Factors influencing the C-O bond homolysis of alkoxyamines: Effects of H-bonding and polar substituents

Article abstract of DOI:10.1021/jo001190z

The synthesis of various new trialkylhydroxylamines is described. The rate constant of the C-O bond cleavage of these new alkoxyamines has been measured. For example, C-O bond homolysis rates in a series of para-substituted TEMPO-styryl compounds TEMPO-CH(CH₃)C₆H₅X 1a (p-MeO), 1b (p-Me), 1d (p-H), 1e (p-Br), and 1f (p-MeO₂C) are presented. Furthermore, rate constants for the C-O bond cleavage of α-heteroaryl-substituted secondary alkoxyamines are discussed. A correlation by which the rate constant for the C-O bond cleavage of TEMPO-derived alkoxyamines can be predicted from the C-H BDEs of the corresponding alkanes is presented. Solvent effects as well as the effect of camphorsulfonic acid on the rate of the C-O bond homolysis are discussed. Finally, EPR and kinetic evidence show that alkoxyamines derived from nitroxides which are capable of intramolecular H-bonding undergo C-O bond cleavage faster than the corresponding non-H-bond-forming analogues.

Full text of DOI:10.1021/jo001190z

1146
J . Org. Chem. 2001, 66, 1146-1156
F a ctor s In flu en cin g th e C-O Bon d Hom olysis of Alk oxya m in es:
Effects of H-Bon d in g a n d P ola r Su bstitu en ts
Sylvain Marque,*,† Hanns Fischer,† Elisabeth Baier,‡ and Armido Studer*,§
Physikalisch-Chemisches Institut der Universita¨t Zu¨rich, Winterthurerstrasse 190, CH-8057 Zu¨rich,
Switzerland, and Laboratorium fu¨r Organische Chemie, Eidgeno¨ssische Technische Hochschule,
ETH Zentrum, Universita¨tstrasse 16, CH-8092 Zu¨rich, Switzerland, and Fachbereich Chemie der
Universita¨t Marburg, Hans-Meerwein-Strasse, D-35032 Marburg, Germany
studer@mailer.uni-marburg.de
Received August 4, 2000
The synthesis of various new trialkylhydroxylamines is described. The rate constant of the C-O
bond cleavage of these new alkoxyamines has been measured. For example, C-O bond homolysis
rates in a series of para-substituted TEMPO-styryl compounds TEMPO-CH(CH3)C6H5X 1a (p-MeO),
1b (p-Me), 1d (p-H), 1e (p-Br), and 1f (p-MeO2C) are presented. Furthermore, rate constants for
the C-O bond cleavage of R-heteroaryl-substituted secondary alkoxyamines are discussed. A
correlation by which the rate constant for the C-O bond cleavage of TEMPO-derived alkoxyamines
can be predicted from the C-H BDEs of the corresponding alkanes is presented. Solvent effects as
well as the effect of camphorsulfonic acid on the rate of the C-O bond homolysis are discussed.
Finally, EPR and kinetic evidence show that alkoxyamines derived from nitroxides which are capable
of intramolecular H-bonding undergo C-O bond cleavage faster than the corresponding non-H-
bond-forming analogues.
Sch em e 1. Ra d ica l Cycliza tion Rea ction Usin g
th e P RE
In tr od u ction
In seminal work, Rizzardo et al. and later Georges et
al. have demonstrated that polymers with polydispersi-
ties well below the theoretical limit of 1.5 can be prepared
by nitroxide-mediated living radical polymerization.1
Since then, many groups have further extended this
concept for the preparation of well-defined polymers.2
These processes are controlled by the so-called persistent
radical effect (PRE).3,4 The PRE is a general principle that
explains the specific coupling of a persistent and a
transient radical when they are formed with equal rates.
There is a buildup of the persistent radical with respect
* To whom correspondence should be addressed. E-mail: (S.M.)
marque@srepir.univ-mrs.fr.
† Physikalisch-Chemisches Institut der Universita¨t Zu¨rich.
‡ Laboratorium fu¨r Organische Chemie der Eidgeno¨ssischen Tech-
nischen Hochschule Zu¨rich.
§ Fachbereich Chemie der Universita¨t Marburg.
(1) (a) Solomon, D. H.; Rizzardo, E.; Cacioli, P. US Patent 4,581,-
429; P. Eur. Pat. Appl. 135280; Chem. Abstr. 1985, 102, 221335q. (b)
Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K.
Macromolecules 1993, 26, 2987.
(2) Reviews: (a) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P.
M.; Hamer, G. K. Trends Polym. Sci. 1994, 2, 66. (b) Moad, G.;
Rizzardo, E. In The Chemistry of Free Radical Polymerization; Per-
gamon Press: Oxford, 1995; p 335. (c) Hawker, C. J . Trends Polym.
Sci. 1996, 4, 183. (d) Hawker, C. J . Acc. Chem. Res. 1997, 30, 373. (e)
Controlled Radical Polymerization; Matyjaszewski, K., Ed.; ACS
Symposium Series No. 685; American Chemical Society: Washington,
DC, 1998. (f) Controlled/ Living Radical Polymerization; Matyjasze-
wski, K., Ed.; ACS Symposium Series No. 768; American Chemical
Society: Washington, DC, 1999.
(3) (a) Fischer, H. J . Am. Chem. Soc. 1986, 108, 3925. (b) Fischer,
H.; Ru¨egge, D. Int. J . Chem. Kinet. 1989, 21, 703. (c) Daikh, B. E.;
Finke, R. G. J . Am. Chem. Soc. 1992, 114, 2938. (d) McFaul, P. A.;
Arends, I. W. C. E.; Ingold, K. U.; Wayner, D. D. M. J . Chem. Soc.,
Perkin Trans. 2 1997, 135. (e) Kothe, T.; Martschke, R.; Marque, S.;
Popov, M.; Fischer, H. J . Chem. Soc., Perkin Trans. 2 1998, 1553.
(4) (a) Fischer, H. Macromolecules 1997, 30, 5666. (b) Fischer, H.
J . Polym. Sci. Part A: Polymer Chemistry 1999, 37, 1885. (c) Ohno,
K.; Tsujii, Y.; Miyamoto, T.; Fukuda, T.; Goto, M.; Kobayashi, K.;
Akaike, T. Macromolecules 1998, 31, 1064. (d) Fukuda, T.; Goto, A.;
Ohno, K. Macromol. Rapid. Commun. 2000, 21, 151.
to the transient counterpart which is due to self-termina-
tion of the latter and leads to a highly selective reaction
of the transient with the persistent radical.
Very recently, we presented first results on radical
cyclization reactions using the PRE.5 Nitroxides have
been used as persistent radicals in these processes. For
example, the 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)-
derived alkoxyamine 1d was readily isomerized to the
corresponding 5-exo (70%) and 6-endo (13%) cyclization
products (Scheme 1). Furthermore, we introduced new
nitroxides, capable of intramolecular hydrogen bonding.
Careful kinetic analysis4 showed that the rate constant
of the C-O bond homolysis of the alkoxyamine is a very
(5) Studer, A. Angew. Chem., Int. Ed. 2000, 6, 1108.
10.1021/jo001190z CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/26/2001

C-O Bond Homolysis of Alkoxyamines
J . Org. Chem., Vol. 66, No. 4, 2001 1147
important parameter in reactions of this type.6 In this
work, we present the preparation of various new alkoxy-
amines in full details. Moreover, we report rate constants
for the C-O bond homolysis of these alkoxyamines under
different conditions. The effect of the para substituent
in various TEMPO-styryl derivatives will be discussed.
Furthermore, we provide evidence that alkoxyamines
derived from nitroxides which are capable of intra-
molecular hydrogen bonding homolyze faster to the
corresponding radicals than their non-H-bond-forming
analogues. In addition, EPR data of new nitroxides will
be reported. The knowledge of the rate constants of the
C-O bond homolysis is essential for synthetic planning
of nitroxide-mediated tin-free radical chemistry and
living free radical polymerizations.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Alk oxya m in es. In Figure 1, all
the alkoxyamines studied in this work are presented. The
alkoxyamines 1a ,d ,e were prepared by reacting the
sodium salt of 1-hydroxy-2,2,6,6-tetramethylpiperidine
(TEMPO-Na) with the corresponding bromide in reflux-
ing THF for 14-20 h (20-80%).7 The phenylsulfanyl-
substituted alkoxyamine 1j, the pyridyl derivative 1g,
and the thienyl-substituted alkoxyamine 1h were syn-
thesized in analogy using (1-chlorohex-5-enylsulfanyl)-
benzene,8 1-mesyloxy-1-(2-pyridyl)-5-hexene, and 1-bromo-
1-(2-thienyl)-5-hexene, respectively. For alkoxyamine 1j,
4-tert-butyldimethylsilyloxy-TEMPO was used instead of
TEMPO. Desilylation was performed using HF‚pyridine
in CH2Cl2 to eventually afford the hydroxy-TEMPO
derivative 1j. Alkoxyamine 2c was prepared from com-
mercially available N,N-di-tert-butylnitroxide and 1-bromo-
1-phenyl-5-hexene by the same method.
Deprotonation of 6-cyano-1-hexene by lithium diiso-
propylamide (LDA, -78 °C) and subsequent addition of
a suspension of CuCl2 and TEMPO in THF afforded after
workup and purification nitrile 1l in 61% yield.9 The
acylated TEMPO derivative 1i was readily available by
reaction of phenylacetic acid chloride with the sodium
salt of TEMPOH in THF in the presence of a catalytic
amount of dimethylaminopyridine (DMAP, 89%).
The alkoxyamines 1k , 2a , and 7b were synthesized
from 6-iodo-6-methyl-1-heptene according to Boger10 by
treatment of the iodide in refluxing benzene with the
corresponding nitroxide and tributyltin hydride. The
nitroxide used for the preparation of 7b has previously
been described.11 Triol 8c was obtained by ortho ester
deprotection of 7b using standard procedures (see the
Experimental Section).
F igu r e 1. Various alkoxyamines studied.
The alkoxyamines 1b, 1f, 3a , 5, and 7a were prepared
from the corresponding benzylic bromides using a pro-
cedure reported by Matyjaszewski.12 Thus, a benzene
suspension containing the bromide, the nitroxide, copper
powder, and a catalytic amount of copper bistriflate and
4,4′-di-tert-butyl-2,2′-bipyridine was stirred for 5-10 h
at 70 °C. Removal of the solids by filtration and subse-
quent purification by chromatography (SiO2) afforded 3a ,
5, and 7a as a mixture of diastereoisomers (dr ≈ 1:1).
Similar alkoxyamines have previously been applied as
initiators in nitroxide-mediated polymerizations.13 Triol
8a was easily obtained from 7a after ortho ester depro-
tection. Alkoxyamine 8b was prepared in analogy. The
Cu method was also applied for the synthesis of 4 and 6
as specified in the Experimental Section. The decay of
the alkoxyamines 1c, 2b, and 3b has previously been
(6) Marque, S.; Fischer, H.; Le Mercier, C.; Tordo, P. Macromolecules
2000, 33, 4403.
(7) Hawker, C. J .; Barclay, G. G.; Orellana, A.; Dao, J .; Devonport,
W. Macromolecules 1996, 29, 5245.
(8) Tuleen, D. L.; Stephens, T. B. J . Org. Chem. 1969, 34, 31.
(9) Braslau, R.; Burrill II, R. C.; Siano, M.; Naik, N.; Howden, R.
K.; Mahal, L. K. Macromolecules 1997, 30, 6445.
(10) Boger, D. L.; McKie, J . A. J . Org. Chem. 1995, 60, 1271.
(11) See the Supporting Information in ref 5.
(12) Matyjaszewski, K.; Woodworth, B. M.; Zhang, X.; Gaynor, S.
G.; Metzner, Z. Macromolecules 1998, 31, 5955.
(13) (a) Grimaldi, S.; Finet, J .-P.; Zeghdaoui, A.; Tordo, P.; Benoit,
D.; Gnanou, Y.; Fontanille, M.; Nicol, P.; Pierson, J .-F. Polym. Prepr.
Am. Chem. Soc. Div. Polym. Chem. 1997, 38, 651. (b) Benoit, D.;
Chaplinski, V.; Braslau, R.; Hawker, C. J . J . Am. Chem. Soc. 1999,
121, 3904.

1148 J . Org. Chem., Vol. 66, No. 4, 2001
Marque et al.
