77), 142
(25), 126 (100); HRMS (ESI): m/z: calcd for C14H26NO4: 272.1862;
found: 272.1858 [M+H]+.
2-(Methoxy-methyl-carbamoyl)-4-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-
decanoic acid methylester (33): GP 4 was applied by using alkoxyamine
29 (160 mg, 0.51 mmol) and 1-octene (284 mg, 2.53 mmol) in DCE
(0.5 mL) at 1358C for 3 d. FC (Et2O/pentane 1:5) yielded 33 (71 mg,
0.17 mmol, 33%). Alkoxyamine 33 was isolated as an unseparable mix-
ture of diastereoisomers (dr 1:1). 1H NMR (400 MHz, CDCl3): both iso-
mers: d=4.06 (t, J=7.1 Hz, 1H, OCCHCO), 3.84–3.75 (m, 1H, OCH),
3.71 (s, 3H, NOCH3), 3.70 (s, 3H, COCH3), 3.20 (s, 3H, NCH3), 2.19–
2.06 (m, 2H, CH2), 1.66–1.37 (m, 6H, CH2), 1.35–1.16 (m, 10H, CH2),
1.07 (s, 12H, CH3), 0.87 (t, J=6.3 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3): both isomers: d=170.9 (OCO), 170.5 (CON), 79.2 (OCH), 61.2
(NOCH3), 60.0 (NC(CH3)2), 59.3 (NC(CH3)2), 52.2 (OCH3), 45.5
(OCCHCO), 40.4 (CH2), 40.2 (CH2), 34.2 (NCH3), 33.2 (CH2), 32.9
(CH2), 32.7 (CH3), 31.9 (CH2), 29.6 (CH2), 25.8 (CH2), 22.6 (CH2), 20.5
3-Oxo-2-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-pentanoic acid methyl
ester (29): Applying GP 3 by using LDA (5.50 mmol), 3-oxo-pentanoic
acid methyl ester (651 mg, 5.00 mmol), TEMPO (859 mg, 5.50 mmol) and
CuCl2 (1.345 g, 10.00 mmol) in DME (23 mL). Stirring at 08C for 6 h. FC
(Et2O/pentane 1:15!1:9) yielded 29 (841 mg, 59%). M.p. 538C;
1H NMR (300 MHz, CDCl3): d=4.85 (s, 1H, OCH), 3.73 (d, J=0.6 Hz,
3H, OCH3), 2.80 (dq, J1 =18.6, J2 =7.2 Hz, 1H, OCCH2), 2.57 (dq, J1
=18.6, J2 =7.2 Hz, 1H, OCCH2), 1.44–0.96 (m, 18H, CH2, CH3), 1.06 (t, J
=7.2 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3): d=205.3 (C), 168.5
(C), 93.1 (CH), 60.3 (C), 60.0 (C), 52.3 (CH3), 40.1 (CH2), 33.0 (CH3),
32.5 (CH3), 32.3 (CH2), 24.2 (CH2), 20.1 (CH3), 16.9 (CH2), 7.0 (CH3); IR
(neat): n˜ = 2980m, 2938s, 2875w, 1740s, 1708s, 1651w, 1452m, 1436w,
1377w, 1360m, 1313m, 1237m, 1169m, 1137s, 1085s, 1051m, 992w, 973w,
957w, 925m, 875w, 839w, 794s, 740m, 689w, 632w, 581w, 516w cmꢀ1; MS
(ESI): m/z: 308 (31) [M+Na]+, 286 (22) [M+H]+, 118 (36), 104 (75), 90
(100), 76 (64), 72 (49), 58 (38); HRMS (ESI): m/z: calcd for
C15H27NO4Na: 308.1832; found: 308.1820 [M+Na]+.
(CH3), 17.4 (CH2), 14.1 (CH3); IR (neat): n˜
= 3470w, 2930s, 2871m,
1745s, 1675s, 1465s, 1377s, 1361m, 1259m, 1181m, 1133m, 992m, 958w,
721w, 593w cmꢀ1; MS (ESI): m/z: 429 (100) [M+H]+; HRMS (ESI): m/z:
calcd for C23H45N2O5: 429.3328; found: 429.3338 [M+H]+.
2-(2,2-Dimethylpropionyl)-4-(2,2,6,6-tetramethyl-piperidin-1-yloxy)-dec-
anoic acid ethylester (36): GP 4 was applied by using alkoxyamine 30
(100 mg, 0.31 mmol) and 1-octene (171 mg, 1.53 mmol) in DCE
(0.31 mL) at 1358C for 3 d. FC (Et2O/pentane 1:10) yielded 36 (68 mg,
0.15 mmol, 51%). Alkoxyamine 36 was isolated as an unseparable mix-
ture of diastereoisomers (dr 1:1). 1H NMR (200 MHz, CDCl3): both iso-
4,4-Dimethyl-3-oxo-2-(2,2,6,6-tetramethyl-piperidin-1-yloxy)- pentanoic
acid ethylester (30): GP 3 was applied by using 4,4-dimethyl-3-oxo-penta-
noic acid methylester (334 mg, 1.94 mmol), DIPA (0.30 mL, 2.13 mmol),
2346
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2335 – 2350

Persistent Radical Effect
FULL PAPER
mers: d=4.46 (dd, J=8.8, J=2.8 Hz, 2H, OCCHCO), 4.16 (q, J=7.0 Hz,
2H, OCH2), 4.13 (q, J=7.3 Hz, 2H, OCH2), 3.81–3.65 (m, 2H, NOCH),
2.34–1.98 (m, 4H, CH2), 1.68–1.41 (m, 12H, CH2), 1.27–1.15 (m, 25H,
C(CH3)3, CH3, CH2), 1.06 (s, 9H, CH3), 1.05 (s, 9H, CH3), 0.87 (t, J
=6.3 Hz, 6H, CH3); 13C NMR (75 MHz, CDCl3): both isomers: d=210.8
((H3C)3CCO), 169.9 (OCO), 169.8 (OCO), 79.8 (OCH), 79.4 (OCH),
61.1 (NC), 61.0 (OCH2), 60.3 (NC), 50.0 (OCCHCO), 48.9 (OCCHCO),
45.5 ((H3C)3C), 45.4 ((H3C)3C), 40.5 (CH2), 40.2 (CH2), 40.1 (CH2), 34.5
(CH2), 34.4 (CH3), 34.1 (CH3), 33.6 (CH2), 33.2 (CH2), 32.7 (CH3), 31.9
(CH2), 29.6 (CH2), 29.6 (CH2), 26.5 (CH3), 26.2 (CH3), 26.0 (CH2), 25.8
(CH2), 22.6 (CH2), 22.6 (CH2), 20.7 (CH3), 20.6 (CH3), 17.4 (CH2), 17.3
(CH2), 14.7 (CH3), 14.6 (CH3), 14.3 (CH3); IR (neat): n˜ =3441w, 2930s,
2872m, 1748s, 1709s, 1466m, 1366m, 1226w, 1182m, 1132w, 1043w, 989w,
957w, 942w, 716w cmꢀ1; MS (ESI): m/Z: 440 (100) [M+H]+, 321 (73), 158
(26), 126 (39); HRMS (ESI): m/z: calcd for C26H50NO4: 440.3740; found:
440.3741 [M+H]+.
