Radical carboaminoxylation with subsequent Pd-catalyzed intramolecular allylation for the construction of five- and six-membered carbocycles

Article abstract of DOI:10.1055/s-2006-942416

Regioselective intermolecular radical carboaminoxylation using various alkoxyamines are presented. These environmentally benign tin-free radical additions can either be performed under microwave conditions at 180 °C or by using conventional heating at 125

Full text of DOI:10.1055/s-2006-942416

PAPER
2129
Radical Carboaminoxylation with Subsequent Pd-Catalyzed Intramolecular
Allylation for the Construction of Five- and Six-Membered Carbocycles
R
egioselective In
i
termole
r
cular Ra
t
dical
C
e
a
rboaminoxylatio
S
n
chulte, Armido Studer*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8336523; E-mail: studer@uni-muenster.de
Received 29 April 2006
Dedicated to Prof. Dr. Dieter Hoppe on the occasion of his 65th birthday
1) CH2=CH(CH2)2Br, Zn or
CH2=CH(CH2)2Br, Mg
OAc
Abstract: Regioselective intermolecular radical carboaminoxyla-
tion using various alkoxyamines are presented. These environmen-
tally benign tin-free radical additions can either be performed under
microwave conditions at 180 °C or by using conventional heating at
CHO
R
R
2) Ac2O, pyridine,
DMAP
n
R = Me, Ph, i-Pr
1a (85%, R = Me, n = 1)
1b (88%, R = Ph, n = 1)
1c (82%, R = i-Pr, n = 1)
1d (61%, R = i-Pr, n = 2)
125 °C. Intermolecular Trost–Tsuji allylation of the carboaminoxy-
lation products provide five- and six-membered carbocycles in
moderate to good yields. The radical addition/Pd-catalyzed in-
tramolecular allylation can be performed as one-pot process.
Scheme 2 Synthesis of the radical acceptors 1a–d.
Key words: radical chemistry, nitroxides, allylations, Pd catalysis
prepared from bromobut-3-ene was used for the synthesis
of allyl acetate 1d.
About five years ago, we introduced the use of TEMPO-
derived alkoxyamines (TEMPO = 2,2,6,6-tetramethylpi-
peridin-N-oxyl radical) as C-radical precursors for envi-
ronmentally benign radical cyclization reactions.1,2 Since
that initial report, this chemistry has been extended to in-
termolecular radical alkoxyamine additions which we call
radical carboaminoxylations (Scheme 1).3 Moreover, we
have shown that if TEMPO as nitroxide component in the
alkoxyamine is replaced by a sterically highly demanding
nitroxide, alkoxyamine additions and isomerizations oc-
cur far more efficiently.4 We also presented initial results
on sequential radical carboaminoxylation/ionic Horner–
Wadsworth–Emmons reactions.5 These alkoxyamine ad-
ditions and isomerizations are controlled by the Persistent
Radical Effect (PRE).6,7 Herein we present first results on
radical carboaminoxylation with subsequent Pd-catalyzed
Trost–Tsuji allylation8 for the construction of five- and
six-membered carbocycles.9
Radical carboaminoxylations were studied with
alkoxyamines 2 and 3a,3b (Figure 1), which were pre-
pared according to published procedures from the corre-
sponding nitroxides in excellent yields (81–97%, see
experimental part).4
O
O
O
O
R1
R2
MeO
OMe
O
N
O
N
OH
2
3a (R1 = R2 = OMe)
3b (R1 = t-Bu, R2 = OEt)
Figure 1 Various alkoxyamines used.
R1
R2
Reaction of TEMPO-derived alkoxyamine 2 with olefin
1a (5 equiv) in DMF (0.07 M) at 135 °C for 3 days afford-
ed adduct 4a in 30% yield as a 1:1 mixture of diastereo-
isomers. Importantly, radical addition occurs highly
regioselectively at the terminally unsubstituted double
bond. The allyl acetate moiety necessary for the planned
transition metal mediated cyclization remains untouched.
Moreover, products deriving from malonyl radical addi-
tion with subsequent 5-endo cyclization and TEMPO-
trapping were not identified. Importantly, this radical ad-
dition reaction can be conducted without the use of any
radical initiator. As previously reported alkoxyamine ad-
ditions can be conducted efficiently under microwave ir-
radiation.3,5,10–12 Indeed, reaction under microwave
irradiation at 180 °C in DMF (sealed tube) for just 10 min-
utes provided 4a in an improved yield (55%, Scheme 3).
O
N
N
R3
R2
O
∆
R1
R3
Scheme 1 Intermolecular alkoxyamine addition using TEMPO as
nitroxide component.
The radical acceptors 1a–c were readily prepared in high
yield from the corresponding aldehydes under Refor-
matsky conditions using Zn and allyl bromide with subse-
quent acylation (Scheme 2). The Grignard reagent
SYNTHESIS 2006, No. 13, pp 2129–2138
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-942416; Art ID: C02106SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

2130
B. Schulte, A. Studer
PAPER
Even under these harsh conditions, addition occurred ex- and diphenylphosphinoethane (DPPE) as ligand in DMF
clusively at the terminal double bond. All further experi- at 110 °C to carbocycle 7a (66%, Scheme 4). Excellent
ments using TEMPO-derived alkoxyamines were yields under these conditions were also obtained for the
therefore performed under microwave conditions. Similar cyclization of alkoxyamines 4b,4c to give 7b (95%) and
yields were obtained in the reaction of alkoxyamine 2 7c (83%), respectively. In analogy, malonates 5a–c and
with olefins 1b,1c to give the corresponding carboamin- 6a–c were successfully transformed to the corresponding
oxylation products 4b,4c (Scheme 3). Unexpectedly, car- 5-membered carbocycles 8a–c and 9a–c in moderate to
boaminoxylation of 2 with homologous radical acceptor excellent yields (Scheme 4). Alkoxyamines 8a–c were
1d did not work.13 As expected based on previous results isolated as 1:1 mixture of isomers. All four possible iso-
with alkoxyamines bearing a sterically highly hindered ni- mers of alkoxyamines 9a–c were identified.17
troxide such as 3a,3b, carboaminoxylation occurs far
more efficiently as compared to the TEMPO-mediated
processes and microwave induced heating is not neces-
O
N
sary. Hence, reaction of alkoxyamines 3a,3b with olefins
1a–c in DMF (1.0 M) for 2 hours at 125 °C afforded ad-
ducts 5a–c and 6a–c in good to excellent yields as mixture
of isomers (74–96%).14 Even for the homologous acceptor
1d where reaction with 2 did not work, a satisfactory yield
in the carboaminoxylation was achieved (→ 5d: 53%)
(Scheme 3).