Ta ble 1. Activa tion P a r a m eter s a n d Ra te Con sta n ts a t 120 °C for th e Dissocia tion of th e C-O Bon d in
Tr ia lk ylh yd r oxyla m in es (NO-R)
b
entry
NO-R
runs
T (°C)
Aa (1014 s-1
)
Ea (kJ ‚mol-1
)
kd (s-1
)
kdMe c (s-1
)
ref
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15f
16
17
18
19
20
21
22
23
24
25
1a
1b
1c
1d
1e
1f
3
7
17
3
5
7
8
7
2
3
3
7
2
13
1
3
10
7
5
3
119-140
105-135
90-150
130-151
110-150
95-130
94-130
79-129
150.8
-
132.8 (est)
129.7
133.0
131.9 (est)
127.2
126.6
5.3 × 10-4
6.9 × 10-4
5.2 × 10-4
7.0 × 10-4
1.1 × 10-3
1.6 × 10-3
1.2 × 10-3
1.2 × 10-2
1.1 × 10-9
5.1 × 10-8
1.3 × 10-5
4.3 × 10-4
3.1 × 10-4
1.4 × 10-2
3.5 × 10-2
3.0 × 10-3
3.3 × 10-3
1.3 × 10-3
3.0 × 10-3
3.6 × 10-3
1.5 × 10-4
1.2 × 10-6
5.6 × 10-3
7.6 × 10-3
7.9 × 10-5
4.2 × 10-4
5.5 × 10-4
d
1.2
2.5
-
0.9
1.1
2.1
0.1
-
5.6 × 10-4
8.8 × 10-4
d
1g
1h
1i
129.7
112.4
9.6 × 10-4
9.6 × 10-3
175.7 (est)
162.7 (est)
144.0 (est)
137.9
134.6 (est)
121.8
119.1 (est)
127.1 (est)
129.6
129.8 (est)
127.1 (est)
126.5 (est)
136.9 (est)
152.8 (est)
125.1 (est)
124.1 (est)
139.1 (est)
1je
1k
1l
150.5
-
-
8.9
4.1 × 10-8
1.0 × 10-5
3.4 × 10-4
2.5 × 10-4
d
130-151
100-152
99-120
60-129
100.0
110-130
60-131
100-130
110-131
110-131
120-131
119-132
115-124
120-126
110-130
2a
2b
2c
3a g
3b
4h
2.2
-
-
5.6
-
-
-
-
-
-
6
6
2.8 × 10-2
2.4 × 10-3
d
d
5h
2.4 × 10-3
2.9 × 10-3
d
6i
7a h
7b
8a h
8bh
8c
6
3
5
3
9.6 × 10-7
d
-
-
6.1 × 10-3
6.3 × 10-5
5
a
b
Statistical errors smaller than a factor of 2. Statistical errors between 2 and 3 kJ ‚mol-1
.
c Corrected rate constants (20% reduction)
for alkoxyamines with longer alkyl chains; see text. No correction necessary. e 4-Hydroxy-TEMPO was used instead of TEMPO. f In
d
g
h
i
t-BuPh/t-BuOH (1:1). Mixture of diastereoisomers (65:35). Mixture of diastereoisomers (1:1). Mixture of diastereoisomers (54:46).
analyzed6 and is included in the present paper for
comparison.
kd were also determined using TMIO-15ND12 as alkyl
radical scavenger. The results of the TMIO-15ND12-
experiments are in fair agreement with the results
obtained by O2-scavenging. In the homolysis experiments
of the alkoxyamines 4-6, 8a , and 8b, N-(2-methyl-1-
phenylpropyl)-N-(1-methyl-2,6,7-trioxabicyclo[2.2.2]oct-
4-yl)-N-oxyl (7′) and N-(tert-butyl)-N-(2-methyl-1-phenyl-
propyl)-N-oxyl (3′) were used as a standard because the
corresponding free nitroxides were not available (see
Figure 5).
We have shown earlier, that the frequency factor A of
the C-O-bond homolysis of various alkoxyamines (15
different compounds studied) does not vary much with
alkoxyamine structure but lies between 1013 and 1015 s-1
with an average value of 2.6 × 1014 s-1.6 Here, we present
Arrhenius parameters for six new alkoxyamines (Table
1; the Arrhenius parameters were determined from the
kd values at various temperatures using a nonlinear
least-squares (NLLS) method). With the exception of 1h ,
the frequency factors are in the above region.
Our activation energies and frequency factors are
somewhat different from earlier data.4c This may be due
to the well-known and unavoidable error compensation
effect of the activation parameters as discussed in our
previous paper.6,17 To circumvent this problem, the dis-
cussions in the present paper are mainly based on
differences of the homolysis rate constants for the various
alkoxyamines. For those alkoxyamines, where the rate
constant was determined only at a few temperatures, the
activation energies Ea were estimated from the rate
constants using A ) 2.4 × 1014 s-1. The estimated Ea
values given in Table 1 correspond to Ea averaged over
the temperature range measured. Individual values
differed less than 2 kJ ‚mol-1 from the average value
presented in Table 1. In some experiments, the pent-4-
Deter m in a tion of th e Ra te Con sta n t of th e C-O
Bon d Hom olysis. The experimental cleavage rate con-
stants kd were measured using the plateau (eq 1) or the
initial slope (eq 2) of the growing EPR nitroxide signal
in the presence of alkyl radical scavengers such as
dioxygen or 2,2,10,10-tetraperdeuteriomethylisoindolin-
15N-oxyl (TMIO-15ND12) as previously described.6
[nitroxide]∞ - [nitroxide]t
ln
) -kdt
(1)
(2)
(
)
[nitroxide]∞
[nitroxide]t/[nitroxide]∞ ) kdt
The kinetic experiments were carried out in tert-
butylbenzene. We6 and others14 have already shown that
O2 is a reliable alkyl radical scavenger in alkoxyamine
homolysis experiments.15 In the present work, most of
the kinetic experiments were performed with O2 as the
scavenger. Results are reproducible, and rate constants
do not change upon varying the alkoxyamine concentra-
tion. For the phenylsulfanyl-substituted alkoxyamine 1j,
however, slightly different rate constants at different
concentrations were obtained. Probably some side reac-
tions due to the presence of the phenylsulfanyl group
occurred.16 For the nitroxides 5 and 6, the rate constants
(14) (a) Kovtun, G. A.; Aleksandrov, A. L.; Golubev, V. A. Bull. Acad.
Chim. USSR, Div. Chem. 1974, 10, 2115. (b) Howard, J . A.; Tait, J . C.
J . Org. Chem. 1978, 43, 4279. (c) Grattan, D. W.; Carlsson, D. J .;
Howard, J . A.; Wiles, D. M. Can. J . Chem. 1979, 57, 2834. (d) Bon, S.
A. F., Chambard, G.; German, A. L. Macromolecules 1999, 32, 8269.
(15) Under air, the scavenger O2 is present in large excess (6.3 mM)
with respect to the concentration of the released C-centered radical
(<0.1 mM). Clever, H. L.; Battino, R. In Solutions and Solubilities;
Dack, M. J . R., Ed.; J ohn Wiley & Sons: New York, 1975; Vol. 3; Part
1, Chapter 7, p 379.
(16) Indeed, the intensity of the appearing nitroxide signal is weaker
than expected and after several hours a signal of a new nitroxide with
ill-resolved hyperfine splitting was observed.
(17) He´berger, K.; Keme´ny, S.; Vido´czy, T. Int. J . Chem. Kinet. 1987,
19, 171.

C-O Bond Homolysis of Alkoxyamines
J . Org. Chem., Vol. 66, No. 4, 2001 1149
enyl substituent at the benzylic position was replaced by
a methyl group. In general, the replacement of the larger
alkyl substituent by a methyl group leads to a decrease
of the cleavage rate by about 20% (see entries 3 and 4 as
well as entries 23 and 24 in Table 1). To better compare
the cleavage rates of the various alkoxyamines, rate
constants of alkoxyamines with longer alkyl chains were
reduced by 20% and the hypothetical rate constants of
alkoxyamines with methyl substitution are displayed in
Me
Table 1 as kd
.
Effect of th e p-P h en yl Su bstitu en t on th e Clea v-
a ge Ra te. It is well-known that p-phenyl substitutents
affect the reactivity at the benzylic position in various
reactions.18 We therefore studied the effect of the p-
phenyl substituent on the rate constant of the C-O bond
homolysis in TEMPO-styryl derivatives 1a (p-MeO), 1b
(p-Me), 1c (p-H), 1e (p-Br), and 1f (p-MeO2C, Table 1).
We can readily see from Table 1 that the reactivity order
(kd,OMe < kd,H ∼ kd,Me < kd,Br < kd,COOMe) correlates neither
with the expected reactivity trends for a polar transition
state (kd,COOMe (σp,COOMe ) 0.45) < kd,Br (σp,Br ) 0.23) <
F igu r e 2. log(kdMe) for the C-ON bond cleavage in para-
subsituted TEMPO-PhEt (square) and TEMPO-CH(CH3)-
heteroaryl (circles) derivatives versus Hammett coefficients
σp and σa:27 log(kdMe/s-1) ) -3.20((0.03) + 0.75((0.13)σp, r2
19
) 0.92.
kd,H (σp,H ) 0) < kd,Me (σp,Me ) -0.17) < kd,OMe (σp,OMe
)
-0.27))19 nor with the reactivity order based on the
used in the plot).27 One can see that both 1g and
especially the thienyl derivative 1h are out of correlation.
However, the increase of kd upon increasing σa is also
observed in the heteroaryl series. It is known that σa
values for heteroarenes are not always reliable, and for
1g this might explain the deviation from the linearity.27
However, for the thienyl derivative 1h , the rate constant
is far above the expected value, and so far, we have no
explanation for this high rate.
Clea va ge Ra te Con sta n ts of Non ben zylic Alk oxy-
a m in es. We have already studied the effect of the radical
stability of the leaving C-radical on the activation energy
of the C-O bond homolysis in 13 different TEMPO-
derived alkoxyamines.6 A linear correlation with an r2
of 0.86 was obtained if Ea was plotted against the C-H
bond dissociation energy of the corresponding hydrocar-
bon (Ea ) -226 ((43) + 0.97((0.12)BDE(C-H)).6 Cor-
respondingly, log(kd) values at 120 C° obey (eq 3).
•
stability of the released benzylic radical (kd,H (σR,H ) 0)
< kd,Br (σR,Br ∼ 0.012)20 < kd,Me (σR,Me ) 0.015) < kd,OMe
•
•
(σR,OMe ) 0.018) < kd,COOMe (σR,COOMe ) 0.043))21c given
•
•
by the Arnold σR scale.21
•
We believe that polar ground-state effects22 play a role
on the activation energy in these alkoxyamine cleavages.
The differences in reactivity is probably the result of
destabilization of the starting alkoxyamine rather than
stabilization of the radical,23,24 as already suggested by
Wayner,23 Nau22 and Matyjaszewski25 for other radical
reactions. Polar ground-state effects are weak in our
reactions as can be seen from the small slope in Figure
2. Similar results have been presented by Ingold26a and
Mulder.26b
We also studied the cleavage rate in systems where
the aryl substituent is replaced by a heteroaryl group.
With the 2-pyridyl derivative 1g a slightly faster homoly-
sis was observed as compared to most of the correspond-
ing non heteroatom containing aryl substituted alkoxy-
amines (compare entry 7 with entries 1-5 in Table 1).
The largest rate constant was obtained for the 2-thienyl
derivative 1h (entry 8). We also included these two values
in Figure 2 (Hammet σa values for heteroarenes were
log(kd/s-1) ) 38.1((5.6) - 0.11((0.02)BDE(C-H)
(3)
To further corroborate this correlation, four additional
alkoxyamines bearing nonaromatic substituents at the
R position of the alkoxyamine oxygen atom were inves-
tigated (Table 1). All these compounds (1i-l) homolyse
slower than the phenyl-substituted TEMPO derivative
1c. The rate constants were then again correlated with
the corresponding C-H BDEs, which were directly
obtained from the literature: H-C(CH3)3 ) 404.0((1.7)
(18) Creary, X.; Mehrsheikh-Mohammadi, M. E.; McDonald, S. J .
Org. Chem. 1987, 52, 3254.
(19) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
Br•
(20) σR,
is unknown and was estimated according to ref 18.