2-[N-(1,1-Diethyl-propyl)-N-(2-methyl-1-phenyl-propyl)-aminooxy]-ma-
lonic acid dimethyl ester (40): GP 3 was applied by using LDA
(2.20 mmol), malonic acid dimethyl ester (229 mL, 2.00 mmol), corre-
sponding nitroxide[16] (525 mg, 2.00 mmol) and CuCl2 (296 mg,
2.20 mmol) in DME (9.0 mL). Stirring at 08C for 6 h. FC (Et2O/pentane
1:30) yielded alkoxyamine 40 (438 mg, 56%). 1H NMR (300 MHz,
CDCl3): d=7.62–7.18 (m, 5H, Ph-H), 5.13 (s, 1H, OCH), 3.84 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 3.41 (d, J=10.5 Hz, 1H, NCH), 1.97 (dhept,
J1 =10.5, J2 =6.6 Hz, 1H, HC(CH3)2), 1.43–1.25 (m, 6H, CH2), 1.14 (d, J
=6.6 Hz, 3H, HCCH3), 0.71 (t, J=7.5 Hz, 9H, CH2CH3), 0.47 (d, J
=6.6 Hz, 3H, HCCH3); 13C NMR (75 MHz, CDCl3): d=168.1 (COO),
167.2 (C), 142.5 (C), 130.6 (CH), 127.6 (CH), 126.6 (CH), 86.2 (CH), 71.7
(CH), 68.6 (C), 52.6 (CH3), 52.5 (CH3), 32.0 (CH), 27.4 (CH2), 22.0
(CH3), 21.6 (CH3), 8.6 (CH3); IR (neat): n˜ = 3481w, 3061w, 2958s, 2881s,
1771w, 1749s, 1600w, 1492w, 1455s, 1435m, 1383m, 1326m, 1274m, 1219s,
1154m, 1095s, 1075w, 1019s, 914s, 853m, 808m, 759m, 735m, 707s, 614w,
571w, 540w cmꢀ1; MS (ESI): m/z: 432 (47) [M+K]+, 416 (47) [M+Na]+,
262 (100) [MꢀC5H7O4]+, 170 (38), 164 (26), 133 (69), 91 (14); HRMS
(ESI): m/z: calcd for C22H35NO5K: 432.2152; found: 432.2161 [M+K]+.
2-(Diethoxyphosphoryl)-4-(2,2,6,6-tetramethylpiperidin-1-yloxy)-decanoic
acid ethylester (37): GP 4 was applied by using alkoxyamine 31 (100 mg,
0.26 mmol) and 1-octene (0.21 mL, 1.32 mmol) in DCE (0.26 mL) at
1358C for 3 d. FC (pentane/acetone 10:1) yielded the desired product 37
(72 mg, 56%). 1H NMR (300 MHz, CDCl3): both isomers: d=4.35–3.98
(m, 7H, OCH2CH3, CHO), 3.78–3.57 (m, 2H, CH2CHP), 3.56–3.29 (m,
1H, EtO2CCHP, single isomer), 3.16–2.87 (m, 1H, EtO2CCHP, single
isomer), 2.44–0.83 (m, 37H), 0.85 (t, J=6.6 Hz, 3H, CH3CH2CH2);
13C NMR (75 MHz, CDCl3): both isomers: d=169.1 (3 signals), 80.3,
80.1, 79.0, 78.8, 65.8, 65.7, 65.6, 65.5, 65.4, 62.9, 62.8, 62.7 (2 signals), 62.5
(2 signals), 62.4, 62.3, 62.2, 61.4, 61.1, 61.0, 60.1, 59.6, 59.2, 58.8, 43.7,
42.7, 42.0, 40.9, 40.2, 40.1, 39.9, 34.0, 33.9, 32.6, 32.1, 31.6, 31.2, 31.1, 30.3,
30.2, 29.3 (2 signals), 25.8, 25.4, 22.4, 20.3, 17.1, 16.1, 13.8; IR (neat): n˜ =
2930s, 2871s, 1736s, 1466m, 1369m, 1258s, 1157m, 1133m, 1027s, 966s,
867w, 786w, 733w cmꢀ1; MS (ESI): m/z: 1005 (11) [2M+Na]+, 492 (100)
[M+H]+; HRMS (ESI): m/z: calcd for C25H51NO6P: 492.3455; found:
492.3454 [M+H]+.
2-(2,2,6,6-Tetraethyl-4-hydroxy-piperidin-1-yloxy)-malonic acid dimethyl
ester (41): Alkoxyamine 42 (100 mg, 0.28 mmol) was dissolved in isopro-
panol (0.4 mL) and NaBH4 (5.3 mg, 0.14 mmol) was added. After stirring
for 18 h at room temperature the reaction was stopped by the addition of
HCl (1m). The aqueous layer was extracted (2ꢃ) with Et2O and the com-
bined organic layers were dried over MgSO4. After removal of the sol-
vents FC (Et2O/pentane 1:10!1:2) yielded 41 (65 mg, 65%). M.p. 114–
1168C; 1H NMR (300 MHz, CDCl3): d=4.93 (s, 1H, OCH), 3.90 (tt, J1
=11.4, J2 =3.9 Hz, 1H, CHOH), 3.77 (s, 6H, OCH3), 2.23–2.11 (m, 2H,
CH2), 1.81–1.69 (m, 4H, OCCH2), 1.52 (brs, 1H, OH), 1.45–1.22 (m, 6H,
CH2), 0.88 (t, J=7.5 Hz, 6H, CH3), 0.85 (t, J=7.5 Hz, 6H, CH3);
13C NMR (75 MHz, CDCl3): d=167.5 (C), 84.4 (CH), 66.3 (C), 62.1
(CH), 52.7 (CH3), 39.3 (CH2), 29.3 (CH2), 27.0 (CH2), 9.9 (CH3), 7.9
(CH3); IR (KBr): n˜ = 3527s, 3350s, 2968s, 2880w, 1760s, 1738w, 1454m,
1436w, 1413w, 1382w, 1331m, 1275m, 1222s, 1153m, 1101m, 1060s, 1038w,
1013m, 984w, 956w, 904m, 839w, 791m, 732m, 627w, 494m cmꢀ1; MS
(ESI): m/z: 382 (47) [M+Na]+, 250 (33), 232 (22), 228 (100)
[MꢀC5H7O4]+, 200 (23), 170 (52), 154 (13); HRMS (ESI): m/z: calcd for
C18H33NO6Na: 382.2206; found: 382.2215 [M+Na]+.