1) NaH, 0 °C
DMF, 20 min
MeO2C
MeO2C
4a–c
2) Pd(OAc)2, DPPE
110 °C, 2 h
R
7a (66%, R = Me)
7b (95%, R = Ph)
7c (83%, R = i-Pr)
N
1a–c (5 equiv)
MeO2C
O
OAc
2
O
N
OH
DMF (0.07 M)
180 °C, MW, 10 min
MeO2C
R
1) NaH, 0 °C
DMF, 20 min
R1
R2
4a (55%, R = Me)
4b (56%, R = Ph)
4c (52%, R = i-Pr)
5a–c,
6a–c
2) Pd(OAc)2, DPPE
110 °C, 2 h
R3
OH
8a (99%, R1 = R2 = CO2Me, R3 = Me)
8b (62%, R1 = R2 = CO2Me, R3 = Ph)
8c (62%, R1 = R2 = CO2Me, R3 = i-Pr)
9a (39%, R1 = CO2Et, R2 = t-Bu, R3 = Me)
9b (13%, R1 = CO2Et, R2 = t-Bu, R3 = Ph)
9c (81%, R1 = CO2Et, R2 = t-Bu, R3 = i-Pr)
N
1a–d (5 equiv)
R1
O
OAc
3a,b
DMF (1.0 M)
125 °C, 2 h
R2
R3
n
Scheme 4 Formation of five-membered carbocycles by intramole-
cular Trost–Tsuji allylation.
5a (83%, R1 = R2 = CO2Me, R3 = Me, n = 1)
5b (96%, R1 = R2 = CO2Me, R3 = Ph, n = 1)
5c (96%, R1 = R2 = CO2Me, R3 = i-Pr, n = 1)
5d (53%, R1 = R2 = CO2Me, R3 = i-Pr, n = 2)
6a (74%, R1 = t-Bu, R2 = CO2Et, R3 = Me, n = 1)
6b (77%, R1 = t-Bu, R2 = CO2Et, R3 = Ph, n = 1)
6c (82%, R1 = t-Bu, R2 = CO2Et, R3 = i-Pr, n = 1)
As expected based on the literature report,16 cyclization
can also be achieved for substrates leading to six-mem-
bered rings as shown for the transformation of malonate
5d to alkoxyamine 10 (57%, diastereomeric ratio = 1:1,
Scheme 5).
Scheme 3 Carboaminoxylations of 1a–d with various alkoxy-
amines under different conditions.
Intramolecular Trost–Tsuji allylation using alkoxyamine
4a as model compound was studied next. Various cycliza-
tion protocols were tested. Good results were obtained in
refluxing THF using NaH as a base and Pd(PPh3)4 (5%) as
catalyst.15 Cyclization product 7a was isolated in 83%
yield as a 1:1 mixture of diastereoisomers. However, in
order to open the door for sequential radical/transition-
metal-catalyzed processes, an allylation protocol which
works in DMF had to be found. Poli and co-workers re-
ported on successful intramolecular Pd-catalyzed allyla-
tions in DMF.16 Using their protocol we were able to
transform malonate 4a with NaH as base and Pd(OAc)2
OH
N
O
1) NaH, 0 °C
DMF, 20 min
MeO2C
MeO2C
5d
2) Pd(OAc)2, DPPE
110 °C, 2 h
10 (57%)
Scheme 5 Formation of six-membered carbocycles by intramolecu-
lar Trost–Tsuji allylation.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Regioselective Intermolecular Radical Carboaminoxylation
2131
(up to 15 bar) which contain pressure-control valves. An advanced
temperature control system from MLS allowing direct contactless
temperature monitoring was used. The microwave power is contin-
uously and dynamically adjusted to follow a defined temperature
profile.
Finally, we tested whether these radical addition/Pd-cata-
lyzed cyclization reactions can be conducted as one-pot
processes. To this end, alkoxyamine 2 was reacted under
microwave conditions with olefin 1a in DMF for 10 min-
utes at 180 °C. The mixture was allowed to cool to room
temperature and NaH was added followed by the Pd-cata-
lyst. Renewed heating to 110 °C for 2 hours afforded
alkoxyamine 7a in only 10% yield. Using olefin 1b as rad-
ical acceptor a slightly better yield was observed. Product
7b was isolated in 29% yield. The reason for the low
yields may be found in the rather inefficient initial car-
boaminoxylation. Indeed, one-pot radical addition/transi-
tion-metal-mediated cyclization using the efficient
alkoxyamine 3a with olefin 1a delivered the correspond-
ing carboaminoxylation/cyclization product 8a in 60%
yield. The sequence comprises reaction of 3a with 1a in
DMF at 125 °C for 2 hours with subsequent deprotonation
with NaH (20 min) followed by addition of Pd catalyst
and renewed heating for 2 hours. Using this protocol, one-
pot reaction of malonate 3a with olefin 1b provided five-
membered carbocycle 8b in 48% yield. In analogy, the
six-membered heterocycle 10 was successfully prepared
in 41% using the one-pot protocol.
Solvents were purified and dried by standard methods. Compounds
sensitive to air and moisture were handled under argon by means of
Schlenk techniques.
Radical Acceptors 1a–c; General Procedure (GP 1)
To a stirred DMF solution of the a,b-unsaturated aldehyde (1.0
equiv, 1.4 M in DMF), were added allyl bromide (1.04–1.10 equiv)
and zinc powder (1.07–1.10 equiv) at r.t. An exothermic reaction
started within 15 min and ceased in 45 min. After addition of sat. aq
NH4Cl, the mixture was extracted with Et2O (3 ×). The combined
organic layers were dried (MgSO4). After careful evaporation of the
solvent, the crude volatile alcohol was treated with pyridine (2.0
equiv) and Ac2O (2.0 equiv). 4-Dimethylaminopyridine (DMAP,
catalytic amount) was added and the mixture was stirred overnight
at r.t. The reaction was stopped upon addition of aq HCl (1 M solu-
tion) and the mixture was extracted with Et2O (3 ×). The combined
organic layers were washed with aq 1 M HCl and brine, and dried
(MgSO4). After removal of the solvent in vacuo the residue was pu-
rified by FC.
(2E)-1-Allylbut-2-enyl Acetate (1a)
According to GP 1, crotonaldehyde (3.50 mL, 42.8 mmol) and allyl
bromide (3.88 mL, 44.6 mmol) in DMF (30 mL) were treated with
zinc powder (3.0 g, 46.0 mmol). The resulting alcohol was acetylat-
ed by adding pyridine (6.92 mL, 85.6 mmol), Ac2O (8.04 mL, 85.6
mmol) and a catalytic amount of DMAP. FC (Et2O–pentane, 1:40)
yielded the desired acetate 1a (5.62 g, 85%).