(21) (a) Dust, J . M.; Arnold, D. R. J . Am. Chem. Soc. 1983, 105, 1221.
(b) Dust, J . M.; Arnold, D. R. J . Am. Chem. Soc. 1983, 105, 6531. (c)
kJ mol-1 28
H-COCH3 ) 360 kJ mol-1 30
(( 6.1) kJ mol-1 31
;
H-CH(CH3)CN ) 375.8((9.6) kJ mol-1 29
;
•
σR -scale is normally used for benzylic radicals, however, Arnold also
showed that for styryl-type radicals the same behaviour is observed:
Arnold, D. R. In Substituent Effects in Radical Chemistry; Viehe, H.
G., J anousek, Z., Mere´nyi, R., Eds.; NATO ASI Series C.; Kluwer
Academy Press: Dordrecht, The Netherlands, 1986; Vol. 189; p 171.
(22) (a) Review: Nau, W. M. J . Phys. Org. Chem. 1997, 10, 445. (b)
Nau, W. M.; Harrer, H. M.; Adam, W. J . Am. Chem. Soc. 1994, 116,
10972.
;
H-CH(CH3)SPh ) 379.0-
.
For nitrile 1l, kd is in fair agreement with the value
predicted according to Equation 3 (predicted: 5.8 × 10-4
(23) Clark, K. B.; Wayner, D. D. M. J . Am. Chem. Soc. 1991, 113,
9363.
(24) (a) Ru¨chardt, C.; Beckhaus, H.-D. Topics Curr. Chem. 1985, 1.
(b) Birkhofer, H.; Beckhaus, H.-D.; Ru¨chardt, C. In Substituent Effects
in Radical Chemistry; Viehe, H. G., J anousek, Z., Mere´nyi, R., Eds.;
NATO ASI Series C.; Kluwer Academy Press: Dordrecht, The Neth-
erlands, 1986; Vol. 189; p 199.
(27) Exner, O. In Correlation Analysis in Chemistry; Chapman, N.
B., Shorter, J ., Eds.; Plenum Press: New York, 1978; p 439.
(28) Berkowitz, J .; Ellison, G. B.; Gutman, D. J . Phys. Chem. 1994,
98, 2744.
(29) King, K. D.; Goddard, R. D. J . Phys. Chem. 1976, 80, 546.
(30) Fossey, J .; Lefort, D.; Sorba, J . In Free Radicals in Organic
Chemistry; Wiley: New York, 1995.
(25) Qiu, J .; Matyjaszewski, K. Macromolecules 1997, 30, 5643.
(26) (a) Pratt, D. A.; Wright, J . C.; Ingold, K. U. J . Am. Chem. Soc.
1999, 121, 4877. (b) Laarhoven, L. J . J .; Born, J . G. P.; Arends, I. W.
C. E.; Mulder, P. J . Chem. Soc., Perkin Trans. 2 1997, 2307.
(31) BDE(C-H) was estimated averaging the values from the
equations defined by Ru¨chardt:33 BDE(C-H) ) 1.61aR + 62.4 ((1.6)
H
and BDE(C-H) ) 1.58aâ + 59.4 (( 1.3) with aR ) 16.8 G34 and aâ
H
H
H
) 20.76 G.34

1150 J . Org. Chem., Vol. 66, No. 4, 2001
Marque et al.
from primary and secondary radicals. For tertiary
alkoxyamines, the predicted values are generally too low,
probably because of steric effects. However, alkoxyamines
with the possibility of stabilization by hyperconjugation
are completely out of the correlation.
Solven t Effects a n d Effect of Ca m p h or su lfon ic
Acid (CSA) on th e Ra te Con sta n t of th e C-O Bon d
Hom olysis. It is well-known in nitroxide-mediated living
radical polymerization that the addition of about 10%
CSA leads to increased polymerization rates.36 Scaiano
reported that CSA decreases the rate of the reaction of
the benzyl radical with TEMPO by about a factor of 2.37
However, little is known about the effect of CSA on the
rate of the C-O bond rupture.38 We therefore decided to
study the C-O bond homolysis of TEMPO-styryl com-
pound 1c in the presence of varying amounts of CSA. The
rate constant was determined at 130 °C in tert-butylben-
zene using 10-4 M alkoxyamine and 0, 0.25, 0.8, and 1.6
equiv of CSA, respectively. TEMPO is rather stable under
these conditions. Thus, in the presence of oxygen with
0.25, 0.8, and 1.6 equiv of TEMPO under the conditions
applied in the kinetic experiments, the half-life of TEMPO
is above 25 h. In the absence of oxygen, similar results
were obtained with 0.25 and 0.8 equiv of CSA. With 1.6
equiv, the half-life of TEMPO is 16 h. In our kinetic
experiments, 95% conversion is obtained after 35 min.
Thus, a steady-state concentration (∼10-4 M) of free
TEMPO was reached before any significant depletion of
TEMPO could have occurred.
It turned out that CSA has no significant effect on the
homolysis rate. Without added CSA, a rate constant of
1.6 × 10-3 s-1 was measured, and the same rate constant
was obtained when the reaction was conducted in the
presence of 0.25 and 1.6 equiv of CSA, respectively. A
similar rate constant (1.9 × 10-3 s-1, within experimental
error) was obtained for the reaction using 0.8 equiv of
CSA. We therefore conclude that the effect of CSA in
nitroxide-mediated living radical polymerization is mainly
to partially remove TEMPO39 in a rather slow process.
Moad and Rizzardo reported that the rate of the C-O
bond homolysis is increasing upon increasing the solvent
polarity.40 We measured the rate of the C-O bond
cleavage of alkoxyamine 2c in the polar solvent system
(t-butylbenzene/t-BuOH ) 1:1) and compared the data
with previously reported values for the analogous reac-
tion of 2b in tert-butylbenzene. In agreement with the
earlier results,40 the reaction was about two times faster
for the polar solvent mixture (2b: k(373) (t-BuPh) ) 1.9 ×
10-3 s-1; 2c: k(373)Me (t-BuPh/t-BuOH)41 ) 4.0 × 10-3 s-1).
Furthermore, the homolysis of 1c at 120 °C was 2.3 times
faster in chlorobenzene than in tert-butylbenzene (k(393)
(t-BuPh) ) 5.2 × 10-4 s-1; k(393) (ClPh) ) 1.2 × 10-3 s-1).
This points to a polar transition state of the homolysis
(vide infra). Furthermore, in polar protic solvents inter-
F igu r e 3. Rate constants log(kd) for the C-ON bond cleavage
of TEMPO derivatives of trialkylhydroxylamines vs BDE-
(C-H)ofthecorrespondinghydrocarbon: (9)tertiaryalkoxyamines,
(() secondary alkoxyamines, (b) primary alkoxyamines, (f)
other alkoxyamines.
s-1; measured: 3.4 × 10-4 s-1). However, for the tertiary
alkoxyamine 1k , the predicted value is too low (pre-
dicted: 4.6 × 10-7 s-1; measured: 1.0 × 10-5 s-1). On
the other hand, for the alkoxyamines 1j (PhS substituent;
32
predicted: 2.6 × 10-4 s-1; measured: 4.1 × 10-8 s-1
)
and 1i (acyl substituent; predicted: 3.2 × 10-2 s-1
;
measured: 1.1 × 10-9 s-1) kd’s calculated according to
eq 3 are too high. For the tertiary alkoxyamine 1k , steric
relief may account for the lowering of the activation
energy. Further, it is not surprising that 1j does not
correlate well with the BDE of the corresponding alkane
since Mulder already reported very high Ea’s for other
R-heteroatom-substituted alkoxyamines (R-alkoxy- as
well as for R-ethylaminyl systems),35 and hyperconjuga-
tion probably accounts for the unusual high activation
energy in these cases. Thus, in 1j the oxygen lone pair
of the alkoxyamine is delocalized into the σ* orbital of
the C-S-bond, and this may lead to a higher BDE. For
the acyl derivative 1i, the lone pair of the alkoxyamine
oxygen can be delocalized into the π* orbital of the
carbonyl group which leads to a partial double bond
character for the C-O-TEMPO bond and thus to a very
high activation energy for the homolysis, as measured.
In Figure 3 , log(kd) is plotted against the BDEs of the
corresponding alkanes. It includes data from our previous
work6 and 1k and 1l but excluding the acyl derivative 1i
and the sulfur 1j. It leads to eq 4 with r2 ) 0.80, which
is practically identical to eq 3.
log(kd/s-1) ) 35.5((5.5) - 0.11((0.02)BDE(C-H)
(4)
One can readily see from Figure 3 that eq 4 can be
used to predict rather accurate rate constants for the
C-O bond homolysis of TEMPO-alkoxyamines deriving
(36) (a) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer,
G. K.; Saban, M. Macromolecules 1994, 27, 7228. (b) Veregin, R. P.
N.; Odell, P. G.; Michalak, O. M.; Georges, M. K. Macromolecules 1996,
29, 4161. (c) Li, C.; He, J .; Li, L.; Cao, J .; Yang, Y. Macromolecules
1999, 32, 7012.
(32) The additional OH group at the nitroxide has only a small effect
on the rate of the C-O bond homolysis and can therefore not account
for the high activation energy observed: Marque, S.; Fischer, H.
Unpublished results.
(33) Brocks, J . J .; Beckhaus, H.-D.; Beckwith, A. L. J .; Ru¨chardt,
C. J . Org. Chem. 1998, 63, 1935.
(37) Baldovi, M. V.; Mohtat, N.; Scaiano, J . C. Macromolecules 1996,
29, 5497.
(38) Greszta, D.; Matyjaszewski, K. Macromolecules 1996, 29, 5497.
(39) (a) Odell, P. G.; Veregin, R. P. N.; Michalak, L. M.; Georges,
M. K. Macromolecules 1997, 30, 2232. (b) Conolly, T. J .; Scaiano, J . C.
Tetrahedron Lett. 1997, 38, 1133.
(34) Hudson, A.; Root, K. D. J . J . Chem. Soc. B 1970, 656.
(35) Ciriano, M. V.; Korth, H. G.; van Scheppingen, W. B.; Mulder,
P. J . Am. Chem. Soc. 1999, 121, 6375.
(40) Moad, G.; Rizzardo, E. Macromolecules 1995, 28, 8722.
(41) A corrected rate constant was used for proper comparison; see
the text.

C-O Bond Homolysis of Alkoxyamines
J . Org. Chem., Vol. 66, No. 4, 2001 1151
F igu r e 4. Intramolecular H-bonding.
molecular H-bonding may also accelerate the C-O-bond
cleavage.
In tr a m olecu la r Hyd r ogen Bon d in g. Beckwith and
Ingold showed that nitroxides interact with polar protic
solvents via intermolecular hydrogen bonding.42 Recom-
bination rates of various C-centered radicals with TEMPO
are affected by the polarity of the solvent with lower rates
in polar solvents. H-bonding of the solvent with the
nitroxide is responsible for the lowering of the recombi-
nation rates (Figure 4).42 Since the alkoxyamine C-O
bond rupture is a rather slow process (late transition
state) hydrogen bonding may also influence the rate of
the homolysis.43
By introducing an appropriately positioned OH group
onto the alkoxyamine however (see Figure 4), the polarity
of the molecule is altered (polar effect).40 By considering
field effects of the attached substituents we believe that
we can distinguish between polar effects and intramo-
lecular H-bonding. Since steric effects also play an
important role in these processes,6 we will only compare
data from alkoxyamines for which steric effects should
be similar.
Derivative 3a (entry 16), the corresponding hydroxy
compound 6 (entry 20), and the silyloxy derivative 5
(entry 19) all have very similar kd’s for the C-O-bond
rupture (Table 1). At first sight, it seems that there is
no H-bonding effect on the rate constant. However, the
hydroxymethyl group is excerting a much stronger field
effect (σ1 ) 0.11)44,45 than the silyloxymethyl group (σ1
∼0.00)46 and the H-atom (σ1 ) 0.00). Probably, the
stabilization gained by the intramolecular H-bonding in
6 is compensated by the field effect, which in the case of
the OH-substituted alkoxyamine 6 strenghtens the C-O
bond. Therefore, the methoxy-substituted alkoxyamine
4 (σ1(CH3OCH2) ) σ1(HOCH2)) was studied.45 Alkoxyamine
4 was shown to undergo C-O bond rupture about three
times slower than the hydroxy derivative 6 (compare
entries 18 and 20), thus supporting the occurrence of
intramolecular H-bonding in 6.