[1-(Dimethoxyphosphoryl)-3-(2,2,6,6-tetramethylpiperidin-1-yloxy)-
nonyl]-phosphonic acid dimethylester (38): GP 4 was applied by using al-
koxyamine 32 (100 mg, 0.258 mmol) and 1-octene (0.20 mL, 1.29 mmol)
in DCE (0.258 mL) at 1358C for 3 d. FC (pentane/acetone 4:1!acetone)
yielded the desired product 38 (73 mg, 57%). 1H NMR (300 MHz,
CDCl3): d=3.98–3.77 (m, 1H, CHON), 3.76–3.71 (m, 13H, OCH3, CHP),
2.87–2.67 (m, 1H, CH2CHP), 2.05–1.92 (m, 3H, CH2-CHP, CH2CHO),
1.92–0.78 (m, 17H), 1.03 (s, 6H, CH3 (TEMPO)), 0.98 (s, 6H, CH3
(TEMPO)); 13C NMR (50 MHz, CDCl3): d=79.2–79.0 (m, CH-ON), 59.9
(C), 59.1 (C), 53.3–52.8 (m, OCH3), 40.2 (m, CH2), 32.4 (CH2), 32.1 (t, J
=89.1 Hz, CH-P), 31.8 (CH2), 29.8–29.7 (m, CH2), 29.4 (CH2), 25.7
(CH2), 22.5 (CH2), 20.5 (CH3), 20.3 (CH3), 17.2 (CH2), 14.0 (CH3); IR
2-(2,2,6,6-Tetraethyl-4-oxo-piperidin-1-yloxy)-malonic acid dimethyl ester
(42): Applying GP 3 by using LDA (1.70 mmol), malonic acid dimethyl
ester (177 mL, 1.55 mmol), the corresponding nitroxide[15] (350 mg,
1.55 mmol) and CuCl2 (416 mg, 3.09 mmol) in DME (6.2 mL). The mix-
ture was stirred at 08C for 4.5 h. FC (Et2O/pentane 1:20!1:10) yielded
42 (403 mg, 73%). M.p. 53–558C; 1H NMR (300 MHz, CDCl3): d=4.95
(s, 1H, OCH), 3.77 (s, 6H, OCH3), 2.42–2.27 (m, 4H, OCCH2), 2.18–2.11
(m, 2H, CH2), 1.70–1.63 (m, 2H, CH2), 1.52–1.39 (m, 4H, CH2), 0.87 (t, J
=6.9 Hz, 12H, CH3); 13C NMR (75 MHz, CDCl3): d=209.1 (C), 170.0
(C), 85.0 (CH), 67.6 (C), 52.7 (CH3), 46.3 (CH2), 30.0 (CH2), 28.3 (CH2),
9.5 (CH3), 8.1 (CH3); IR (KBr): n˜ = 2971s, 2881w, 1764s, 1728m, 1453s,
1426m, 1379m, 1326m, 1278m, 1215s, 1149s, 1098s, 986m, 961w, 917m,
(neat): n˜
= 2955s, 2929s, 2855s, 1464s, 1376m, 1360m, 1257s, 1183m,
1132m, 1034s, 958w, 828m, 733m, 530m cmꢀ1; MS (ESI): m/z: 1021 (51)
[2M+Na]+, 500 (100) [M+H]+; HRMS (ESI): m/z: calcd for
C22H48NO7P2: 500.2907; found: 500.2906 [M+H]+.
2-[N-tert-Butyl-N-(2-methyl-1-phenyl-propyl)-aminooxy]-malonic acid di-
methylester (39): GP 3 was applied by using DIPA (1.87 mL,
13.20 mmol), nBuLi (2.35m in hexane, 5.61 mL, 13.20 mmol), dimethyl-
malonate (1.585 g, 12.00 mmol), corresponding nitroxide[20] (2.908 g,
13.20 mmol) and CuCl2 (4.840 g, 36.00 mmol) in DME (72 mL) and stir-
ring at room temperature for 5 h. FC (Et2O/pentane 1:10) yielded alkoxy-
amine 39 (2.724 g, 7.75 mmol, 65%). M.p. 88–918C; 1H NMR (300 MHz,
CDCl3): d=7.64 (brs, 2H, Ph-H), 7.45–7.30 (m, 3H, Ph-H), 5.26 (s, 1H,
NOCH), 3.97 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.49 (d, J=10.5 Hz,
1H, NCH), 2.12–2.00 (m, 1H, (H3C)2CH), 1.23 (d, J=6.3 Hz, 3H,
CHCH3), 1.06 (s, 9H, C(CH3)3), 0.59 (d, J=6.6 Hz, 3H, CHCH3);
13C NMR (75 MHz, CDCl3): d=168.1 (OCO), 167.3 (OCO), 141.5 (C),
130.5 (CH), 127.7 (CH), 126.6 (CH), 86.0 (NOCH), 72.9 (NCH), 61.2
(C(CH3)3), 52.6 (OCH3), 52.6 (OCH3), 31.3 (CH), 27.6 (C(CH3)3), 21.7
(CH3), 21.2 (CH3); IR (KBr): n˜ = 3068w, 2971m, 2867w, 1766s, 1734s,
1736w, 1436m, 1362m, 1350m, 1283m, 1236s, 1197m, 1166m, 1105s, 917m,
703s cmꢀ1; MS (ESI): m/z: 374 (100) [M+Na]+, 220 (20), 154 (6), 133 (9);
HRMS (ESI): m/z: calcd for C19H29NO5Na: 374.1938; found: 374.1943
[M+Na]+.
840w, 823w, 799s, 742m, 646m, 625w, 579w, 518m, 451w, 435w, 405w cmꢀ1
;
MS (ESI): m/z: 396 (10) [M+K]+, 380 (30) [M+Na]+, 226 (100)
[MꢀC5H7O4]+, 170 (34), 154 (62), 86 (34); HRMS (ESI): m/z: calcd for
C18H31NO6Na: 380.2049; found: 380.2057 [M+Na]+.
2-(cis-2,6-Bis-(tert-butyl-dimethylsilanoxymethyl)-2,6-diethylpiperidin-1-
yloxy)-malonic acid dimethylester (cis-43): GP 3 was applied by using
DIPA (0.11 mL, 787 mmol), nBuLi (1.64m in hexane; 0.48 mL, 787 mmol),
dimethyl malonate (86 mL, 749 mmol), corresponding nitroxide[14]
(350 mg, 787 mmol) and CuCl2 (252 mg, 1.87 mmol) in DME (10 mL).
The mixture was stirred at 08C for 2 h and at room temperature for 18 h.