In conclusion, we have shown that nitroxide-mediated in-
termolecular radical carboaminoxylation can be conduct-
ed under microwave conditions in the presence of allyl
acetates. The radical addition occurs highly regioselec-
tively at the terminally unsubstituted double bond in
dienes. Importantly, these radical additions can be con-
ducted under environmentally benign tin-free conditions.
The carboaminoxylation products can be cyclized in an
intramolecular Trost–Tsuji allylation to provide five- and
IR (film): 2942, 1735, 1372, 1233, 1018, 965, 918 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.81–5.64 (m, 2 H, CH=CH2,
CH=CHCH3), 5.43 (ddq, J = 15.3, 7.3, 1.6 Hz, 1 H, CH=CHCH3),
5.29–5.20 (m, 1 H, CHOAc), 5.11–5.02 (m, 2 H, CH=CH2), 2.34–
six-membered carbocyles in moderate to excellent yields. 2.28 (m, 2 H, CH2), 2.02 (s, 3 H, COCH3), 1.69 (dd, J = 6.5 Hz, 1.6
Hz, 3 H, CH3).
Moreover, the radical addition is a thermal reaction that
13C NMR (75 MHz, CDCl3): d = 166.2 (C), 133.3 (CH), 129.2
(CH), 129.0 (CH), 117.5 (CH2), 73.8 (CH), 38.9 (CH2), 21.1 (CH3),
17.5 (CH3).
MS (ESI): m/z = 177 [M + Na]+.
HRMS (ESI): m/z calcd for C9H14O2 [M + Na]+: 177.0892; found:
occurs with an alkoxyamine and a radical acceptor with-
out using any additional reagents which can possibly dis-
turb the Pd-catalyzed reaction. Hence, the presented
radical addition Pd-catalyzed cyclization reaction can be
performed as a one-pot process. To date, there are only
few reports on sequential radical/transition-metal-mediat-
ed reactions.9,18
177.0886.
1-[(E)-2-Phenylvinyl]but-3-enyl Acetate (1b)
Applying GP 1 to cinnamylaldehyde (1.00 mL, 7.95 mmol), allyl
bromide (0.76 mL, 8.75 mmol) in DMF (5.7 mL) and zinc powder
(572 mg, 8.75 mmol), the crude alcohol obtained was treated with
pyridine (1.42 mL, 17.5 mmol), Ac2O (1.64 mL, 17.5 mmol) and a
catalytic amount of DMAP. The residue was purified by FC (Et2O–
pentane, 1:20) to yield 1b (1.51 g, 88%).
1H NMR (500 MHz, 400 MHz, 300 MHz) and 13C NMR (100 MHz,
75 MHz) spectra were recorded on either a Varian Inova 500, a
Bruker ARX 400 or a Bruker ARX 300 spectrometer. Chemical
shifts (d) in ppm are referenced to the solvent residue peak as an in-
ternal standard. TLC was carried out on Merck silica gel 60 F254
plates; detection by UV or dipping into a solution of KMnO4 (1.5
g), NaHCO3 (5.0 g), and H2O (400 mL) or a solution of
Ce(SO4)2·H2O (10 g), phosphomolybdic acid hydrate (25 g), conc.
H2SO4 (60 mL), and H2O (940 mL), followed by heating. Flash
chromatography (FC) was carried out on Merck or Fluka silica gel
60 (40–63 mm) at about 0.4 bar. IR spectra were recorded on a Dig-
ilab FTS 4000 equipped with a MKII Golden Gate Single Reflec-
tion ATR System. ESI-MS and HRMS were performed using a
Bruker MicroTof. Elemental analyses were performed on a Vario
EL III. The microwave experiments were conducted using profes-
sional laboratory microwave equipment. A MLS-Ethos 1600 Mik-
rowellen System (Milestone) was used for the present studies. The
reactions were run in 40-mL MLS-reaction high-pressure vessels
IR (film): 3028, 1734, 1370, 1230, 1018, 964, 918, 749, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.30 (m, 2 Harom), 7.29–7.23
(m, 2 Harom), 7.22–7.17 (m, 1 Harom), 6.57 (d, J = 16.0 Hz, 1 H,
CHPh), 6.11 (dd, J = 7.1 Hz, 16.0 Hz, 1 H, CH=CHPh), 5.75 (tdd,
J = 7.0, 10.2, 17.2 Hz, 1 H, CH2=CH), 5.65–5.41 (m, 1 H, CHO-
Ac), 5.13–5.02 (m, 2 H, CH=CH2), 2.53–2.38 (m, 2 H, CH2), 2.02
(s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 170.0 (C), 136.2 (C), 133.0 (CH),
132.5 (CH), 128.4 (2 × CH), 127.8 (CH), 127.0 (CH), 126.5
(2 × CH), 117.9 (CH2), 73.6 (CH), 39.0 (CH2), 21.1 (CH3).
MS (ESI): m/z = 239 [M + Na]+.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

2132
B. Schulte, A. Studer
PAPER
HRMS (ESI): m/z calcd for C14H16O2 [M + Na]+: 239.1043; found:
Alkoxyamines 2, 3a,3b; General Procedure (GP 2)
239.1047.
LDA was prepared from diisopropylamine (DIPA, 1.2 equiv) and n-
BuLi (1.6 M in hexane, 1.2 equiv) in DME at –60 °C. After stirring
for 30 min at –60 °C, the 1,3-dicarbonyl compound (1.1 equiv) was
added dropwise. After stirring for another 30 min, the nitroxide
(1.0–1.1 equiv) and anhyd CuCl2 (2.0–3.0 equiv) were added fol-
lowed by stirring for 3 h at 0 °C. The reaction was quenched by the
addition of aq sat. NH4Cl and the aqueous layer was extracted with
Et2O (3 ×). The combined organic layers were dried (MgSO4) and
the solvents were removed in vacuo. FC finally yielded the desired
alkoxyamine.
Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.78; H,
7.51.
(2E)-1-Allyl-4-methylpent-2-enyl Acetate (1c)
According to GP 1, 4-methylpent-2-enal (2.36 mL, 20.3 mmol) and
allyl bromide (1.94 mL, 22.3 mmol) in DMF (30 mL) were treated
with zinc powder (1.46 g, 22.3 mmol). The resulting alcohol was
acetylated by addition of pyridine (3.28 mL, 40.6 mmol), Ac2O
(3.81 mL, 40.6 mmol) and DMAP (cat. amount). FC (Et2O–pen-
tane, 1:40) yielded the desired acetate 1c (3.03 g, 82%).