F igu r e 5. Nitroxides studied by EPR: N-(tert-butyl)-N-(2-
methyl-1-phenylpropyl)-N-oxyl (3′), N-(1,1-dimethyl-2-meth-
oxypropyl)-N-(2-methyl-1-phenylpropyl)-N-oxyl (4′), N-(1,1-
dimethyl-2-[tert-butyldimethylsilanyloxy]propyl)-N-(2-methyl-
1-phenylpropyl)-N-oxyl (5′), N-(1,1-dimethyl-2-hydroxypropyl)-
N-(2-methyl-1-phenylpropyl)-N-oxyl (6′), N-(2-methyl-1-phenyl-
propyl)-N-(1-methyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)-N-oxyl (7′),
N-(2-methyl-1-phenylpropyl)-N-(tris[hydroxymethyl]methyl)-
N-oxyl (8′).
Ta ble 2. EP R P a r a m eter s of th e New Nitr oxid esa
H
b
nitroxide
aN
aâ
g
σ1
3′
4′
5′
6′
7′
8′
14.83
14.45
14.76
14.84
13.81
14.88
2.66
2.76
2.73
2.72
2.72
2.69
2.006
2.006
2.006
2.006
2.006
2.007
Me, -0.01
CH2OMe, 0.11
CH2OSiMe3, 0.00
CH2OH, 0.11
c
c
a
Hyperfine coupling constants are given in G with an error of
b
( 0.05 G. σ1 values are appropriate when the substituent is
bonded to a tetrahedral center (i.e., where inductive (throughbond)
and field (throughspace) effects are dominant and π-delocalization
is minimal). c See text.
ortho ester 7b (compare entries 22 and 25). These results
can be nicely interpreted in terms of intramolecular
H-bonding. To provide additional evidence for the in-
tramolecular H-bonding in these systems we decided to
study the free nitroxides by EPR spectroscopy.
EP R Hyp er fin e Cou p lin g Con sta n ts. The various
nitroxides 3′-8′ studied are presented in Figure 5. Hy-
H
perfine coupling constants aN and aâ were measured
after in situ generation of the nitroxide by thermolysis
(120 °C) of deoxygenated solutions of the corresponding
alkoxyamine (4-6, 8a ) in tert-butylbenzene.47 In Table 2
the data of the various new nitroxides are summarized.48
Furthermore, σ1-values (field effect) of the various sub-
stituents of the nitroxides are also included.44,45
Furthermore, alkoxyamine 7a homolyses about 40
times slower than triol 8a (compare entries 21 and 23,
field effects in 7a and 8a should be very similar). Also
for the tertiary alkoxyamines 7b and 8c the same
behavior was observed. Thus, the C-O bond homolysis
in the H-bond forming triol 8c is 66 times faster than in
Nitroxides have two different resonance structures (see
A and B in Figure 6).49 Polar solvents as well as hydrogen
bonding stabilize structure B which leads to an increase
of aN.45,49,50 Intramolecular H-bonding will also induce a
change in the conformation and consequently a change
(42) Beckwith, A. L. J .; Bowry, V. W.; Ingold, K. U. J . Am. Chem.
Soc. 1992, 114, 4983.
(43) (a) Matyjaszewski, K.; Gaynor, S.; Greszta, D.; Mardare, D.;
Shigemoto, T. J . Phys. Org. Chem. 1995, 8, 306. (b) Matyjaszewski,
K.; Gaynor, S.; Greszta, D.; Mardare, D.; Shigemoto, T. Macromol.
Symp. 1995, 98, 73.
H
45
in aâ
.
However, for the nitroxides studied herein,
(44) Charton, M. In Progress in Physical Organic Chemistry; Taft,
R. W., Ed.; Wiley: New York, 1987; Vol. 16; p 287. Positive σ1 values
indicate electron-withdrawing substituents whereas negative σ1’s
define electron-donating groups, with respect to the H-atom as the
internal standard (H: σ1 ) 0).
(47) This in situ nitroxide generation is very useful for obtaining
EPR data of rather unstable nitroxides.
(48) EPR parameters of 3′, generated by reacting isopropyl radicals
with phenyl N-tert-butyl nitrone, have already been reported, and are
in good agreement with our data. Maillard, Ph.; Massot, J . C.;
Giannotti, C. J . Organomet. Chem. 1978, 159, 219.
(45) Haire, D. L.; Oehler, V. M.; Krygsman, P. H.; J anzen, E. G. J .
Org. Chem. 1988, 53, 4535.
(46) σ1-value for Me3SiOCH2 ) 0.00.19 We assume that the TBDM-
SOCH2 group induces as similar field effect than the Me3SiOCH2 group.
(49) J anzen, E. G. In Topics in Stereochemistry; Allinger, E. G., Eliel,
E. L., Eds.; Wiley-Interscience: New York, 1971; Vol. 6, p 177.

1152 J . Org. Chem., Vol. 66, No. 4, 2001
Marque et al.
TEMPO-mediated polymerizations.51 In addition, het-
eroaryl-substituted vinyl compounds are predicted to be
suitable monomers for nitroxide-mediated living free
radical polymerization.52
Furthermore, we suggest a correlation by which rate
constants for the C-O bond cleavage of TEMPO-derived
alkoxyamines can be predicted from the C-H BDEs of
the corresponding alkanes. Moreover, we show that the
addition of CSA, which is often used as an additive in
polymerization,36 has no effect on the rate of the C-O
bond rupture in TEMPO-styryl alkoxyamine 1c. Polar
solvents are shown to increase the rate of the bond
homolysis.
Finally, we present EPR and kinetic evidence that
alkoxyamines derived from nitroxides which are capable
of intramolecular H-bonding undergo C-O bond cleavage
faster than the corresponding non-H-bond-forming ana-
logues. The concept of intramolecular H-bonding is very
important for the design of new alkoxyamines for which
the bond homolysis should occur under much milder
conditions. Experiments along this line are underway.
F igu r e 6. Two resonance structures of a nitroxide.
hydrogen bonding will not lock the conformation around
H
N-Câ, and therefore no change of aâ is occurring (Table
2). No significant differences of aN exists between 3′ (aN
) 14.83 G), 5′ (aN ) 14.76 G), and 6′ (aN ) 14.84 G). This
result does not necessarily exclude the occurrence of
intramolecular H-bonding in 6′ since J anzen pointed out,
that electron-withdrawing substituents (field effect, posi-
tive σ1 value) will stabilize structure A45 and in turn lead
to a smaller aN hyperfine coupling constant. We believe
that the H-bonding effect in 6′ is compensated by the field
effect. To clarify this point, we also studied the methyl
ether 4′, where H-bonding is impossible and the field
effect is very similar to the corresponding value in 6′.
Indeed, a much smaller aN value (14.45) was measured
as compared to 6′ (aN ) 14.84 G). This supports our
assumption of the formation of an intramolecular H-bond
in nitroxides of this type.
Exp er im en ta l Section
We also studied the EPR data of 8′ and compared the
value with the corresponding protected, non-H-bond-
forming nitroxide 7′. In agreement with the formation
of an intramolecular H-bond in 8′, a much higher aN value
(14.88) was obtained than for the non-H-bond-forming
nitroxide 7′ (aN ) 13.81 G). These results support that
the rate accelerations of the C-O-bond cleavage in
alkoxyamines capable of intramolecular H-bonding (late
transition state with high nitroxide character) reported
in the previous section, are probably caused by the
interaction of the HO groups with the nitroxide oxygen
atom.
Gen er a l Meth od s. All reactions were carried out in oven-
dried glassware under an argon atmosphere. Tetrahydrofuran
(THF) and benzene (PhH) were freshly distilled from sodium/
benzophenone under argon. Melting points are uncorrected.
IR spectra were recorded using an FTIR apparatus. Mass
spectra were obtained by EI, ESI, or MALDI methods. Flash
column chromatography was performed using Fluka silica gel
60 (40-63 µm). Elemental analyses were performed by the
Microanalytical Laboratory of the Laboratorium fu¨r Orga-
nische Chemie, ETH-Zu¨rich. Experimental setup for the
kinetic EPR experiments has previously been described.6
Gen er a l P r oced u r e (GP 1) for th e P r ep a r a tion of th e
Alk oxya m in es via Nu cleop h ilic Su bstitu tion . To a su-
pension of TEMPO in H2O was added calcium L-ascorbate
dihydrate. The suspension was stirred at rt for 10-15 min
until all of the TEMPO was consumed. The reaction mixture
was then extracted twice with Et2O. The combined organic
phases were dried (MgSO4) and evaporated to afford 1-hy-
droxy-2,2,6,6-tetramethylpiperidine. The 1-hydroxy-2,2,6,6-
tetramethylpiperidine was dissolved under Ar in THF and
added to a suspension of NaH in THF at rt. After the mixture
was stirred for 30 min, a solution of the bromide or mesylate
in THF was added. The resulting reaction mixture was heated
to reflux and stirred for 10-20 h. H2O was added, and the
mixture was extracted twice with Et2O. The combined organic
phases were dried (MgSO4) and evaporated. Purification by
FC afforded the pure alkoxyamine.
Gen er a l P r oced u r e (GP 2) for th e P r ep a r a tion of th e
Alk oxya m in es via th e Ma tyia szew sk i Meth od .12 The
benzylic bromide, nitroxide, Cu powder, Cu(OTf)2, and 4,4′-
di-tert-butyl-2,2′-bipyridyl were suspended under Ar in ben-
zene (sealed tube). The reaction mixture was stirred at 65-
70 °C for 6-20 h. The solids were then removed by filtration
(washing with Et2O). Purification by FC afforded the pure
alkoxyamine.
2,2,6,6-Tetr am eth yl-1-(1-(4-m eth oxyph en yl)h ex-5-en oyl-
oxy)p ip er id in e (1a ). According to GP1 with TEMPO (344 mg,
2.20 mmol), H2O (15 mL), Ca-ascorbate (864 mg, 2.20 mmol),
1-bromo-1-(4-methoxyphenyl)-5-hexene (250 mg, 0.93 mmol)
in THF (1 mL), NaH (92 mg, 60%, 2.30 mmol) in THF (3 mL)
for 14 h. Purification by FC (Et2O/pentane ) 1:100) afforded
1a , 74 mg (23%). IR (CHCl3): 3005 w, 2934 s, 1610 m, 1512 s,
Con clu sion s
In this work, we report the synthesis and the kinetics
of the C-O bond cleavage of various new alkoxyamines.
We present homolysis rate constants in a series of para-
substituted TEMPO-styryl compounds: TEMPO-CH-
(CH3)C6H5X (1a (p-MeO), 1b (p-Me), 1d (p-H), 1e (p-Br),
and 1f (p-MeO2C, Table 1)). The reactivity order 1f (p-
MeO2C) > 1e (p-Br) > 1d (p-H) > 1b (p-Me) > 1a (p-
MeO) can be understood by assuming a polar ground-
state effect.22 Furthermore, rate constants for the C-O
bond cleavage of R-heteroaryl-substituted secondary
alkoxyamines are discussed. It turned out, that by
replacing the phenyl group of the TEMPO-styryl deriva-
tive 1c by a heteroaryl group (f 1g (2-pyridyl), 1h (2-
thienyl)) a higher reactivity of the modified alkoxyamine
is observed.
These results are especially important for nitroxide-
mediated living free radical polymerizations. A fast C-O
bond cleavage of the alkoxyamine (the initator or the
“dormant” polymer, respectively) leads to an efficient
polymerization.4 Thus, vinylstyrenes bearing electron-
withdrawing substituents at the para position (π-accep-
tors) such as p-alkoxycarbonylphenylstyrene or p-cy-
anophenylstyrene should be readily polymerized by
(51) Kazmaier, P. M.; Daimon, K.; Georges, M. K.; Hammer, G. K.;
Veregin, R. P. N. Macromolecules 1997, 30, 2228.
(52) Fischer, A.; Brembella, A.; Lochon, P. Macromolecules 1999,
32, 6069. Bohrisch, J .; Wendler, U.; J aeger, W. Macromol. Rapid.
Commun. 1997, 975.
(50) Haire, D. L.; Kotake, Y.; J anzen, E. G. Can. J . Chem. 1988,
66, 1901. (b) Kotake, Y.; Kuwata, K. Bull. Chem. Soc. J pn. 1982, 55,
3686. (c) J anzen, E. G.; I-Ping Liu, J . J . Magn. Reson. 1973, 9, 510.