FC (MTBE/pentane 1:19) yielded alkoxyamine cis-43 (337 mg, 585 mmol,
78%). M.p. 51–578C; 1H NMR (300 MHz, CDCl3): d=4.93 (s, 1H, CH),
3.94–3.80 (m, 3H, OCHH), 3.78 (s, 6H, OCH3), 3.40 (s, 1H, OCHH),
2.19–1.15 (m, 10H, 5ꢃCH2), 0.82–0.93 (m, 24H, 2ꢃC(CH3)3, 2ꢃ
CH2CH3), 0.04 (s, 12H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d=167.4,
85.2, 68.2, 66.8, 65.9, 63.9, 52.7, 31.6, 28.6, 28.4, 25.9, 24.3, 22.3, 18.2, 15.5,
9.9, 7.8, ꢀ5.4, ꢀ5.5; IR (KBr): n˜ = 2955s, 2884m, 2857m, 1771s, 1752s,
1471m, 1435w, 1255s, 1218m, 1089s, 837s, 776s, 669w cmꢀ1; MS (ESI):
Chem. Eur. J. 2005, 11, 2335 – 2350
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2347

A. Studer et al.
m/z: 614 (7) [M+K]+, 598 (47) [M+Na]+, 576 (6) [M+H]+, 483 (43), 467
(100), 444 (35) [Mꢀmalonyl]+, 337 (35), 284 (23); HRMS (ESI): m/z:
calcd for C28H57NO7Si2Na: 598.3571; found: 598.3581 [M+Na]+.
1341m, 1253s, 1196w, 1155s, 1011s, 911s, 863m, 754s, 734w, 704s, 593m,
526m cmꢀ1; MS (ESI): m/z: 544 (22) [M+K]+, 528 (100) [M+Na]+, 428
(6), 408 (7); HRMS (ESI): m/z: calcd for C30H51NO5Na: 528.3665; found:
528.3660 [M+Na]+.
2-[trans-2,6-Bis-(tert-butyl-dimethylsilanoxymethyl)-2,6-diethylpiperidin-
1-yloxy]-malonic acid dimethylester (trans-43): GP 3 was applied by
using DIPA (0.16 mL, 1.12 mmol), nBuLi (1.64m in hexane, 0.68 mL,
1.12 mmol), malonic acid dimethylester (122 mL, 1.07 mmol), correspond-
ing nitroxide[14] (500 mg, 1.12 mmol) and CuCl2 (376 mg, 2.80 mmol,
2.60 equiv) in dimethoxyethane (19 mL). The reaction mixture was stir-
red at room temperature for 18 h. FC (MTBE/pentane 1:9) yielded al-
koxyamine trans-43 (580 mg, 1.01 mmol, 94%). M.p. 67–698C; 1H NMR
(300 MHz, CDCl3): d=5.30 (s, 1H, CH), 3.96 (d, J=9.8 Hz, 1H,
OCHH), 3.76 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.75 (d, J=8.5 Hz, 1H,
OCHH), 3.47 (d, J=10.5 Hz, 1H, OCHH), 3.25 (d, J=10.5 Hz, 1H,
OCHH), 2.18–1.20 (m, 10H, 5ꢃCH2), 0.92–0.79 (m, 24H, 2ꢃC(CH3)3,
2ꢃCH2CH3), 0.11–(ꢀ0.07) (m, 12H, Si(CH3)2); 13C NMR (50 MHz,
CDCl3): d=167.9, 167.7, 84.7, 66.6, 66.4, 65.9, 63.5, 52.5, 52.4, 30.2, 28.6,
28.3, 25.9, 25.8, 23.7, 18.1 (2 signals), 15.7, 9.4, 7.6, ꢀ5.5 (2 signals), ꢀ5.6,
ꢀ5.7; IR (neat): n˜ = 2954s, 2885m, 2857m, 1770s, 1752s, 1471m, 1435w,
1255s, 1220m, 1089s, 837s, 776s cmꢀ1; MS (ESI): m/z: 598 (7) [M+Na]+,
467 (18), 444 (100) [Mꢀmalonyl]+; HRMS (ESI): m/z: calcd for
C28H57NO7Si2Na: 598.3571; found: 598.3572 [M+Na]+.
2-[2-(2,2,6,6-Tetraethyl-4-hydroxy-piperidin-1-yloxy)-octyl]-malonic acid
dimethyl ester (46): Applying GP 4 alkoxyamine 41 (47 mg, 0.13 mmol),
1-octene (103 mL, 0.65 mmol) and DCE (131 mL) were heated to 1258C
for 1.5 h. FC (Et2O/pentane 2:3) yielded 46 (52 mg, 85%). 1H NMR
(400 MHz, CDCl3): d=3.97–3.78 (m, 1H, OCH), 3.73 (s, 3H, OCH3),
3.72 (s, 3H, OCH3), 3.68–3.53 (m, 2H, HOCH, OCCHCO), 2.21–1.10 (m,
25H, CH2, CH3, OH), 0.89–0.86 (m, 15H, CH3); 13C NMR (100 MHz,
CDCl3): d=170.0 (C), 169.9 (C), 78.6 (CH), 66.1 (C), 62.7 (CH), 52.5
(CH3), 52.4 (CH3), 48.4 (CH), 40.4 (CH2), 32.8 (CH2), 32.7 (CH2), 31.7
(CH2), 30.5 (CH2), 30.3 (CH2), 29.5 (CH2), 27.3 (CH2), 27.1 (CH2), 25.3
(CH2), 22.5 (CH2), 14.0 (CH3), 10.3 (CH3), 10.0 (CH3), 8.7 (CH3), 7.8
(CH3); IR (neat): n˜ = 3371s, 2956s, 2879m, 1739s, 1464s, 1436s, 1378m,
1337m, 1256s, 1197w, 1155s, 1107w, 1060m, 1040m, 1012m, 913m, 789w,
734s, 648w cmꢀ1; MS (ESI): m/z: 510 (29) [M+K]+, 494 (100) [M+Na]+,
472 (36) [M+H]+, 344 (28), 276 (16), 228 (14), 170 (10); HRMS (ESI):
m/z: calcd for C26H49NO6Na: 494.3458; found: 494.3463 [M+Na]+.
2-[2-(2,2,6,6-Tetraethyl-4-oxo-piperidin-1-yloxy)-octyl]-malonic acid di-
methyl ester (47): Applying GP 4 alkoxyamine 42 (70 mg, 0.20 mmol), 1-
octene (154 mL, 0.98 mmol) and DCE (196 mL) were heated to 1258C for
1.5 h. FC (Et2O/pentane 1:20!1:4) yielded 47 (72 mg, 78%). 1H NMR
(300 MHz, CDCl3): d=3.73 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.64–3.59
(m, 2H, OCH, OCCHCO), 2.46–2.27 (m, 4H, CH2), 2.23–2.00 (m, 2H,
CH2), 1.77–1.49 (m, 8H, CH2), 1.32–1.17 (m, 10H, CH2), 0.89–0.83 (m,
15H, CH3); 13C NMR (75 MHz, CDCl3): d=210.8 (C), 169.9 (C), 169.8
(C), 79.2 (CH), 66.1 (C), 65.4 (C), 52.6 (CH3), 52.5 (CH3), 48.4 (CH),
47.0 (CH2), 32.6 (CH2), 32.5 (CH2), 31.9 (CH2), 31.7 (CH2), 29.5 (CH2),
29.3 (CH2), 29.1 (CH2), 25.4 (CH2), 22.5 (CH2), 14.0 (CH3), 9.8 (CH3), 9.4
(CH3), 8.7 (CH3), 8.3 (CH3); IR (neat): n˜ = 3469w, 2959s, 2882w, 1755w,
1738s, 1464w, 1436s, 1378w, 1331m, 1253s, 1197w, 1155m, 1045m, 970w,
920w, 806w, 733mcmꢀ1; MS (ESI): m/z: 492 (100) [M+Na]+, 470 (12)
[M+H]+, 287 (42), 144 (66), 60 (30); HRMS (ESI): m/z: calcd for
C26H47NO6Na: 492.3301; found: 492.3300 [M+Na]+.