Dimethyl 2-(2,2,6,6-Tetramethylpiperidine-1-yloxy)malonate
(2)
IR (film): 2961, 1736, 1370, 1233, 1019, 971, 916 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.77–5.60 (m, 2 H, CH=CH2 and
CHvinylic), 5.32 (ddd, J = 1.1, 7.2, 15.6 Hz, 1 H, CHvinylic), 5.27–5.19
(m, 1 H, CHOAc), 5.13–4.98 (m, 2 H, CH=CH2), 2.38–2.19 [m, 3
H, CH(CH3)2, CH2], 2.04–1.98 (m, 3 H, COCH3), 0.96 (d, J = 6.8
Hz, 3 H, CH3), 0.95 (d, J = 6.8 Hz, 3 H, CH3).
According to GP 2, LDA (30.7 mmol), dimethyl malonate (3.20
mL, 27.7 mmol), TEMPO (4.8 g, 30.7 mmol) and CuCl2 (5.60 g,
41.5 mmol) were reacted in DME (120 mL). FC [tert-butyl methyl
ether (TBME)–pentane, 1:4] yielded the alkoxyamine 2 (7.39 g,
84%).
13C NMR (100 MHz, CDCl3): d = 170.0 (C), 141.1 (CH), 133.4
(CH), 124.8 (CH), 117.5 (CH2), 73.8 (CH), 39.1 (CH2), 30.6 (CH),
22.0 (2 × CH3), 21.2 (CH3).
MS (ESI): m/z = 205 [M + Na]+.
HRMS (ESI): m/z calcd for C11H18O2 [M + Na]+: 205.1199; found:
The spectroscopic data are in agreement with those reported in the
literature.4
Dimethyl 2-(2,2,6,6-Tetraethyl-4-hydroxypiperidin-1-
yloxy)malonate (3a)
According to GP 2, LDA (390 mmol), dimethyl malonate (41 mL,
360 mmol), TEMPO (90.0 mg, 390 mmol) and CuCl2 (159 mg, 1.17
mmol) were reacted in DME (2.2 mL). FC (TBME–pentane, 1:3)
yielded the alkoxyamine 3a (137 mg, 97%).
205.1201.
Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.20; H,
10.05.
The spectroscopic data are in agreement with those reported in the
literature.4
(2E)-1-But-3-enyl-4-methylpent-2-enyl Acetate (1d)
3-Butenylmagnesium bromide was prepared by the dropwise addi-
tion of 4-bromobut-1-ene (1.00 mL, 9.85 mmol) to a well-stirred
suspension of Mg turnings (479 mg, 19.7 mmol, 2 equiv) in anhyd
Et2O (15 mL). The mixture was stirred for 1 h and held at reflux for
30 min. 4-Methylpent-2-enal (1.16 mL, 9.85 mmol) was added
dropwise and the mixture was refluxed for another 2 h. After cool-
ing to r.t., the mixture was hydrolyzed with 1 M HCl. The organic
layer was washed with sat. aq NaHSO3, sat. aq NaHCO3 and H2O,
dried (MgSO4) and the solvent was carefully evaporated in vacuo.
The crude volatile alcohol was treated with pyridine (1.59 mL, 19.7
mmol, 2.0 equiv) and Ac2O (1.85 mL, 19.7 mmol, 2.0 equiv).
DMAP (catalytic amount) was added and the mixture was stirred
overnight at r.t. The reaction was stopped upon addition of aq 1 M
HCl and the mixture was extracted with Et2O (3 ×). The organic lay-
er was separated, washed with aq 1 M HCl and brine, and dried
(MgSO4). After removal of the solvent in vacuo the residue was pu-
rified by FC (Et2O–pentane, 1:20) to yield 1d (1.18 g, 61%).
4,4-Dimethyl-3-oxo-2-(2,2,6,6-tetraethyl-4-hydroxypiperidin-1-
yloxy)pentanoic Acid Ethyl Ester (3b)
Applying GP 2, LDA, ethyl pivaloylacetate (123 mL, 689 mmol, 1.1
equiv), TEMPO (143 mg, 627 mmol) and CuCl2 (253 mg, 1.88
mmol, 3 equiv) were reacted in DME (3.6 mL). Purification of the
crude product by FC (Et2O–pentane, 1:3) afforded the alkoxyamine
3b (203 mg, 81%).
IR (film): 3416, 2964, 2880, 1748, 1716, 1465, 1368, 1248, 1183,
1037, 983, 910, 789 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.29 (s, 1 H, CHON), 4.30–4.15
(m, 2 H, OCH2), 4.00–3.85 (m, 1 H, CHOH), 2.33–2.07 (m, 2 H,
CH2), 1.86–1.66 (m, 4 H, 2 × CH2), 1.45–1.21 (m, 7 H, 3 × CH2,
OH), 1.29 (t, J = 7.1 Hz, 1 H, OCH2CH3), 1.20 [s, 9 H, C(CH3)3],
0.98–0.78 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d = 207.8 (C), 167.5 (C), 88.0 (CH),
66.4 (C), 65.9 (C), 62.2 (CH2), 61.5 (CH), 44.2 (C), 39.5 (CH2),
39.5 (CH2), 29.9 (CH2), 29.6 (CH2), 27.2 (3 × CH3), 27.1 (CH2),
26.7 (CH2), 14.0 (CH3), 9.9 (CH3), 9.8 (CH3), 8.3 (CH3), 8.0 (CH3).
IR (film): 2960, 1735, 1370, 1233, 1019, 971, 912 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.79 (tdd, J = 6.6, 10.2, 16.6 Hz,
1 H, CH=CH2), 5.67 (ddd, J = 0.6, 6.5, 15.5 Hz, 1 H, CHi-Pr), 5.31
(ddd, J = 1.3, 7.3, 15.4 Hz, 1 H, CH=CHi-Pr), 5.25–5.16 (m, 1 H,
MS (ESI): m/z = 821 [2 M + Na]+, 422 [M + Na]+, 400 [M + H]+.