(d) J anzen, E. G.; Lopp, I. G. ibid. 1973, 7, 1107.

C-O Bond Homolysis of Alkoxyamines
1463 m, 1035 m, 914 m, 833 s cm-1 1H NMR (400 MHz,
J . Org. Chem., Vol. 66, No. 4, 2001 1153
.
p ip er id in e (1g). According to GP1 with TEMPO (868 mg, 5.56
mmol), H2O (37 mL), Ca-ascorbate (2.19 g, 5.56 mmol),
1-mesyloxy-1-(2-pyridyl)-5-hexene (670 mg, 2.78 mmol) in THF
(2 mL), NaH (222 mg, 60%, 5.56 mmol) in THF (9 mL) for 15
h. Purification by FC (Et2O/pentane ) 1:7) afforded 1g, 214
mg (24%). IR (CHCl3): 2935 s, 1639 w, 1592 m, 1434 m, 1361
CDCl3): δ 7.19 (d, J ) 8.6 Hz, 2 H), 6.83 (d, J ) 8.6 Hz, 2 H),
5.77-5.67 (m, 1 H), 4.96-4.87 (m, 2 H), 4.52 (dd, J 1 ) 4.1 Hz,
J 2 ) 10.0 Hz, 1 H, HCO), 3.80 (s, 3 H, OCH3), 2.12-1.91 (m,
3 H), 1.80-1.70 (m, 1 H), 1.60-0.90 (m, 18 H), 0.52 (s, br, 3
H, CH3). 13C NMR (100 MHz, CDCl3): δ 158.6, 138.9, 136.0,
128.9, 114.3, 113.1, 86.7, 60.0, 59.3, 55.2, 40.4, 35.3, 34.2, 33.8,
25.0, 20.3, 17.2. EI-MS: 189.1 (71), 147.1 (43), 121.0 (100).
Anal. Calcd for C22H35NO2 (345.52): C, 76.48; H, 10.21; N, 4.05.
Found: C, 76.59; H, 10.17; N, 3.86.
1
m, 1133 m, 914 m cm-1. H NMR (400 MHz, CDCl3): δ 8.57-
8.52 (m, 1 H), 7.66-7.62 (m, 1 H), 7.38-7.35 (m, 1 H), 7.16-
7.12 (m, 1 H), 5.76-5.66 (m, 1 H), 4.96-4.86 (m, 2 H), 4.76
(dd, J 1 ) 4.2 Hz, J 2 ) 9.4 Hz, 1 H, HCO), 2.15-1.92 (m, 4 H),
2,2,6,6-Tet r a m et h yl-1-(1-t olylh ex-5-en oyloxy)p ip er i-
d in e (1b). According to GP2 with 1-bromo-1-tolyl-5-hexene
(293 mg, 1.16 mmol), TEMPO (357 mg, 1.39 mmol), Cu (78
mg, 1.22 mmol), Cu(OTf)2 (4.2 mg, 12 µmol), and 4,4′-di-tert-
butyl-2,2′-bipyridyl (13 mg, 0.046 mmol) in benzene (1.74 mL)
for 14 h. Purification by FC (Et2O/pentane ) 1:150) afforded
1b, 95 mg (25%). IR (CHCl3): 2933 s, 1514 m, 1360 m, 1132
1.60-1.10 (m, 17 H), 1.01 (s, 3 H, CH3), 0.43 (s, 3 H, CH3). 13
C
NMR (100 MHz, CDCl3): δ 163.0, 148.7, 138.7, 135.8, 123.0,
122.0, 114.4, 88.1, 60.1, 59.3, 40.4, 34.2, 33.7, 24.6, 20.3, 17.2.
EI-MS: 317.2 (2, [M + 1]+), 160.0 (100). Anal. Calcd for
C20H32N2O (316.49): C, 75.90; H, 10.19; N, 8.85. Found: C,
75.97; H, 9.97; N, 8.84.
2,2,6,6-Tet r a m et h yl-1-(1-(2-t h ien yl)h ex-5-en oyloxy)-
p ip er id in e (1h ). According to GP1 with TEMPO (1.12 g, 7.20
mmol), H2O (48 mL), Ca-ascorbate (2.84 g, 7.20 mmol),
1-bromo-1-(2-thienyl)-5-hexene (960 mg, 3.57 mmol) in THF
(3 mL), NaH (287 mg, 60%, 7.20 mmol) in THF (10 mL) for 14
h. Purification by FC (Et2O/pentane ) 1:100 f 1:10) afforded
1h , 306 mg (27%). IR (CHCl3): 2933 s, 1639 m, 1461 m, 1376
1
m, 972 m, 914 m cm-1. H NMR (400 MHz, CDCl3): δ 7.20-
7.00 (m, 5 H), 5.76-5.66 (m, 1 H), 4.95-4.86 (m, 2), 4.54 (dd,
J 1 ) 9.8 Hz, J 2 ) 4.0 Hz, 1 H, HCO), 2.33 (s, 3 H, CH3), 2.12-
1.90 (m, 3 H), 1.85-1.75 (m, 1 H), 1.60-1.06 (m, 14 H), 0.99
(s, br, 3 H, CH3); 0.56 (s, br, 3 H, CH3). 13C NMR (100 MHz,
CDCl3): δ 140.7, 138.9, 136.4, 128.5, 127.7, 114.3, 87.1, 60.0,
40.5, 35.4, 34.3, 33.8, 24.8, 21.2, 20.3, 17.2. EI-MS: 329.2 (<1,
[M]+), 173.1 (13, [M - TEMPO]+), 105.0 (100).
1
m, 1361 m, 1132 m, 915 m cm-1. H NMR (400 MHz, CDCl3):
δ 7.23-7.21 (m, 1 H), 6.94-6.91 (m, 2 H), 5.80-5.70 (m, 1 H),
5.00-4.90 (m, 2 H), 4.85 (dd, J 1 ) 4.5 Hz, J 2 ) 9.6 Hz, 1 H,
HCO), 2.19-1.96 (m, 3 H), 1.85-1.76 (m, 1 H), 1.60-1.20 (m,
11 H), 1.15 (s, 3 H, CH3), 1.01 (s, 3 H, CH3), 0.61 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ 147.2, 138.7, 125.9, 125.6,
124.4, 114.5, 82.0, 60.2, 59.5, 40.4, 35.8, 34.3, 33.6, 33.0, 25.2,
20.4, 17.2. EI-MS: 165.1 (52, [M - TEMPO]+), 123.1 (79), 97.1
(100). Anal. Calcd for C19H31NOS (321.53): C, 70.98; H, 9.72;
N, 4.36. Found: C, 70.92; H, 9.71; N, 4.25.
2,2,6,6-Tetr a m eth yl-1-(1-p h en ylh ex-5-en oyloxy)p ip er i-
d in e (1d ). According to GP1 with TEMPO (438 mg, 2.80
mmol), H2O (10 mL), Ca-ascorbate (1.194 g, 2.80 mmol),
1-bromo-1-phenyl-5-hexene (300 mg, 1.28 mmol) in THF (1
mL), NaH (112 mg, 60%, 2.80 mmol) in THF (5 mL) for 14 h.
Purification by FC (Et2O/pentane ) 1:130) afforded 1d , 314
mg (80%). IR (CHCl3): 3007 s, 2932 s, 2870 s, 1639 m, 1454 s,
1376 s, 1361 s, 1257 m, 1133 s, 972 s, 915 s cm-1 1H NMR
.
(400 MHz, CDCl3): δ 7.30-7.20 (m, 5 H), 5.76-5.67 (m, 1 H),
4.95-4.87 (m, 2), 4.57 (dd, J 1 ) 9.8 Hz, J 2 ) 4.0 Hz, 1 H, HCO),
2.12-1.90 (m, 3 H), 1.85-1.75 (m, 1 H), 1.60-1.06 (m, 14 H),
0.99 (s, br, 3 H, CH3), 0.53 (s, br, 3 H, CH3). 13C NMR (100
MHz, CDCl3): δ 143.8, 138.8, 127.8, 126.9, 114.4, 87.4, 59.4,
40.5, 35.4, 34.3, 34.1, 33.8, 24.7, 20.3, 17.2. EI-MS: 316.3 (<1,
[M + 1]+), 142.1 (100). Anal. Calcd for C21H33NO (315.50): C,
79.95; H, 10.54; N, 4.44. Found: C, 79.96; H, 10.81; N, 4.49.
2,2,6,6-Tetr a m eth yl-1-(1-(4-br om op h en yl)h ex-5-en oyl-
oxy)p ip er id in e (1e). According to GP1 with TEMPO (313 mg,
2.00 mmol), H2O (10 mL), Ca-ascorbate (785 mg, 2.00 mmol),
1-bromo-1-(4-bromophenyl)-5-hexene (580 mg, 1.82 mmol) in
THF (1 mL), NaH (88 mg, 60%, 2.20 mmol) in THF (3 mL) for
20 h. Purification by FC (Et2O/pentane ) 1:100) afforded 1e,
338 mg (47%). IR (CHCl3): 2934 s, 2870 w, 1639 w, 1485 m,
1376 m, 1361 m, 1132 m, 1071 m, 915 m, 828 m cm-1. 1H NMR
(400 MHz, CDCl3): δ 7.42 (d, J ) 8.4 Hz, 2 H), 7.15 (d, J )
8.3 Hz, 2 H), 5.75-5.65 (m, 1 H), 4.96-4.88 (m, 2 H), 4.54
(dd, J 1 ) 4.0 Hz, J 2 ) 9.8 Hz, 1 H, HCO), 2.09-1.90 (m, 3 H),
1.79-1.71 (m, 1 H), 1.50-0.90 (m, 17 H), 0.52 (s, br, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ 142.8, 138.6, 131.0, 129.5,
120.7, 114.6, 86.7, 60.0, 59.5, 40.4, 35.3, 34.3, 33.7, 24.6, 20.3,
17.2. EI-MS: 378.2 (<1, [M - CH3]+), 142.2 (100). Anal. Calcd
for C21H32NOBr (394.39): C, 63.95; H, 8.18; N, 3.55. Found:
C, 64.16; H, 8.22; N, 3.34.
P h en yla cet ic Acid 2,2,6,6-Tet r a m et h ylp ip er id in -1-yl
Ester (1i). To a supension of TEMPO (1.16 g, 7.44 mmol) in
H2O (50 mL) was added calcium L-ascorbate dihydrate (2.93
g, 7.44 mmol). The suspension was stirred at rt until all of
the TEMPO was consumed. The reaction mixture was then
extracted twice with Et2O. The combined organic phases were
dried (MgSO4) and evaporated to afford 1-hydroxy-2,2,6,6-
tetramethylpiperidine. The 1-hydroxy-2,2,6,6-tetramethylpi-
peridine was dissolved under Ar in THF (2 mL) and added to
a suspension of NaH (298 mg, 7.44 mmol) in THF (10 mL) at
rt. After the mixture was stirred for 30 min, a solution of
phenylacetyl chloride (0.99 mL, 7.44 mmol) was added followed
by a catalytic amount of (dimethylamino)pyridine. The result-
ing reaction mixture was stirred at rt for 15 h. Saturated
aqueous NH4Cl solution was added, and the mixture was
extracted twice with Et2O. After the mixture was washed with
brine, the combined organic phases were dried (MgSO4) and
evaporated. Purification by FC (Et2O/pentane ) 1:5) afforded
1i, 1.84 g (89%). IR (CHCl3): 2980 s, 2941 s, 1752 s, 1117 s,
936 m cm-1 1H NMR (400 MHz, CDCl3): δ 7.36-7.24 (m, 5
.
H), 3.66 (s, 2 H), 1.69-1.36 (m, 6 H), 1.04 (s, 6 H, 2 CH3), 0.94
(s, 6 H, 2 CH3), 1.16 (s, 3 H, CH3), 1.11 (s, 3 H, CH3), 1.09 (s,
6 H, 2 CH3). 13C NMR (100 MHz, CDCl3): δ 170.8, 134.1, 129.4,
128.5, 127.0, 60.1, 40.6, 39.0, 31.7, 20.4, 16.9. EI-MS: 275.2
(1, [M + 1]+), 126.2 (100).