2-{2-[N-tert-Butyl-N-(2-methyl-1-phenyl-propyl)-aminooxy]-octyl}-malon-
ic acid dimethylester (44): GP 4 was applied using alkoxyamine 39
(100 mg, 0.29 mmol) and 1-octene (160 mg, 1.42 mmol) in DCE
(0.29 mL) at 1258C for 7 h. FC (pentane/diethylamine 30:1) yielded the
desired product 44 (103 mg, 0.22 mmol, 77%). Alkoxyamine 44 was iso-
lated as an unseparable mixture of diastereoisomers (dr 1:1). 1H NMR
(200 MHz, CDCl3): both isomers: d=7.31–7.16 (m, 5H, Ph-H), 3.92–3.59
(m, 8H, OCCHCO, NOCH, OCH3), 3.45 (d, J=10.2 Hz, 1H, NCH,
single isomer), 3.40 (d, J=10.3 Hz, 1H, NCH, single isomer), 2.41–2.19
(m, 2H, CH2), 2.16–1.97 (m, 1H, (H3C)2CH), 1.50–1.23 (m, 10H, CH2),
1.17 (d, J=6.5 Hz, 3H, CHCH3, single isomer), 1.16 (d, J=6.3 Hz, 3H,
CHCH3, single isomer), 0.99–0.85 (m, 12H, C(CH3)3, CHCH3), 0.43 (t, J
=6.5 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3): both isomers: d
=170.1 (OCO), 170.0 (OCO), 141.5 (C), 131.4 (CH), 131.0 (CH), 127.2
(CH), 127.0 (CH), 126.3 (CH), 126.2 (CH), 79.3 (NOCH), 79.1 (NOCH),
72.4 (NCH), 71.9 (NCH), 61.2 (C(CH3)3), 60.2 (C(CH3)3), 52.4 (OCH3),
52.3 (OCH3), 48.4 (OCCHCO), 48.1 (OCCHCO), 32.9 (CH2), 32.6
(CH2), 32.4 (CH2), 32.4 (CH2), 32.3 (CH), 31.8 (CH2), 31.7 (CH2), 31.6
(CH2), 29.6 (CH2), 29.5 (CH2), 28.4 (C(CH3)3), 28.4 (C(CH3)3), 27.2
(CH3), 25.8 (CH2), 25.2 (CH2), 22.6 (CH2), 22.1 (CH3), 21.7 (CH3), 21.5
(CH3), 21.0 (CH3), 14.0 (CH3); IR (neat): n˜ = 3474w, 2955s, 2870s, 1739s,
1454m, 1436s, 1385m, 1362m, 1254s, 1203s, 1155s, 1046m, 957w, 864w,
835w, 773w, 744w, 703s, 599w cmꢀ1; MS (ESI): m/z: 486 (100) [M+Na]+,
464 (43) [M+H]+, 332 (58), 265 (22), 150 (12), 94 (9); HRMS (ESI): m/z:
calcd for C27H46NO5: 464.3376; found: 464.3367 [M+H]+.
2-[2-(cis-2,6-Bis-(tert-butyl-dimethylsilanoxymethyl)-2,6-diethylpiperidin-
1-yloxy)octyl]-malonic acid dimethylester (cis-48): Applying GP 4 al-
koxyamine cis-43 (52 mg, 90 mmol) and 1-octene (71 mL, 452 mmol,
5.00 equiv) were heated in DCE (0.11 mL) to 1258C for 6 h. FC (MTBE/
pentane 1:19) yielded the addition product cis-48 (53 mg, 77 mmol, 85%).
1H NMR (300 MHz, CDCl3): d=3.94–3.22 (m, 6H, CH(CO), OCH, 2ꢃ
OCH2), 3.73 (s, 6H, OCH3), 2.23–1.01 (m, 22H, CH2, CH3), 1.00–0.76 (m,
27H, 2ꢃC(CH3)3, CH2, CH3), 0.09–(ꢀ0.08) (m, 12H, 2ꢃSi(CH3)2);
13C NMR (75 MHz, CDCl3): d=169.9, 79.2, 66.1, 64.5, 52.5, 52.4, 48.5,
32.4, 31.8, 29.6, 29.3, 27.0, 25.9, 22.6, 18.3, 18.2, 15.9, 14.1, 8.8, 7.9, ꢀ5.5;
IR (neat): n˜ = 2955s, 2930s, 2883m, 2857s, 1758s, 1742s, 1463m, 1436m,
1254s, 1196w, 1153m, 1089s, 1007w, 862s, 837s, 776s cmꢀ1; MS (ESI): m/z:
726 (18) [M+K]+, 710 (71) [M+Na]+, 688 (30) [M+H]+, 284 (100), 195
(73), 163(70); HRMS (ESI): m/z: calcd for C36H73NO7Si2Na: 710.4823;
found: 710.4833 [M+Na]+.