HRMS (ESI): m/z calcd for C22H41NO5 [M + Na]+: 422.2877;
CHOAc), 5.05–4.94 (m,
2
H, CH=CH2), 2.27 [dqd,
J = 1.1, 6.7, 13.4 Hz, 1 H, CH(CH3)2], 2.09–2.00 (m, 2 H, CH2),
2.03 (s, 3 H, COCH3), 1.80–1.57 (m, 2 H, CH2), 0.97 [d, J = 6.8 Hz,
6 H, CH(CH3)2].
13C NMR (100 MHz, CDCl3): d = 170.2 (C), 141.3 (CH), 137.7
(CH), 125.1 (CH), 114.9 (CH2), 74.5 (CH), 33.8 (CH2), 30.7 (CH),
29.5 (CH2), 22.1 (2 × CH3), 21.3 (CH3).
MS (ESI): m/z = 219 [M + Na]+.
HRMS (ESI): m/z calcd for C12H20O2 [M + Na]+: 219.1356; found:
found: 422.2866.
Intermolecular Additions of Alkoxyamines 2 to Alkenes 1a–c
under Microwave Irradiation; General Procedure (GP 3)
The alkoxyamine 2 (1.0 equiv) was dissolved in DMF (0.07–0.1 M
solution) and the alkene 1a–c (5.0 equiv) was added under argon.
The solution was heated to 180 °C under microwave irradiation in a
sealed tube for 10 min. The mixture was allowed to cool to r.t. and
after addition of H2O, the mixture was extracted with Et2O (3 ×).
The organic layer was separated and dried (MgSO4). Removal of
the volatiles in vacuo and purification by FC afforded the product.
219.1333.
Anal. Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C, 73.19; H,
10.63.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Regioselective Intermolecular Radical Carboaminoxylation
2133
Dimethyl [(5E)-4-(Acetyloxy)-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)hept-5-enyl]malonate (4a)
According to GP 3, alkoxyamine 2 (200 mg, 696 mmol) and alkene
1a (537 mg, 3.48 mmol) were reacted in DMF (10 mL). FC
(TBME–pentane, 1:15) afforded 4a (167 mg, 55%) as a mixture of
two diastereoisomers (dr = 1:1).
Dimethyl [(5E)-4-(Acetyloxy)-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)-7-methyloct-5-enyl]malonate (4c)
According to GP 3, alkoxyamine 2 (100 mg, 348 mmol) and alkene
1c (317 mg, 1.74 mmol) were reacted in DMF (3 mL). FC (TBME–
pentane, 1:15 → 1:7) afforded 4c (85.6 mg, 52%) as a mixture of
two diastereoisomers (dr = 1:1).
IR (film): 2934, 1735, 1436, 1370, 1234, 1153, 1045, 1018, 963,
944 cm–1.
IR (film): 2956, 2934, 2873, 1733, 1436, 1364, 1239, 1155, 1045,
1018, 972, 943, 909, 729 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.80–5.56 (m, 1 H,
CH=CHCH3), 5.46–5.34 (m, 1 H, CH=CHCH3), 5.32–5.21 (m, 1 H,
CHOAc), 3.92–3.67 [m, 2 H, CHON, CH(CO2Me)2], 3.72 (s, 3 H,
OCH3), 3.71 (s, 3 H, OCH3), 2.58–2.49 (m, 1 H, CHH, single iso-
mer), 2.41–2.32 (m, 1 H, CHH, single isomer), 2.31–2.10 (m, 2 H,
CH2), 2.02 (s, 3 H, COCH3, single isomer), 2.00 (s, 3 H, COCH3,
single isomer), 1.78–1.64 (m, 3 H, CH3), 1.60–1.22 (m, 7 H,
3 × CH2, CHH), 1.19–0.94 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 170.7 (C), 170.1
(C), 169.9 (2 × C), 169.8 (C), 169.7 (C), 129.7 (CH), 129.6 (CH),
129.4 (CH), 129.3 (CH), 75.8 (CH), 75.4 (CH), 73.0 (CH), 72.2
(CH), 60.2 (C), 60.1 (C), 59.5 (C), 59.4 (C), 52.4 (4 × CH3), 48.7
(2 × CH), 40.4 (CH2), 40.2 (CH2), 37.6 (2 × CH2), 34.0 (CH3), 33.9
(CH3), 33.8 (2 × CH3), 33.7 (CH2), 33.2 (CH2), 21.4 (CH3), 21.2
(CH3), 20.6 (CH3), 20.5 (CH3), 17.6 (2 × CH2), 17.3 (2 × CH3).
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.78–5.66 (m, 1 H,
CH=CHi-Pr or CH=CHi-Pr), 5.44–5.22 (m, 2 H, CHOAc,
CH=CHi-Pr or CH=CHi-Pr), 3.91–3.69 [m,
8 H, CHON,
CH(CO2Me)2, 2 × OCH3], 2.57–2.47 (m, 1 H, CHH, single isomer),
2.44–2.35 (m, 1 H, CHH, single isomer), 2.33–2.13 (m, 3 H, CH2,
CHH), 2.03 (s, 3 H, COCH3, single isomer), 2.00 (s, 3 H, COCH3,
single isomer), 1.66–1.21 [m, 7 H, 3 × CH2, CH(CH3)2], 1.15–1.00
(m, 12 H, 4 × CH3), 0.97 [d, J = 6.8 Hz, 6 H, CH(CH3)2].
13C NMR (100 MHz, CDCl3): d (both isomers) = 170.1 (C), 170.0
(C), 169.9 (2 × C), 169.7 (2 × C), 141.5 (2 × CH), 125.3 (CH),
125.2 (CH), 75.7 (CH), 75.5 (CH), 73.1 (CH), 72.3 (CH), 60.1 (C),
59.4 (C), 52.4 (4 × CH3), 48.8 (CH), 48.7 (CH), 40.4 (2 × CH2),
40.2 (2 × CH2), 37.9 (CH2), 37.8 (CH2), 34.2 (2 × CH3), 34.0 (CH3),
33.8 (CH3), 33.7 (CH2), 33.2 (CH2), 30.7 (CH), 30.6 (CH), 22.1
(CH3), 22.0 (2 × CH3), 21.9 (CH3), 21.4 (CH3), 21.3 (CH3), 20.7
(CH3), 20.6 (3 × CH3), 17.3 (2 × CH2).
MS (ESI): m/z = 905 [2 M + Na]+, 464 [M + Na]+, 442 [M + H]+.
HRMS (ESI): m/z calcd for C23H39NO7 [M + Na]+: 464.2619;
MS (ESI): m/z = 961 [2 M + Na]+, 492 [M + Na]+, 470 [M + H]+.
HRMS (ESI): m/z calcd for C25H43NO7 [M + Na]+: 492.2932;
found: 464.2625.
found: 492.2933.
Anal. Calcd for C23H39NO7: C, 62.56; H, 8.90; N, 3.17. Found: C,
62.46; H, 8.86; N, 2.94.