4-[1-(2,2,6,6-Tetr a m eth ylp ip er id in -1-yloxy)eth yl]ben -
zoic Acid Meth yl Ester (1f). According to GP2 with 4-(1-
bromoethyl)benzoic acid methyl ester (338 mg, 1.39 mmol),
TEMPO (426 mg, 1.66 mmol), Cu (93 mg, 1.46 mmol), Cu(OTf)2
(4.9 mg, 0.014 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (15.5
mg, 0.055 mmol) in benzene (2.1 mL) for 14 h. Purification by
FC (Et2O/pentane ) 1:20) afforded 1f, 110 mg (25%). Mp: 88-
89 °C. IR (CHCl3): 2933 m, 1718 s, 1282 s cm-1. 1H NMR (400
MHz): δ 7.98 (d, J ) 8.4 Hz, 2 H), 7.38 (d, J ) 8.1 Hz, 2 H),
4.82 (q, J ) 6.7 Hz, 1 H, HCO), 3.91 (s, 3 H, OCH3), 1.48 (d, J
) 6.7 Hz, 3 H, CH3), 1.60-1.20 (m, 6 H), 1.29 (s, br, 3 H, CH3),
1.17 (s, br, 3 H, CH3), 1.02 (s, br, 3 H, CH3), 0.62 (s, br, 3 H,
CH3).13C NMR (100 MHz): δ 167.2, 151.2, 129.5, 126.5, 83.0,
59.7, 52.0, 40.4, 34.2, 23.6, 20.3, 17.2. ESI-MS: 319.2 (<1,
[M]+), 156.1 (100). Anal. Calcd for C19H29NO3 (319.44): C,
71.44; H, 9.15; N, 4.38. Found: C, 71.38; H, 9.26; N, 4.35.
2,2,6,6-Tet r a m et h yl-1-(1-(2-p yr id yl)h ex-5-en oyloxy)-
4-H yd r oxy-2,2,6,6-t et r a m et h yl-1-((1-p h en ylsu lfa n yl)-
h ex-5-en oyloxy)p ip er id in e (1j). According to GP1 with
4-TBDMSO-TEMPO (2.29 g, 8.0 mmol), H2O (14 mL)/MeOH
(27 mL), Ca-ascorbate (3.49 g, 8.20 mmol), 1-chloro-1-phenyl-
sulfanyl-5-hexene (1.18 g, 5.21 mmol) in THF (2 mL), NaH
(328 mg, 60%, 8.20 mmol) in THF (7 mL) for 16 h. Purification
by FC (Et2O/pentane ) 1:100) afforded TBDMS-potected 1j,
532 mg (21%). TBDMS-protected 1j (530 mg) was dissolved
in THF (14 mL). TBAF‚(H2O)3 (868 mg, 2.75 mmol) was added
and the resulting solution stirred at rt for 3.5 h. After addition
of Et2O, the reaction mixture was washed with aqueous NH4-
Cl and brine. The organic layer was dried (MgSO4) and
evaporated. Purification by FC (Et2O/pentane ) 1:1) afforded
1j, 170 mg (43%). IR (CHCl3): 3603 s, 3442 m br, 2940 s, 1478
1
s, 1378 s, 1365 s, 1045 s, 1026 s, 998 s, 955 s, 916 s cm-1. H
NMR (400 MHz, CDCl3): δ 7.61-7.57 (m, 2 H), 7.31-7.19 (m,
3 H), 5.80-5.70 (m, 1 H), 5.19 (dd, J 1 ) 3.9 Hz, J 2 ) 9.0 Hz,

1154 J . Org. Chem., Vol. 66, No. 4, 2001
Marque et al.
1 H, HCO), 5.00-4.91 (m, 2 H), 3.98-3.95 (m, 1 H), 2.20-
2.10 (m, 3 H), 1.90-1.40 (m, 7 H), 1.34 (s, 3 H, CH3), 1.21 (s,
3 H, CH3), 1.16 (s, 6 H, 2CH3). 13C NMR (100 MHz, CDCl3): δ
138.5, 135.6, 132.2, 128.6, 126.7, 114.7, 94.0, 63.2, 61.0, 60.3,
48.9, 48.7, 34.7, 34.01, 33.96, 33.4, 25.5, 21.64, 21.55. EI-MS:
191.1 (20, [M - TEMPO - OH]+), 110.1 (100). Anal. Calcd for
C21H33NO2S (363.56): C, 69.38; H, 9.15; N, 3.85. Found: C,
69.41; H, 9.30; N, 3.79.
(303.49): C, 79.15; H, 10.96; N, 4.62. Found: C, 79.24; H,
11.02; N, 4.51.
N-ter t-Bu t yl-N-(2-m et h yl-1-p h en ylp r op yl)-O-(1-p h en -
ylh ex-5-en yl)h yd r oxyla m in e (3a ). According to GP2 with
1-bromo-1-phenyl-5-hexene (478 mg, 2.00 mmol), TIPNO13b
(469 mg, 2.13 mmol), Cu (135 mg, 2.11 mmol), Cu(OTf)2 (7 mg,
20 µmol) and 4,4‘-di-tert-butyl-2,2‘-bipyridyl (22 mg, 0.08 mmol)
in benzene (4.0 mL) for 14 h. Purification by FC (Et2O/pentane
) 1:120) afforded 3a as mixture of diastereoisomers (∼1:1),
236 mg (31%). 1H NMR (400 MHz): isomer A, δ 7.50-7.10
(m, 10 H), 5.79-5.66 (m, 1 H), 4.99-4.88 (m, 2 H), 4.73 (dd,
J 1 ) 3.7 Hz, J 2 ) 10.0 Hz, 1 H, PhCHO), 3.41 (d, J ) 10.6 Hz,
1 H, iPrCHPh), 2.40-2.15 (m, 2 H), 2.15-1.70 (m, 3 H), 1.30
(d, J ) 6.4 Hz, 3 H, CH3), 1.30-1.10 (m, 2 H), 0.73 (s, 9 H,
tBu), 0.55 (d, J ) 6.6 Hz, 3 H); isomer B, δ 7.50-7.10 (m, 10
H), 5.79-5.66 (m, 1 H), 4.99-4.88 (m, 2 H), 4.63 (dd, J 1 ) 4.1
Hz, J 2 ) 10.8 Hz, 1 H, PhCHO), 3.24 (d, J ) 10.7 Hz, 1 H,
iPrCHPh), 2.40-2.15 (m, 2 H), 2.15-1.70 (m, 3 H), 1.30-1.10
(m, 2 H), 1.04 (s, 9 H, tBu), 0.80 (d, J ) 6.3 Hz, 3 H, CH3),
0.17 (d, J ) 6.6 Hz, 3 H). 13C NMR (100 MHz): isomer A, δ
143.4, 142.6, 138.7, 130.8, 127.9, 127.5, 127.4, 127.4, 126.8,
126.3, 114.6, 87.7, 72.5, 60.2, 36.1, 33.7, 32.0, 28.3, 24.7, 22.1,
21.2; isomer B, δ 143.2, 142.3, 138.7, 130.9, 128.2, 127.9, 127.6,
127.2, 126.1, 114.5, 87.7, 72.0, 60.8, 35.4, 33.7, 31.3, 28.4, 25.3,
22.1, 20.9. FAB-MS: 380.3 (29, [M + H]+), 178.2 (100). Anal.
Calcd for C26H37NO (379.58): C, 82.27; H, 9.82; N, 3.69.
Found: C, 82.05; H, 9.70; N, 3.66.
1-(1,1-Dim eth ylh ex-5-en yloxy)-2,2,6,6-tetr a m eth ylp ip -
er id in e (1k ). 6-Iodo-6-methyl-1-heptene (238 mg, 1.0 mmol)
and TEMPO (468 mg, 3.0 mmol) were dissolved under Ar in
benzene (10 mL) and heated to reflux. Bu3SnH (0.54 mL, 2.0
mmol) was added in three portions in 60 min intervals. After
complete addition, stirring was continued for 30 min. Removal
of the solvent and purification by FC (Et2O/pentane ) 1:150)
afforded 1k , 63 mg (24%). IR (CHCl3): 2973 s, 2935 s, 1468
m, 1375 s, 1361 s, 1132 s, 916 s cm-1 1H NMR (400 MHz,
.
CDCl3): δ 5.89-5.78 (m, 1 H), 5.04-4.92 (m, 2 H), 2.07-2.01
(m, 2 H), 1.65-1.40 (m, 12 H), 1.24 (s, 6 H, 2 CH3), 1.10 (s, 6
H, 2 CH3), 1.07 (s, 6 H, 2 CH3). 13C NMR (100 MHz, CDCl3):
δ 139.3, 114.2, 78.6, 59.2, 43.1, 40.9, 34.8, 34.5, 26.9, 23.7, 20.7,
17.2. EI-MS: 268.3 (<1, [M + 1]+), 142.1 (100). Anal. Calcd
for C17H33NO (267.45): C, 76.34; H, 12.44; N, 5.24. Found: C,
76.37; H, 12.37; N, 5.24.
2-(2,2,6,6-Tet r a m et h ylp ip er id in -1-yloxy)h ep t -6-en e-
n itr ile (1l). A solution of hept-6-enenitrile (300 mg, 2.75 mmol)
in THF (2 mL) was added at -78 °C to an LDA solution (2.90
mmol) in THF (6 mL). Stirring was continued at -78 °C for
90 min. A suspension of TEMPO (455 mg, 2.90 mmol) and
CuCl2 (389 mg, 2.90 mmol) in THF (10 mL) was added, and
the resulting reaction mixture was allowed to warm to rt
overnight. Saturated aqueous NH4Cl solution was added, and
the biphasic mixture was extracted with Et2O (three times).
The combined organic layers were washed with brine, dried
(MgSO4), and evaporated. Purification by FC (Et2O/pentane
) 1:20) afforded 1l: 485 mg (67%). IR (CHCl3): 2936 s, 2872
N-[1,1-Dim eth yleth yl-2-(m eth oxy)]-N-(2-m eth yl-1-ph en -
ylp r op yl-O-(1-p h en yleth yl)h yd r oxyla m in e (4). According
to GP2 with (1-bromoethyl)benzene (0.41 mL, 3.0 mmol),
TBDMSTIPNO13b (1.12 g, 3.20 mmol), Cu (202 mg, 3.16 mmol),
Cu(OTf)2 (10.6 mg, 0.03 mmol) and 4,4′-di-tert-butyl-2,2′-
bipyridyl (33 mg, 0.12 mmol) in benzene (6.0 mL) for 12 h.
Purification by FC (Et2O/pentane ) 1:150) afforded TBDMS-4
as mixture of diastereoisomers (∼1.5:1): 875 mg (64%). De-
silylation according to the preparation of 6 with TBAF‚(H2O)3
(1.21 g, 3.84 mmol) in THF (60 mL) afforded after purification
by FC (Et2O/pentane ) 1:10) HO-4 (546 mg, 83%). A solution
of the hydroxy compound HO-4 (300 mg, 0.88 mmol) in THF
(2 mL) was added at rt to a suspension of NaH (54 mg, 1.32
mmol) in THF (10 mL). After stirring for 30 min at rt, MeI
(0.17 mL, 2.64 mmol) was added and the resulting mixture
was heated to reflux for 7 h. Saturated aqueous NH4Cl was
added, and the biphasic mixture was extracted three times
with Et2O. The combined organic phases were additionally
washed with brine and dried (MgSO4). Evaporation of the
solvents and purification by FC (Et2O/pentane ) 1:100)
afforded 4, 195 mg (62%). IR (CHCl3): 2980 s, 1451 m, 1104 s
m, 1461 m, 1378 m, 1364 m, 1132 s, 992 m, 918 s cm-1 1H
.
NMR (400 MHz, CDCl3): δ 5.99-5.75 (m, 1 H), 5.08-4.99 (m,
2 H), 4.62 (dd, J 1 ) 5.8 Hz, J 2 ) 7.1 Hz, 1 H, HCO), 2.15-2.10
(m, 2 H), 1.95-1.80 (m, 2 H), 1.80-1.40 (m, 8 H), 1.34 (s, 3 H,
CH3), 1.16 (s, 3 H, CH3), 1.11 (s, 3 H, CH3), 1.09 (s, 6 H, 2
CH3). 13C NMR (100 MHz, CDCl3): δ 137.7, 119.7, 115.4, 74.1,
60.9, 59.9, 40.0, 39.9, 34.1, 33.7, 33.2, 32.3, 24.0, 20.4, 20.3,
17.0. EI-MS: 265.2 (1, [M + 1]+), 156.1 (100). Anal. Calcd for
C
16H28N2O (264.41): C, 72.68; H, 10.67; N, 10.59. Found: C,
72.84; H, 10.36; N, 10.46.