2-{2-[N-(1,1-Diethyl-propyl)-N-(2-methyl-1-phenyl-propyl)-aminooxy]-
octyl}-malonic acid dimethyl ester (45): Applying GP 4 alkoxyamine 40
(50 mg, 0.13 mmol), 1-octene (100 mL, 0.64 mmol) and DCE (127 mL)
were heated to 1258C for 1.5 h. FC (Et2O/pentane 1:10) yielded 45
(50 mg, 78%) as a mixture of diastereoisomers (dr (syn/anti) 1:1, deter-
mined by 1H NMR analysis). 1H NMR (300 MHz, CDCl3): both isomers:
d=7.36–7.12 (m, 5H, Ph-H), 3.85–3.61 (m, 2H, OCH, OCCHCO), 3.76
(s, 3H, OCH3, single isomer), 3.73 (s, 3H, OCH3, single isomer), 3.72 (s,
3H, OCH3, single isomer), 3.70 (s, 3H, OCH3, single isomer), 3.49–3.42
(m, 1H, NCH), 2.37–2.01 (m, 3H, OCHCH2, HC(CH3)2), 1.52–1.15 (m,
19H, CH2, CH3), 0.92–0.87 (m, 3H, HCCH3), 0.68, 0.65 (2 t, J=7.8 Hz,
9H, CH2CH3), 0.44, 0.41 (2d, J=6.6 Hz, 3H, HCCH3); 13C NMR
(75 MHz, CDCl3): both isomers: d=170.2 (C), 170.1 (C), 170.2 (C), 167.2
(C), 142.8 (C), 142.1 (C), 131.5 (CH), 131.0 (CH), 127.0 (CH), 126.8
(CH), 126.2 (CH), 126.1 (CH), 79.2 (CH), 78.8 (CH), 71.4 (CH), 70.8
(CH), 68.4 (C), 67.6 (C), 52.5 (CH3), 52.5 (CH3), 52.5 (CH3), 52.3 (CH3),
48.3 (CH), 48.2 (CH), 33.0 (CH2), 32.9 (CH), 32.7 (CH2), 32.6 (CH2), 32.6
(CH2), 32.1 (CH), 31.8 (CH2), 31.7 (CH2), 29.7 (CH2), 29.6 (CH2), 27.6
(CH2), 27.4 (CH2), 25.6 (CH2), 25.3 (CH2), 22.6 (CH2), 22.4 (CH3), 21.9
(CH3), 21.5 (CH3), 14.1 (CH3), 14.1 (CH3), 8.8 (CH3), 8.7 (CH3); IR
(neat): n˜ = 3472w, 2956s, 2872w, 1740s, 1600w, 1457m, 1436s, 1380m,
2-[2-(trans-2,6-Bis-(tert-butyl-dimethylsilanoxymethyl)-2,6-diethylpiperi-
din-1-yloxy)octyl]-malonic acid dimethylester (trans-48): Applying GP 4
alkoxyamine trans-43 (65 mg, 113 mmol) and 1-octene (89 mL, 568 mmol)
were heated in DCE (0.11 mL) to 1258C for 5 h. FC (MTBE/pentane
1:19) yielded the addition product trans-48 (67 mg, 97 mmol, 86%). Sepa-
ration of the formed diastereoisomers (dr 1:1, determined by 13C NMR
analysis) was not possible. 1H NMR (300 MHz, CDCl3): both isomers: d
=4.11–3.31 (m, 6H, CH(CO), OCH, OCH2), 3.73 (s, 6H, OCH3), 2.34–
1.05 (m, 25H, 11ꢃCH2, CH2CH2CH3), 1.00–0.77 (m, 24H, 2ꢃC(CH3)3,
2ꢃCCH2CH3), 0.06–0.00 (m, 12H, 2ꢃSi(CH3)2); 13C NMR (50 MHz,
CDCl3): both isomers: d=170.3, 170.0, 169.9 (2 signals), 79.0, 78.9, 52.5,
52.4 (2 signals), 48.6, 48.2, 33.2, 32.7, 32.5, 32.4, 31.9, 31.8, 29.7, 25.9, 25.6,
22.6, 18.2, 16.0, 14.1 (2 signals), ꢀ5.5 (2 signals); IR (neat): n˜ = 2955s,
2883s, 2857s, 1758s, 1742s, 1463m, 1435m, 1254s, 1089s, 866s, 837s, 775s
cmꢀ1; MS (ESI): m/z: 727 (3) [M+K]+, 711 (60), 688 (24) [M+H]+, 284
(78), 222 (49), 195 (97), 163 (100), 130 (100); HRMS (ESI): m/z: calcd
for C36H73NO7Si2Na: 710.4823; found: 710.4829 [M+Na]+.
2348
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2335 – 2350

Persistent Radical Effect
FULL PAPER
O-tert-Butyl-N-(1,1-diethyl-propyl)-N-(2-methyl-1-phenyl-propyl)-hy-
droxylamine (49): Corresponding nitroxide[16] (380 mg, 1.49 mmol) was
dissolved in THF (6 mL) under argon. The mixture was cooled to ꢀ788C
followed by the addition of tBuLi (2.90 mmol) and CuCl2 (214 mg,
1.59 mmol). After stirring for 23 h at room temperature the reaction was
stopped upon the addition of NH4Cl (aq. sat.). The aqueous layer was ex-
tracted with Et2O (3ꢃ) and the combined organic layers were dried over
MgSO4. Evaporation of the solvents in vacuo followed by FC (pentane)
CDCl3): d=3.97–3.86 (m, 1H, CH), 3.73–3.59 (m, 1H, CH), 2.17–1.91
(m, 4H, CH2), 1.81–1.43 (m, 12H, CH2), 1.39–1.14 (m, 12H), 1.04–0.83
(m, 20H); 13C NMR (50 MHz, CDCl3): d=69.8 (C), 64.8 (C), 62.8 (C),
61.9 (CH), 48.2 (CH2), 40.6 (CH2), 40.2 (CH2), 32.6 (CH2), 31.7 (CH2),
29.9 (CH2), 29.8 (CH2), 29.4 (3ꢃCH3), 29.2 (CH2), 27.4 (CH2), 27.1
(CH2), 25.7 (CH2), 22.8 (C), 22.4 (CH2), 13.9 (CH2), 10.6 (CH3), 10.1
(CH3), 8.8 (CH3), 8.0 (CH3); IR (neat): n˜
= 3353br, 2961s, 2878m,
1464m, 1379m, 1148w, 1039m cmꢀ1; MS (ESI): m/z: 447 (100), 398 (12)
[M+H]+, 235 (67); HRMS (ESI): m/z: calcd for C25H52NO2: 398.3998;
found: 398.4011 [M+H]+.
1
yielded 49 (207 mg, 45%). H NMR (400 MHz, CDCl3): d=7.51–7.46 (m,
2H, Ph-H), 7.26–7.15 (m, 3H, Ph-H), 3.45 (d, J=10.4 Hz, 1H, NCH),
2.16 (dhept, J1 =10.4, J2 =6.4 Hz, 1H, HC(CH3)2), 1.48–1.38 (m, 6H,
CH2), 1.41 (s, 9H, C(CH3)3), 1.20 (d, J=6.0 Hz, 3H, HCCH3), 0.66 (t, J
=7.2 Hz, 9H, CH2CH3), 0.43 (d, J=6.4 Hz, 3H, HCCH3); 13C NMR
(100 MHz, CDCl3): d=143.7 (C), 131.5 (CH), 126.8 (CH), 125.9 (CH),
78.9 (C), 71.4 (CH), 67.7 (C), 32.5 (CH), 29.9 (CH3), 28.0 (CH2), 23.0
(CH3), 21.6 (CH3), 8.8 (CH3); IR (neat): n˜ = 3059w, 2970s, 2876w, 1601w,
1456s, 1385m, 1362s, 1252w, 1222w, 1173s, 1072w, 1006m, 910m, 867s,
780w, 754s, 737w, 700s, 665m, 593m, 522w, 454w cmꢀ1; MS (ESI): m/z:
320 (12) [M+H]+, 222 (100) [MꢀC7H13]+, 166 (33) [MꢀC11H21]+, 148
(16) [MꢀC11H20O]+, 133 (16) [MꢀONC11H24]+; HRMS (ESI): m/z: calcd
for C21H38NO: 320.2948; found: 320.2963 [M+H]+.