Anal. Calcd for C25H43NO7: C, 63.94; H, 9.23; N, 2.98. Found: C,
63.93; H, 9.21; N, 2.85.
Dimethyl [(5E)-4-(Acetyloxy)-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)-6-phenylhex-5-enyl]malonate (4b)
According to GP 3, alkoxyamine 2 (100 mg, 348 mmol) and alkene
1b (376 mg, 1.74 mmol) were reacted in DMF (3 mL). FC (TBME–
pentane, 1:20 → 1:5) afforded 4b (98.3 mg, 56%) as a mixture of
two diastereoisomers (dr = 1:1).
Intermolecular Additions of Alkoxyamines 3a,3b to Alkenes
1a–d; General Procedure (GP 4)
The alkene 1a–d (5.0 equiv) was added to a 1 M solution of the
alkoxyamine 3a,3b (1.0 equiv) in DMF. The mixture was heated in
a sealed tube to 125 °C for 2 h. The mixture was allowed to cool to
r.t. and after addition of H2O, the mixture was extracted with Et2O
(3 ×). The combined organic layers were dried (MgSO4) and the sol-
vents were removed in vacuo. FC yielded the desired product.
IR (film): 2933, 1734, 1436, 1363, 1232, 1153, 1045, 1017, 964 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 7.40–7.18 (m, 5
Harom), 6.63 (dd, J = 15.9, 1.9 Hz, 1 H, CH=CHPh), 6.14 (dd,
J = 6.4, 16.9 Hz, 1 H, CH=CHPh, single isomer), 6.11 (dd,
J = 6.7, 16.9 Hz, 1 H, CH=CHPh, single isomer), 5.58–5.43 (m, 1
H, CHOAc), 3.99–3.80 (m, 1 H, CHON), 3.80–3.63 [m, 1 H,
CH(CO2Me)2], 3.74 (s, 3 H, OCH3, single isomer), 3.72 (s, 3 H,
OCH3, single isomer), 3.69 (s, 3 H, OCH3, single isomer), 3.66 (s, 3
H, OCH3, single isomer), 2.73–2.60 (m, 1 H, CHH, single isomer),
2.57–2.47 (m, 1 H, CHH, single isomer), 2.37–2.15 (m, 2 H, CH2),
2.07 (s, 3 H, COCH3, single isomer), 2.06 (s, 3 H, COCH3, single
isomer), 1.74–1.23 (m, 7 H, 3 × CH2, CHH), 1.16–0.97 (m, 12 H,
4 × CH3).
13C NMR (100 MHz, CDCl3): d = 170.1 (2 × C), 169.9 (2 × C),
169.8 (C), 169.6 (C), 136.2 (C), 132.9 (CH), 132.7 (CH), 128.5
(2 × CH), 127.9 (CH), 127.5 (CH), 127.4 (CH), 126.5 (2 × CH),
75.7 (CH), 75.3 (CH), 73.0 (CH), 72.0 (CH), 60.1 (2 × C), 59.4
(2 × C), 52.5 (CH3), 52.4 (CH3), 48.7 (2 × CH), 40.4 (2 × CH2),
40.1 (2 × CH2), 37.7 (CH2), 37.6 (CH2), 34.1 (CH3), 33.9 (CH3),
33.8 (2 × CH3), 33.1 (2 × CH2), 21.3 (CH3), 21.2 (CH3), 20.6 (CH3),
20.5 (CH3), 17.3 (CH2).
Dimethyl [(5E)-4-(Acetyloxy)-2-(2,2,6,6-tetraethyl-4-hydroxy-
piperidin-1-yloxy)hept-5-enyl]malonate (5a)
According to GP 4, alkoxyamine 3a (50.0 mg, 139 mmol) and alk-
ene 1a (107 mg, 696 mmol) were reacted in DMF (139 mL). FC
(Et2O–pentane, 1:3) afforded 5a (59.4 mg, 83%) as a mixture of two
diastereoisomers (dr = 1:1).
IR (film): 3445, 2956, 2882, 1735, 1436, 1370, 1333, 1235, 1154,
1038, 966, 941 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.73 (qd,
J = 6.2, 15.2 Hz,
1 H, CH=CHCH3), 5.46–5.33 (m, 1 H,
CH=CHCH3), 5.31–5.12 (m, 1 H, CHOAc), 3.96–3.84 (m, 1 H,
CHON), 3.76–3.60 [m, 8 H, CHOH, CH(CO2Me)2, 2 × OCH3],
2.43–2.06 (m, 4 H, 2 × CH2), 2.06–1.99 (m, 3 H, COCH3), 1.98–
1.21 (m, 16 H, OH, 6 × CH2, CH3), 0.94–0.78 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 170.1 (C), 170.0
(C), 169.8 (2 × C), 169.6 (C), 169.5 (C), 129.7 (CH), 129.5 (CH),
129.3 (2 × CH), 76.1 (CH), 75.2 (CH), 73.0 (CH), 71.8 (CH), 66.3
(2 × C), 62.6 (CH), 52.5 (CH3), 52.4 (CH3), 48.3 (CH), 48.2 (CH),
40.7 (CH2), 40.6 (CH2), 37.7 (CH2), 37.6 (CH2), 33.4 (CH2), 32.6
(CH2), 30.6 (4 × CH2), 30.5 (CH2), 30.4 (CH2), 27.3 (2 × CH2), 27.1
(2 × CH2), 21.3 (CH3), 21.2 (CH3), 17.6 (2 × CH3), 10.3 (CH3), 10.1
(CH3), 8.6 (2 × CH3), 8.2 (2 × CH3).
MS (ESI): m/z = 526 [M + Na]+, 504 [M + H]+.
HRMS (ESI): m/z calcd for C28H41NO7 [M + Na]+:526.2775; found:
526.2778.
Anal. Calcd for C28H41NO7: C, 66.78; H, 8.21; N, 2.78. Found: C,
66.69; H, 8.38; N, 2.66.
MS (ESI): m/z = 536 [M + Na]+, 514 [M + H]+.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

2134
B. Schulte, A. Studer
PAPER
HRMS (ESI): m/z calcd for C27H47NO8 [M + Na]+: 536.3194;
found: 536.3181.
Dimethyl [(6E)-4-(Acetyloxy)-2-(2,2,6,6-tetraethyl-4-hydroxy-
piperidin-1-yloxy)-8-methylnon-6-enyl]malonate (5d)
GP 4 was applied to the reaction of alkoxyamine 3a (100 mg, 278
mmol) with alkene 1d (273 mg, 1.39 mmol) in DMF (139 mL). FC
(Et2O–pentane, 1:3 → 1:1) yielded 5d (81.3 mg, 53%) as a mixture
of two diastereoisomers (dr = 1:1).