N,N-Di-ter t-bu tyl-O-(1,1-d im eth ylh ex-5-en yl)h yd r oxyl-
a m in e (2a ). 6-Iodo-6-methyl-1-heptene (500 mg, 2.10 mmol)
and N,N-di-tert-butyl nitroxide (756 mg, 5.25 mmol) were
dissolved under Ar in benzene (20 mL) and heated to reflux.
Bu3SnH (1.02 mL, 3.78 mmol) was added in three portions in
60 min intervals. After complete addition, stirring was con-
tinued for 30 min. Removal of the solvent and purification by
FC (Et2O/pentane ) 1:150) afforded 2a , 252 mg (47%). IR
1
cm-1. H NMR (400 MHz, CDCl3): both isomers δ 7.51-7.15
(m, 10 H), 4.95-4.88 (m, 1 H, HC(Ph)O), 3.45 (d, J ) 10.6 Hz,
1 H, CHO, isomer A), 3.32 (d, J ) 10.3 Hz, 1 H, CHO, A), 3.30
(s, 3 H, OCH3, A), 3.15-3.12 (m, 1 H, NCH, B), 2.99 (s, 3 H,
OCH3, B), 2.86 (d, J ) 9.1 Hz, 1 H, CHO, B), 2.64 (d, J ) 9.1
Hz, 1 H, CHO, B), 2.39-2.28 (m, 1 H), 1.63 (d, J ) 6.7 Hz, 3
H, CH3, B), 1.55 (d, J ) 6.6 Hz, 3 H, CH3, A), 1.32 (d, J ) 6.4
Hz, 3 H, CH3, B), 1.12 (s, 3 H, CH3, A), 0.95 (s, 3 H, CH3, B),
0.93 (d, J ) 6.3 Hz, 3 H, CH3, A), 0.90 (s, 3 H, CH3, A), 0.59 (s,
3 H, CH3, B), 0.54 (d, J ) 6.6 Hz, 3 H, CH3, B), 0.22 (d, J )
6.6 Hz, 3 H, CH3, B). 13C NMR (100 MHz, CDCl3): isomer A,
δ 144.8, 142.2, 127.3, 127.2, 127.0, 126.8, 126.4, 126.3, 82.6,
80.1, 72.0, 63.6, 59.0, 31.7, 29.6, 23.8, 23.0, 22.3, 22.1, 21.1;
isomer B, δ ) 145.7, 142.5, 130.9, 128.14, 128.07, 127.4, 126.3,
83.3, 80.2, 72.1, 63.2, 58.7, 32.0, 24.6, 23.7, 22.0, 21.3, 21.2.
Anal. Calcd for C23H33NO2 (355.52): C, 77.70; H, 9.36; N, 3.94.
Found: C, 77.63; H, 9.19; N, 3.73.
1
(CHCl3): 2973 s, 1384 s, 1362 s, 1178 w, 914 s cm-1. H NMR
(400 MHz, CDCl3): δ 5.88-5.76 (m, 1 H), 5.03-4.91 (m, 2 H),
2.06-2.00 (m, 2 H), 1.64-1.45 (m, 4 H), 1.25 (s, 6 H, 2 CH3),
1.21 (s, 18 H). 13C NMR (100 MHz, CDCl3): δ 139.2, 114.2,
79.5, 60.9, 42.8, 34.5, 31.0, 27.0, 23.6. ESI-MS: 256.4 (100,
[M + 1]+).
N ,N -Di-t er t -b u t yl-O-(1-p h e n ylh e x-5-e n yl)h yd r oxyl-
a m in e (2c). According to GP1 with N,N-di-tert-butyl nitroxide
(403 mg, 2.80 mmol), H2O (10 mL), Ca-ascorbate (1.194 g, 2.80
mmol), 1-bromo-1-phenyl-5-hexene (300 mg, 1.28 mmol) in
THF (1 mL), NaH (112 mg, 60%, 2.80 mmol) in THF (5 mL)
for 44 h. Purification by FC (Et2O/pentane ) 1:120) afforded
2c, 185 mg (24%). IR (CHCl3): 2971 s, 2931 s, 1494 m, 1453
N-[2-(ter t-Bu tyldim eth ylsilan yloxy)-1,1-dim eth yleth yl]-
N-(2-m eth yl-1-p h en ylp r op yl-O-(1-p h en ylh ep t-6-en yl)h y-
d r oxyla m in e (5). According to GP2 with 1-bromo-1-phenyl-
6-heptene (359 mg, 1.50 mmol), TBDMSTIPNO13b (560 mg,
1.60 mmol), Cu (101 mg, 1.58 mmol), Cu(OTf)2 (5.3 mg, 15
µmol), and 4,4′-di-tert-butyl-2,2′-bipyridyl (16.5 mg, 0.06 mmol)
in benzene (3.0 mL) for 22 h. Purification by FC (Et2O/pentane
) 1:150) afforded 5 as mixture of diastereoisomers (∼2:1): 605
mg (79%). IR (CHCl3): 2929 s, 2857 m, 1471 m, 1098 s, 913
m, 1386 m, 1362 s, 976 m, 912 s cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.35-7.20 (m, 5 H), 5.76-5.66 (m, 1 H), 4.96-4.87
(m, 2 H), 4.60 (dd, J 1 ) 3.9 Hz, J 2 ) 10.3 Hz, 1 H, HCO), 2.21-
2.12 (m, 1 H), 2.07-1.91 (m, 2 H), 1.83-1.73 (m, 1 H), 1.31 (s,
9 H, t-Bu), 1.20-1.00 (m, 2 H), 0.97 (s, 9 H, t-Bu). 13C NMR
(100 MHz, CDCl3): δ 143.1, 138.8, 128.3, 127.8, 127.1, 114.4,
87.4, 62.1, 61.7, 34.5, 33.8, 30.7, 30.6, 25.1. FAB-MS: 304.3
(25, [M + 1]+), 145.2 (100). Anal. Calcd for C20H33NO
m, 838 s cm-1 1H NMR (400 MHz, CDCl3): both isomers, δ
.

C-O Bond Homolysis of Alkoxyamines
J . Org. Chem., Vol. 66, No. 4, 2001 1155
7.52-7.14 (m, 5 H), 5.81-5.68 (m, 1 H), 4.98-4.87 (m, 2 H),
4.74 (dd, J 1 ) 3.7 Hz, J 2 ) 10.1 Hz, 1 H, HCO, major), 4.64
(dd, J 1 ) 4.0 Hz, J 2 ) 11.1 Hz, 1 H, HCO, minor), 3.55 (d, J )
9.5 Hz, 1 H, H-COSi, minor), 3.47 (d, J ) 10.6 Hz, 1 H,
PhCHN, major), 3.34 (d, J ) 9.5 Hz, 1 H, H-COSi, minor),
3.28 (d, J ) 10.8 Hz, 1 H, PhCHN, minor), 2.98 (d, J ) 9.5
Hz, 1 H, H-COSi, major), 2.87 (d, J ) 9.5 Hz, 1 H, H-COSi,
major); 2.40-2.30 (m, 1 H, minor), 2.30-2.10 (m, 1 H, major),
2.05-1.80 (m, 2 H), 1.50-0.80 (m, 6 H), 1.31 (d, J ) 6.4 Hz, 3
H, CH3, major), 1.10 (s, 3 H, CH3, minor), 0.93 (s, 9 H, tBu,
major), 0.92 (s, 3 H, CH3, major), 0.87 (s, 3 H, CH3, minor),
0.82 (d, J ) 6.3 Hz, 3 H, CH3, minor), 0.79 (s, 9 H, tBu, major),
0.57 (d, J ) 6.6 Hz, 3 H, CH3, major), 0.48 (s, 3 H, CH3, major),
0.17 (d, J ) 6.6 Hz, 3 H, CH3, minor), 0.04 (s, 3 H, CH3, minor),
0.03 (s, 3 H, CH3, minor), -0.21 (s, 3 H, SiCH3, major), -0.26
(s, 3 H, SiCH3, major). 13C NMR (100 MHz, CDCl3): major
isomer, δ 143.4, 142.8, 138.9, 130.7, 128.0, 127.5, 127.2, 126.4,
114.3, 87.4, 72.3, 69.9, 64.2, 36.6, 33.6, 32.1, 28.9, 25.8, 24.8,
23.5, 22.0, 21.3, 20.1, 18.0, -5.5, -5.7; minor isomer, δ 143.2,
142.4, 138.8, 130.8, 128.1, 127.9, 127.2, 126.9, 126.2, 114.3,
87.5, 71.8, 69.8, 64.7, 35.9, 33.6, 31.2, 29.0, 26.0, 25.5, 23.8,
22.1, 20.9, 20.0, 18.3, -5.3, -5.4. FAB-MS: 524.3 (7, [M +
1]+). Anal. Calcd for C33H53NO2Si (523.87): C, 75.66; H, 10.20;
N, 2.67. Found: C, 75.52; H, 10.34; N, 2.69.
2-Hydr oxym eth yl-2-[(2-m eth yl-1-ph en ylpr opyl)(1-ph en -
yleth yl)a m in o]p r op a n -1,3-d iol (8a ). According to GP2 with
(1-bromoethyl)benzene (0.22 mL, 1.6 mmol), PO3TIPNO11 (500
mg, 1.71 mmol), Cu (109 mg, 1.70 mmol), Cu(OTf)2 (5.7 mg,
0.016 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridyl (19.3 mg, 0.12
mmol) in benzene (4.2 mL) for 14 h. Purification by FC (Et2O/
pentane ) 1:10) afforded 7a as mixture of diastereoisomers
(∼1:1), 325 mg (51%).
Ortho ester 7a (320 mg, 0.81 mmol) was dissolved in THF
(7.5 mL). H2O (0.15 mL) and p-TosOH‚H2O (7.6 mg) were
added, and the reaction mixture was stirred for 30 min at rt.
After addition of CH2Cl2, the mixture was washed with
saturated aqueous NaHCO3 and brine (the aqueous phases
were back-extracted (three times) with CH2Cl2). Drying of the
combined organic layers (MgSO4) and evaporation of the
solvents afforded the corresponding diol ester, which was
subsequently dissolved at rt in glyme (5.5 mL). LiOH (1 N,
1.62 mL) was added, and the solution was stirred for 1.5 h at
rt. After addition of saturated aqueous NaHCO3, the mixture
was extracted with CH2Cl2 (three times). Drying of the
combined organic layers (MgSO4) and evaporation of the
solvents afforded the crude product, which was purified by FC
(Et2O/pentane ) 3:1) to yield 8a , 265 mg (88%). Mp: 96.5-98
°C. IR (CHCl3): 3550 br s, 2979 s, 1452 m, 1046 s cm-1.1H
NMR (400 MHz): isomer A, δ 7.70-7.20 (m, 10 H), 5.02 or
4.97 (q, J ) 6.7 Hz, 1 H, CHO), 3.80-3.50 (m, 4 H), 3.40-3.30
(m, 3 H), 2.48 (s, br, OH), 2.50-2.40 (m, 1 H), 2.24 (t, J ) 6.2
Hz, OH), 1.63 (d, J ) 6.6 Hz, 3 H), 1.41 (d, J ) 6.4 Hz, 3 H),
0.60 (d, J ) 6.4 Hz, 3 H); isomer B, δ 7.70-7.20 (m, 10 H),
5.02 or 4.97 (q, J ) 6.7 Hz, 1 H, CHO), 3.80-3.50 (m, 4 H),
3.40-3.30 (m, 3 H), 2.48 (s, br., OH), 2.50-2.40 (m, 1 H), 2.24
(t, J ) 6.2 Hz, OH), 1.71 (d, J ) 6.7 Hz, 3 H), 0.94 (d, J ) 6.3
Hz, 3 H), 0.27 (d, J ) 6.6 Hz, 3 H). 13C NMR (100 MHz): isomer
A, δ 142.9, 141.2, 129.0, 128.5, 128.2, 127.5, 126.9, 126.6, 84.0,
72.9, 68.5, 64.8, 32.2, 23.1, 22.0, 21.4; isomer B, δ 143.1, 140.7,
128.7, 128.2, 128.0, 127.4, 84.1, 72.6, 69.5, 64.1, 31.8, 22.9, 21.9,
21.0. HiResMALDI (M + H): calcd for C22H32NO4 374.2331,
found 374.2316. Anal. Calcd for C22H31NO4 (373.49): C, 70.75;
H, 8.37; N, 3.75. Found: C, 70.71; H, 8.42; N, 3.74.