2-(2,2,6,6-Tetraethyl-4-oxo-piperidin-1-yloxy)-propionic acid methyl ester
(53): GP 2 was applied by using 3-bromo-propionic acid methyl ester
(181 mL, 1.58 mmol), the corresponding nitroxide[15] (340 mg, 1.50 mmol),
Cu (100 mg, 1.58 mmol), Cu(OTf)2 (5.4 mg, 15 mmol) and 4,4’-di-tert-
butyl-[2,2’]bipyridine (16.0 mg, 60 mmol) in benzene (3.0 mL) for 18 h at
758C. FC (Et2O/pentane 1:6) yielded 53 (436 mg, 93%). 1H NMR
(400 MHz, CDCl3): d=4.37 (q, J=6.8 Hz, 1H, OCH), 3.72 (s, 3H,
OCH3), 2.36 (d, J=6.8 Hz, 4H, OCCH2), 2.24–1.97 (m, 2H, CH2), 1.64–
1.60 (m, 4H, CH2), 1.49–1.35 (m, 2H, CH2), 1.39 (d, J=6.8 Hz, 3H,
OCCH3), 0.97–0.81 (m, 12H, CH3); 13C NMR (100 MHz, CDCl3): d
=210.0 (C), 174.1 (C), 80.6 (CH), 66.6 (C), 51.6 (CH3), 46.6 (CH2), 31.0
(CH2), 28.8 (CH2), 18.4 (CH3), 9.4 (CH3), 8.2 (CH3); IR (neat): n˜
=
N-(1,1-Diethyl-propyl)-O-[1-(2,2-dimethylpropyl)-heptyl]-N-(2-methyl-1-
phenyl-propyl)-hydroxylamine (50): Alkoxyamine 49 (55 mg, 0.17 mmol)
was dissolved in degassed tBuOH (172 mL) under an argon atmosphere
and 1-octene (136 mL, 0.86 mmol) was added. The mixture was heated to
1308C in a sealed tube for 4 d. After removal of the solvent in vacuo the
residue was purified by FC (pentane) to yield 50 (30 mg, 40%) as a mix-
3423w, 2969s, 2882m, 1751m, 1717s, 1614w, 1460s, 1377m, 1333m, 1272m,
1198s, 1129s, 1078s, 1036m, 976m, 761w, 582w, 521w cmꢀ1; MS (ESI): m/z:
336 (100) [M+Na]+, 267 (41), 249 (33), 212 (42), 109 (32), 85 (64);
HRMS (ESI): m/z: calcd for C17H31NO4Na: 336.2145; found: 336.2153
[M+Na]+.
1
ture of diastereoisomers (dr (syn/anti) 1:1, determined by H NMR analy-
(2,2,6,6-Tetraethyl-4-oxo-piperidin-1-yloxy)-acetic acid methyl ester (54):
GP 2 was applied by using bromo-acetic acid methyl ester (102 mL,
1.05 mmol), corresponding nitroxide[15] (226 mg, 1.00 mmol), Cu (67 mg,
1.05 mmol), Cu(OTf)2 (3.6 mg, 10 mmol) and 4,4’-Di-tert-butyl-[2,2’]bipyr-
idine (11.0 mg, 40 mmol) in benzene (2.0 mL) for 16 h at 758C. FC (Et2O/
pentane 1:10) yielded 54 (145 mg, 48%). 1H NMR (300 MHz, CDCl3): d
=4.41 (s, 2H, OCH2), 3.71 (s, 3H, OCH3), 2.35, 2.30 (2 brs, 4H,
OCCH2), 2.03 (brs, 2H, CH2), 1.59 (brs, 6H, CH2), 0.91 (brs, 12H, CH3);
13C NMR (75 MHz, CDCl3): d=209.3 (C), 169.3 (C), 73.6 (CH2), 67.6
(C), 51.4 (CH3), 46.4 (CH2), 29.8 (CH2), 28.2 (CH2), 9.4 (CH3), 8.0 (CH3);
sis). 1H NMR (300 MHz, CDCl3): both isomers: d=7.51–7.31 (m, 2H,
Ph-H), 7.26–7.12 (m, 3H, Ph-H), 3.92–3.79 (m, 1H, OCH), 3.47–3.34 (m,
1H, NCH), 2.24–2.00 (m, 2H, CH2), 1.85, 1.80 (2d, J=5.4 Hz, 1H, CH),
1.54–1.17 (m, 22H, CH2, CH3), 1.00–0.98 (m, 3H, CH3), 0.93–0.86 (m,
6H, CH3), 0.75–0.63 (m, 9H, CH3), 0.50–0.39 (m, 3H, CH3); 13C NMR
(75 MHz, CDCl3): both isomers: d=142.9 (C), 142.6 (C), 131.7 (CH),
131.5 (CH), 126.7 (CH), 126.7 (CH), 125.9 (CH), 79.7 (CH), 79.7 (CH),
71.2 (CH), 70.8 (CH), 68.2 (C), 68.2 (C), 46.9 (CH2), 46.4 (CH2), 35.1
(C), 34.2 (C), 32.5 (CH), 32.4 (CH), 31.9 (CH2), 31.9 (CH2), 30.8
(C(CH3)3), 30.7 (CH3), 30.0 (CH2), 30.0 (CH2), 29.9 (CH2), 29.9 (CH2),
28.0 (CH2), 27.9 (CH2), 27.5 (CH2), 25.5 (CH2), 25.5 (CH2), 23.0 (CH3),
23.0 (CH3), 22.7 (CH2), 22.6 (CH2), 21.8 (CH3), 21.6 (CH3), 14.1 (CH3),
14.1 (CH3), 9.0 (CH3), 8.9 (CH3); IR (neat): n˜ = 3060w, 2956s, 2871w,
1600w, 1467s, 1381s, 1363m, 1248w, 1158m, 1072w, 1033w, 1009m, 910m,
863m, 753m, 702s, 676w, 595w, 525w cmꢀ1; MS (ESI): m/z: 432 (22)
[M+H]+, 331 (100) [MꢀC7H16]+, 202 (3), 165 (3), 147 (59), 132 (29)
[MꢀC19H41NO]+; HRMS (ESI): m/z: calcd for C29H54NO: 432.4200;
found: 432.4219 [M+H]+.
IR (neat): n˜
= 2968s, 2882m, 1759m, 1716s, 1522w, 1462m, 1436m,
1377m, 1333m, 1280m, 1201s, 1087s, 1016m, 922w, 898w, 802m, 733m,
650w, 580m, 524m cmꢀ1; MS (ESI): m/z: 300 (22) [M+H]+, 215 (13), 194
(4), 173 (100), 110 (9), 83 (13), 56 (8); HRMS (ESI): m/z: calcd for
C16H29NO4Na: 322.1989; found: 322.1953 [M+Na]+.