Anal. Calcd for C27H47NO8: C, 63.13; H, 9.22; N, 2.73. Found: C,
63.06; H, 9.52; N, 2.53.
Dimethyl [(5E)-4-(Acetyloxy)-2-(2,2,6,6-tetraethyl-4-hydroxy-
piperidin-1-yloxy)-6-phenylhex-5-enyl]malonate (5b)
According to GP 4, alkoxyamine 3a (50.0 mg, 139 mmol) and alk-
ene 1b (150 mg, 696 mmol) were reacted in DMF (139 mL). FC
(Et2O–pentane, 1:2) afforded 3a (77.1 mg, 96%) as a mixture of two
diastereoisomers (dr = 1:1).
IR (film): 3454, 2957, 2880, 1734, 1437, 1371, 1237, 1153, 1017,
972, 914, 733 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.77–5.61 (m, 1 H, CHvinylic),
5.36–5.25 (m, 1 H, CHvinylic), 5.22–5.10 (m, 1 H, CHOAc), 3.96–
3.83 (m, 1 H, CHON), 3.81–3.52 [m, 8 H, CHOH, CH(CO2Me)2,
2 × OCH3], 2.34–1.11 [m, 20 H, OH, CH(CH3)2, 9 × CH2], 2.02 (s,
3 H, COCH3, single isomer), 2.00 (s, 3 H, COCH3, single isomer),
0.98 [d, J = 6.8 Hz, 6 H, CH(CH3)2, single isomer], 0.96 [d, J = 6.8
Hz, 6 H, CH(CH3)2, single isomer], 0.90–0.75 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 170.2 (C), 170.1
(C), 169.8 (C), 169.7 (C), 169.6 (C), 169.5 (C), 141.5 (CH), 141.2
(CH), 125.1 (CH), 125.0 (CH), 74.9 (CH), 74.8 (CH), 73.1 (CH),
71.8 (CH), 66.2 (2 × C), 62.6 (CH), 52.5 (2 × CH3), 52.4 (2 × CH3),
48.3 (CH), 48.2 (CH), 40.7 (CH2), 40.6 (CH2), 40.4 (2 × CH2), 37.8
(CH2), 37.7 (CH2), 32.8 (CH2), 32.7 (CH2), 30.6 (2 × CH), 30.5
(2 × CH2), 30.4 (CH2), 30.3 (CH2), 28.4 (CH2), 28.3 (CH2), 27.3
(2 × CH2), 27.1 (CH2), 27.0 (CH2), 22.0 (2 × CH3), 21.9 (2 × CH3),
21.3 (2 × CH3), 10.3 (CH3), 9.9 (CH3), 8.8 (CH3), 8.7 (CH3), 8.6
(2 × CH3).
1H NMR (300 MHz, CDCl3): d (both isomers) = 7.44–7.04 (m, 5
Harom), 6.61 (dd, J = 15.9, 4.3 Hz, 1 H, CH=CHPh), 6.11 (dd,
J = 7.4, 16.0 Hz, 1 H, CH=CHPh, single isomer), 6.09 (dd,
J = 7.6, 16.2 Hz, 1 H, CH=CHPh, single isomer), 5.57–5.36 (m, 1
H, CHOAc), 3.98–3.78 (m, 1 H, CHON), 3.77–3.43 [m, 2 H,
CHOH, CH(CO2Me)2], 3.73 (s, 3 H, OCH3, single isomer), 3.72 (s,
3 H, OCH3, single isomer), 3.70 (s, 3 H, OCH3, single isomer), 3.65
(s, 3 H, OCH3, single isomer), 2.52–1.15 (m, 17 H, 8 × CH2, OH),
2.07 (s, 3 H, COCH3, single isomer), 2.05 (s, 3 H, COCH3, single
isomer), 1.01–0.79 (m, 12 H, 4 × CH3).
13C NMR (75 MHz, CDCl3): d (both isomers) = 170.1 (2 × C),
169.8 (2 × C), 169.6 (C), 169.5 (C), 136.2 (C), 136.1 (C), 132.9
(CH), 132.7 (CH), 128.5 (2 × CH), 128.0 (CH), 127.5 (CH), 127.0
(CH), 126.6 (2 × CH), 76.0 (CH), 75.1 (CH), 72.0 (CH), 71.7 (CH),
66.3 (2 × C), 62.6 (CH), 52.6 (CH3), 52.5 (CH3), 48.3 (CH), 48.2
(CH), 41.3 (CH2), 41.0 (CH2), 40.6 (CH2), 40.5 (CH2), 37.7 (CH2),
37.6 (CH2), 33.5 (CH2), 32.5 (CH2), 30.6 (2 × CH2), 30.4 (CH2),
27.3 (CH2), 27.1, (CH2), 26.8 (CH2), 21.3 (CH3), 21.2 (CH3), 10.4
(CH3), 10.1 (CH3), 8.7 (CH3), 8.2 (CH3).
MS (ESI): m/z = 578 [M + Na]+, 556 [M + H]+.
HRMS (ESI): m/z calcd for C30H53NO8 [M + Na]+: 578.3663.
Found: 578.3664.
Ethyl (7E)-6-Acetyloxy-2-(2,2-dimethylpropanoyl)-4-(2,2,6,6-
tetraethyl-4-hydroxypiperidin-1-yloxy)non-7-enoate (6a)
According to GP 4, alkoxyamine 3b (81.3 mg, 204 mmol) and alk-
ene 1a (157 mg, 1.02 mmol) were reacted in DMF (204 mL). FC
(Et2O–pentane, 1:3 → 1:2) afforded 6a (84.0 mg, 74%) as a mixture
of four diastereoisomers (ratio = 1:1:1:1).
MS (ESI): m/z = 598 [M + Na]+, 576 [M + H]+.
HRMS (ESI): m/z calcd for C32H49NO8 [M + H]+: 576.3531; found:
576.3532.
Dimethyl [(5E)-4-(Acetyloxy)-2-(2,2,6,6-tetraethyl-4-hydroxy-
piperidin-1-yloxy)-7-methyloct-5-enyl]malonate (5c)
According to GP 4, alkoxyamine 3a (50.0 mg, 139 mmol) and alk-
ene 1c (127 mg, 696 mmol) were reacted in DMF (139 mL). FC
(TBME–pentane, 1:3 → 1:1) afforded 5c (72.2 mg, 96%) as a mix-
ture of two diastereoisomers (dr = 1:1).