2-Meth yl-2-[(2-m eth yl-1-p h en ylp r op yl)(1-p h en yl-h ex-
5-en yloxy)a m in o]p r op a n -1-ol (6). TBDMS-6 (200 mg, 0.39
mmol) was dissolved at rt in THF (15 mL) and treated with
TBAF‚(H2O)3 (372 mg, 1.18 mmol). The reaction mixture was
stirred at RT for 14 h. Saturated aqueous NH4Cl was added,
and the biphasic mixture was extracted three times with Et2O.
The combined organic phases were washed with brine and
dried (MgSO4). Evaporation of the solvents and purification
by FC (Et2O/pentane ) 1:10) afforded 6: 132 mg (85%). IR
(CHCl3): 2956 s, 2867 m, 1453 m, 1048 s, 915 m cm-1. 1H NMR
(400 MHz, CDCl3): both isomers, δ 7.55-7.21 (m, 5 H), 5.78-
5.67 (m, 1 H), 5.00-4.89 (m, 2 H), 4.72 (dd, J 1 ) 3.9 Hz, J 2
)
10.5 Hz, 1 H, HCPh), 4.62 (dd, J 1 ) 4.4 Hz, J 2 ) 10.3 Hz, 1 H,
HCPh), 3.63 (d, J ) 10.8 Hz, 1 H, HCO), 3.36 (d, J ) 10.5 Hz,
1 H, HCO), 3.16 (d, J ) 10.6 Hz, 1 H, HCO), 3.13-3.08 (m, 1
H, HC(iPr)), 2.89-2.84 (m, 2 H, HC(iPr), HCO), 2.60-1.70 (m,
5 H), 1.34 (d, J ) 6.3 Hz, 3 H, CH3), 1.27 (s, 3 H, CH3), 1.40-
1.00 (m, 2 H), 1.10 (s, 3 H, CH3), 0.72 (d, J ) 6.2 Hz, 3 H,
CH3), 0.68 (s, 3 H, CH3), 0.58 (d, J ) 6.6 Hz, 3 H, CH3), 0.38
(s, 3 H, CH3), 0.19 (d, J ) 6.6 Hz, 3 H, CH3). 13C NMR (100
MHz, CDCl3): both isomers, δ 142.3, 142.1, 141.6, 141.2, 138.4,
130.6, 128.2, 128.2, 128.1, 128.0, 127.7, 127.5, 127.2, 126.9,
126.7, 114.8, 114.7, 87.6, 87.5, 72.8, 72.0, 70.1, 69.6, 63.9, 63.3,
36.0, 35.5, 33.6, 33.5, 31.9, 31.1, 25.7, 25.1, 24.8, 22.2, 21.9,
21.3, 20.8, 20.1, 19.4, 18.0. FAB-MS: 396.3 (100, [M + 1]+).
Anal. Calcd for C26H37NO2 (395.58): C, 78.94; H, 9.43; N, 3.54.
Found: C, 78.78; H, 9.47; N, 3.36.
2-Hydr oxym eth yl-2-[(2-m eth yl-1-ph en ylpr opyl)(1-ph en -
ylh ep t-6-en yloxy)a m in o]p r op a n e-1,3-d iol (8b). According
to GP2 with PO3TIPNO11 (470 mg, 1.61 mmol), 1-bromo-1-
phenyl-6-heptene (380 mg, 1.50 mmol), 4,4′-di-tert-butyl-2,2′-
bipyridyl (16.5 mg, 0.06 mmol), Cu (102 mg, 1.59 mmol) and
Cu(OTf)2 (5.3 mg, 0.015 mmol) in benzene (4 mL) for 13 h.
Purification by FC (Et2O/pentane ) 1:15) afforded the corre-
sponding ortho ester, 384 mg (55%, dr ) 1:1). The ortho ester
(360 mg, 0.77 mmol) was dissolved in THF (7 mL) at 0 °C.
H2O (0.14 mL) and p-TosOH‚H2O (7.2 mg) were added, and
the reaction mixture was stirred for 1 h at 0 °C. After addition
of CH2Cl2 the mixture was washed with saturated aqueous
NaHCO3 and brine (the aqueous phases were backextracted
(three times) with CH2Cl2). Drying of the combined organic
layers (MgSO4) and evaporation of the solvents afforded the
corresponding diol ester, which was subsequently dissolved at
rt in glyme (5.2 mL). 1 N LiOH (1.54 mL) was added, and the
solution was stirred for 1.5 h at rt. After addition of saturated
aqueous NaHCO3 the mixture was extracted with CH2Cl2
(three times). Drying of the combined org. layers (MgSO4) and
evaporation of the solvents afforded the crude product which
was purified by FC (Et2O/pentane ) 3:1) to yield 8b, 303 mg
N -(2-Me t h yl-1-p h e n ylp r op yl)-N -(1-m e t h yl-2,6,7-t r i-
oxabicyclo[2.2.2]oct-4-yl)-O-(1,1-dimethylhex-5-enyl)hydroxyl-
a m in e (7b). 6-Iodo-6-methyl-1-heptene (238 mg, 1.0 mmol)
and PO3TIPNO11 (584 mg, 2.0 mmol) were dissolved under
Ar in benzene (20 mL) and heated to reflux. Bu3SnH (0.27 mL,
1.0 mmol) was added in 3 portions in 60 min intervals. After
complete addition, stirring was continued for 30 min. Removal
of the solvent and purification by FC (Et2O/pentane ) 1:10)
afforded 7b: 216 mg (54%). IR (CHCl3): 2954 s, 1402 s, 1299
s, 1132 s, 1062 m, 874 s cm-1. 1H NMR (400 MHz, CDCl3, two
isomers due to chirality center at nitrogen): δ (both isomers)
7.50-7.48 (m, 1 H), 7.36-7.22 (m, 4 H), 5.87-5.76 (m, 1 H),
5.06-4.96 (m, 2 H), 4.05-4.02 (m, 3 H, CHO, isomer A), 4.01-
3.94 (m, 3 H, CHO, isomer B), 3.87-3.84 (m, 3 H, CHO, isomer
B), 3.53-3.50 (m, 3 H, CHO, isomer A), 2.93 (d, J ) 10.4 Hz,
1 H, Ph CHN), 2.32-2.00 (m, 3 H), 1.70-1.00 (m, 16 H), 0.86
(d, J ) 6.3 Hz, 3 H, CH3(iPr), isomer A), 0.46 (d, J ) 6.7 Hz,
3 H, CH3(iPr), isomer B). 13C NMR (100 MHz, CDCl3, both
isomers): δ 140.0, 138.7, 138.58, 138.57, 131.0, 128.4, 128.0,
127.8, 127.3, 114.83, 114.80, 108.6, 108.2, 81.7, 81.4, 75.3, 73.6,
68.8, 67.8, 58.3, 58.2, 42.7, 42.3, 34.28, 34.25, 31.2, 29.4, 27.52,
27.49, 26.2, 25.4, 24.2, 23.7, 22.93, 22.89, 22.8, 22.3, 21.6, 21.1.
HiResMALDI (M + H): calcd for C24H38NO4 404.2801, found
404.2793.
1
(89%, dr ) 1:1). H NMR (400 MHz): both isomers, δ 7.70-
7.20 (m, 10), 5.79-5.66 (m, 1 H), 4.98-4.88 (m, 2 H), 4.82 (dd,
J 1 ) 4.1 Hz, J 2 ) 11.2 Hz, 1 H, HC(Ph)O, isomer A), 4.70 (dd,
J 1 ) 4.1 Hz, J 2 ) 11.0 Hz, 1 H, HC(Ph)O, B), 3.80-3.60 (m, 4
H), 3.30-3.20 (m, 3 H), 2.60-2.10 (m, 4 H), 2.10-1.70 (m, 3
H), 1.50-0.90 (m, 3 H), 1.41 (d, J ) 6.4 Hz, 3 H), 0.84 (d, J )
6.2 Hz, 3 H), 0.61 (d, J ) 6.6 Hz, 3 H), 0.24 (d, J ) 6.6 Hz, 3
H). 13C NMR (100 MHz): both isomers, δ 141.3, 141.2, 140.9,
140.7, 138.6, 138.5, 130.3, 128.91, 128.89, 128.4, 128.33,
128.29, 128.0, 127.9, 127.6, 127.5, 127.3, 114.6, 114.5, 88.5,
88.3, 73.1, 72.5, 69.6, 68.3, 64.8, 64.0, 35.53, 35.48, 33.5, 32.2,
31.7, 28.7, 28.6, 25.3, 25.1, 22.0, 21.8, 20.9. FAB-MS: 442.2
(100, [M + H]+). Anal. Calcd for C27H39NO4 (441.61): C, 73.44;
H, 8.90; N, 3.17. Found: C, 73.20; H, 8.91; N, 3.22.

1156 J . Org. Chem., Vol. 66, No. 4, 2001
Marque et al.
2-H yd r oxym et h yl-2-[(2-m et h yl-1-p h en ylp r op yl)(1,1-
d im eth ylh ex-5-en yl)a m in o]p r op a n e-1,3-d iol (8c). Ortho
ester 7b (216 mg, 0.53 mmol) was dissolved in THF (7.5 mL).
H2O (0.15 mL) and p-TosOH‚H2O (7 mg) were added, and the
reaction mixture was stirred for 30 min at rt. After addition
of CH2Cl2, the mixture was washed with saturated aqueous
NaHCO3 and brine (the aqueous phases were back-extracted
(three times) with CH2Cl2). Drying of the combined organic
layers (MgSO4) and evaporation of the solvents afforded the
corresponding diol ester, which was subsequently dissolved at
rt in glyme (5.5 mL). LiOH (1 N, 1.62 mL) was added, and the
solution was stirred for 1.5 h at rt. After addition of saturated
aqueous NaHCO3 the mixture was extracted with CH2Cl2
(three times). Drying of the combined organic layers (MgSO4)
and evaporation of the solvents afforded the crude product
which was purified by FC (Et2O/pentane ) 5:1) to yield 8c,
2.50 (m, 4 H), 2.20-1.40 (m, 6 H), 1.45 (s, 3 H, CH3), 1.41 (s,
3 H, CH3), 1.20 (d, J ) 6.3 Hz, 3 H, CH3(iPr)), 0.47 (d, J ) 6.7
Hz, 3 H, CH3(iPr)); δ minor isomer, 7.54-7.23 (m, 5 H), 5.87-
5.76 (m, 1 H), 5.06-4.96 (m, 2 H), 4.18 (d, J ) 11.6 Hz, 1 H,
PhCHN), 3.75-3.50 (m, 6 H, CHO), 2.65-2.50 (m, 4 H), 2.20-
1.40 (m, 6 H), 1.47 (s, 3 H, CH3), 1.34 (d, J ) 6.5 Hz, 3 H,
CH3(iPr)), 0.80 (d, J ) 6.4 Hz, 3 H, CH3(iPr)). 13C NMR (100
MHz, CDCl3): δ major isomer, 140.9, 138.4, 130.9, 127.8, 127.2,
115.0, 83.1, 72.6, 69.7, 64.3, 42.6, 34.3, 31.8, 27.3, 26.2, 24.5,
22.4, 21.3; δ minor isomer, 139.7, 138.4, 128.2, 127.5, 115.0,
82.7, 75.8, 70.9, 63.1, 42.5, 34.2, 31.6, 27.3, 25.7, 24.0, 23.2,
21.2. HiResMALDI (M + H): calcd for C22H38NO4 380.2801,
found 380.2788.
Ack n ow led gm en t. We are grateful to Prof. Dr.
Dieter Seebach for generous support and thank the
Swiss Science National Foundation for funding.
1
153 mg (74%). H NMR (400 MHz, CDCl3, two isomers due to
chirality center at nitrogen, dr ≈ 3:1): δ major isomer, 7.54-
7.23 (m, 5 H), 5.87-5.76 (m, 1 H), 5.06-4.96 (m, 2 H), 3.75-
3.50 (m, 6 H, CHO), 3.45 (d, J ) 10.4 Hz, 1 H, Ph CHN), 2.65-
J O001190Z