2-Methyl-4-(2,2,6,6-tetraethyl-4-oxo-piperidin-1-yloxy)-decanoic
acid
methyl ester (55): Applying GP 4 alkoxyamine 53 (52 mg, 0.17 mmol), 1-
octene (130 mL, 0.83 mmol) and DCE (165 mL) were heated to 1358C for
24 h. FC (Et2O/pentane 1:10) yielded 55 (53 mg, 75%) as a mixture of di-
astereoisomers (dr (syn/anti) 1:1, determined by 1H NMR analysis).
1H NMR (400 MHz, CDCl3): both isomers: d=3.66 (s, 3H, OCH3, single
isomer), 3.65 (s, 3H, OCH3, single isomer), 3.66–3.58 (m, 1H, OCH),
2.72–1.28 (m, 25H, CH, CH2), 1.17 (t, J=8.8 Hz, 3H, CH3), 0.90–0.81 (m,
15H, CH3); 13C NMR (100 MHz, CDCl3): both isomers: d=210.8 (C),
177.1 (C), 177.0 (C), 79.9 (CH), 79.6 (CH), 65.7 (C), 51.4 (CH3), 51.4
(CH3), 47.1 (CH2), 37.5 (CH2), 37.2 (CH2), 36.3 (CH), 36.2(CH), 33.0
(CH2), 32.9 (CH2), 32.5 (CH2), 31.7 (CH2), 29.6 (CH2), 25.5 (CH2), 25.3
(CH2), 22.5 (CH2), 18.3 (CH3), 18.1 (CH3), 14.0 (CH3), 9.5 (CH3), 8.8
(CH3); IR (neat): n˜ = 3433w, 2964s, 2932s, 2881m, 1736s, 1718s, 1597w,
1461s, 1377w, 1331w, 1253m, 1196s, 1169s, 1145w, 1093m, 979m, 922w,
806w, 763w, 537w cmꢀ1; MS (ESI): m/z: 448 (79) [M+Na]+, 212 (100)
[MꢀC12H21O3]+, 152 (100), 85 (45); HRMS (ESI): m/z: calcd for
C25H47NO4Na: 448.3397; found: 448.3421 [M+Na]+.
1-tert-Butoxy-2,2,6,6-tetraethylpiperidin-4-ol (51): tBuLi (5.94 mmol) was
added dropwise at ꢀ788C to a solution of the corresponding nitroxide[15]
(616 mg, 2.70 mmol) in THF (10 mL). After 5 min anhydrous CuCl2
(399 mg, 2.97 mmol) was added and the reaction mixture was allowed to
warm to room temperature and was stirred overnight. The reaction was
quenched with NH4Cl (aq. sat.) and extracted with MTBE. Drying over
MgSO4 and evaporation of the solvent in vacuo yielded alkoxyamine 51
(312 mg, 41%). 1H NMR (300 MHz, CDCl3): d=3.91–3.83 (m, 1H, CH),
2.05–1.93 (m, 2H, CH2), 1.81–1.66 (m, 4H, CH2), 1.55–1.47 (m, 3H,
CH2), 1.34–1.19 (m, 1H, CH2), 1.55 (s, 9H, CH3), 1.05–0.96 (m, 2H,
CH2), 0.93–0.85 (m, 12H, CH3); 13C NMR (75 MHz, CDCl3): d=77.9
(C), 65.2 (2ꢃC), 61.9 (CH), 40.2 (2ꢃCH2), 29.8 (2ꢃCH2), 29.0 (3ꢃCH3),
26.6 (2ꢃCH2), 10.0 (2ꢃCH3), 8.3 (2ꢃCH3); IR (neat): n˜ = 3333br, 2966s,
2879m, 1463m, 1383m, 1279w, 1257w, 1223w, 1175m cmꢀ1; MS (ESI): m/z:
286 (56) [M+H]+, 230 (100), 184 (34); HRMS (ESI): m/z: calcd for
C17H36NO2: 286.2741; found: 286.2741 [M+H]+.
4-(2,2,6,6-Tetraethyl-4-oxo-piperidin-1-yloxy)-decanoic acid methyl ester
(56): Applying GP 4 alkoxyamine 54 (42 mg, 0.14 mmol), 1-octene
(110 mL, 0.70 mmol) and DCE (140 mL) were heated to 1358C for 4 d. FC
(Et2O/pentane 1:20) yielded 56 (33 mg, 57%). Some of the starting mate-
rial 54 could be reisolated (6 mg, 14%). 1H NMR (400 MHz, CDCl3): d
=3.68–3.60 (m, 1H, OCH), 3.67 (s, 3H, OCH3), 2.41–2.32 (m, 6H,
OCCH2), 2.08–1.58 (m, 12H, CH2), 1.34–1.17 (m, 8H, CH2), 0.95–0.77
(m, 15H, CH3); 13C NMR (75 MHz, CDCl3): d=210.8 (C), 174.0 (C),
1-[1-(2,2-Dimethyl-propyl)-heptyloxy]-2,2,6,6-tetraethylpiperidin-4-ol
(52): Alkoxyamine 51 (50 mg, 0.175 mmol) and 1-octene (98 mg,
0.875 mmol) were dissolved in tBuOH (0.18 mL) and heated to 1308C in
a sealed tube for 2 d (5 mL) under an argon atmosphere. The solvent was
removed in vacuo and the residue was purified by FC (Et2O/pentane 1:2)
yielding the addition product 52 (17 mg, 24%). 1H NMR (200 MHz,
Chem. Eur. J. 2005, 11, 2335 – 2350
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2349

A. Studer et al.
80.8 (CH), 67.8 (C), 51.5 (CH3), 47.1 (CH2), 32.3 (CH2), 31.8 (CH2), 30.2
(CH2), 29.9 (CH2), 29.6 (CH2), 28.4 (CH2), 27.9 (CH2), 25.6 (CH2), 22.6
(CH2), 14.0 (CH3), 9.6 (CH3), 8.7 (CH3); IR (neat): n˜ = 3427w, 2960s,
2930s, 2882m, 1739m, 1718s, 1462m, 1438m, 1376w, 1331w, 1253m, 1197s,
1169s, 1091m, 1013m, 966m, 804m, 726w, 700w, 578w, 529w cmꢀ1; MS
(ESI): m/z: 434 (100) [M+Na]+, 412 (6) [M+H]+, 322 (33); HRMS
(ESI): m/z: calcd for C24H45NO4Na: 434.3241; found: 434.3193 [M+Na]+.
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for support. Katja Jantos and Katharina Woithe
are acknowledged for performing some experiments. Dr. Burghaus is ac-
knowledged for assistance during the EPR experiments. LONZA AG is
acknowledged for a generous gift of solvents.
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Received: September 8, 2004
Published online: February 4, 2005
2350
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2335 – 2350