IR (film): 3422, 2966, 2881, 1739, 1708, 1464, 1369, 1235, 1175,
1039, 1019, 733 cm–1.
1H NMR (400 MHz, CDCl3): d (all four isomers) = 5.80–5.66 (m, 1
H, CHvinylic), 5.42–5.32 (m, 1 H, CHvinylic), 5.29–5.13 (m, 1 H, CHO-
Ac), 4.36–4.25 (m, 1 H, CHON, two isomers), 4.17–4.06 (m, 2 H,
OCH2), 4.04–3.55 (m, 2 H, CHCO, CHOH, CHON two isomers),
2.52–1.11 [m, 32 H, OH, 8 × CH2, CH2CH3, CHCH3, C(CH3)3],
2.03 (s, 3 H, COCH3, single isomer), 2.01 (s, 3 H, COCH3, single
isomer), 2.00 (s, 3 H, COCH3, single isomer), 1.99 (s, 3 H, COCH3,
single isomer), 0.92–0.82 (m, 12 H, 4 × CH3).
IR (film): 3457, 2958, 2880, 1735, 1436, 1370, 1235, 1152, 1039,
1017, 971, 941, 914 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.74–5.65 (m, 1 H,
CHvinylic), 5.42–5.16 (m, 2 H, CHOAc, CHvinylic), 3.96–3.84 (m, 1 H,
CHON), 3.83–3.55 [m, 8 H, CH(CO2Me)2, CHOH, 2 × OCH3],
2.38–1.16 [m, 18 H, CH(CH3)2, 8 × CH2, OH], 2.03 (s, 3 H,
COCH3, single isomer), 2.00 (s, 3 H, COCH3, single isomer), 0.97
[d, J = 6.8 Hz, 6 H, CH(CH3)2], 0.93–0.82 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 170.0 (2 × C),
169.8 (2 × C), 169.6 (2 × C), 141.5 (CH), 141.4 (CH), 125.4 (CH),
125.0 (CH), 76.2 (CH), 75.4 (CH), 73.1 (CH), 71.9 (CH), 66.3
(2 × C), 62.7 (CH), 52.5 (2 × CH3), 52.4 (2 × CH3), 48.3 (2 × CH),
40.9 (2 × CH2), 40.7 (2 × CH2), 37.9 (CH2), 37.8 (CH2), 33.4 (CH2),
32.6 (CH2), 30.7 (2 × CH2), 30.6 (2 × CH), 30.4 (2 × CH2), 27.3
(2 × CH2), 22.1 (CH3), 22.0 (CH3), 21.9 (2 × CH3), 21.4 (CH3), 21.3
(CH3), 8.7 (CH3), 8.6 (CH3).
13C NMR (100 MHz, CDCl3): d (all four isomers) = 210.0 (C),
209.9 (C), 209.1 (C), 209.0 (C), 170.1 (C), 170.0 (3 × C), 169.5
(2 × C), 169.3 (2 × C), 129.7 (2 × CH), 129.5 (CH), 129.4 (CH),
129.3 (2 × CH), 129.2 (CH), 129.1 (CH), 76.8 (CH), 76.4 (CH),
76.3 (CH), 75.4 (CH), 73.2 (CH), 72.8 (CH), 72.1 (CH), 72.0 (CH),
66.4 (C), 66.1 (C), 66.0 (C), 65.7 (C), 62.7 (CH), 62.6 (CH), 61.2
(2 × CH2), 61.0 (2 × CH2), 50.0 (CH), 49.9 (CH), 49.0 (CH), 48.9
(CH), 45.4 (2 × C), 45.3 (C), 45.2 (C), 41.3 (CH2), 41.1 (CH2), 40.8
(2 × CH2), 40.7 (CH2), 40.5 (CH2), 38.2 (2 × CH2), 38.1 (CH2), 37.7
(CH2), 35.0 (CH2), 33.9 (CH2), 33.8 (CH2), 33.0 (CH2), 30.7 (CH2),
30.6 (2 × CH2), 30.5 (CH2), 30.4 (CH2), 27.3 (CH2), 27.2 (CH2),
26.5 (2 × CH3), 26.3 (CH3), 26.2 (CH3), 21.3 (2 × CH3), 21.2
(2 × CH3), 17.6 (2 × CH3), 14.0 (2 × CH3), 13.9 (2 × CH3), 8.9
(2 × CH3), 8.5 (CH3), 8.4 (CH3), 8.3 (CH3), 8.0 (CH3).
MS (ESI): m/z = 564 [M + Na]+, 542 [M + H]+.
HRMS (ESI): m/z calcd for C29H51NO8 [M + Na]+: 564.3507;
found: 564.3497.
MS (ESI): m/z = 576 [M + Na]+, 554 [M + H]+.
HRMS (ESI): m/z calcd for C31H55NO7 [M + Na]+: 576.3871;
found: 576.3878.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Regioselective Intermolecular Radical Carboaminoxylation
2135
Ethyl (7E)-6-Acetyloxy-2-(2,2-dimethylpropanoyl)-4-(2,2,6,6-
tetraethyl-4-hydroxypiperidin-1-yloxy)-8-phenyloct-7-enoate
(6b)
GP 4 was applied to the reaction alkoxyamine 3b (64.4 mg, 161
mmol) and alkene 1b (174 mg, 806 mmol) in DMF (161 mL). FC
(Et2O–pentane, 1:3) afforded 6b (76.7 mg, 77%) as a mixture of
four diastereoisomers (ratio = 1:1:1:1).
33.5 (CH2), 32.7 (CH2), 30.5 (2 × CH2), 30.3 (CH2), 30.3 (2 × CH),
30.1 (CH2), 30.0 (2 × CH2), 27.0 (2 × CH2), 26.2 (2 × CH3), 26.0
(CH3), 25.8(CH3), 21.7 (3 × CH3), 21.6 (3 × CH3), 21.1 (CH3), 21.0
(2 × CH3), 20.9 (CH3), 13.7 (2 × CH3), 13.6 (2 × CH3), 8.6
(2 × CH3), 8.2 (2 × CH3).
MS (ESI): m/z = 604 [M + Na]+, 582 [M + H]+.
HRMS (ESI): m/z calcd for C33H59NO7 [M + Na]+: 604.4184.
IR (film): 3412, 2965, 2880, 1738, 1707, 1464, 1369, 1234, 1163,
1039, 749, 734, 695 cm–1.
Found: 604.4189.
1H NMR (400 MHz, CDCl3): d (all four isomers) = 7.40–7.20 (m, 5
Cyclization of Alkoxyamines 4–6; General Procedure (GP 5)
A solution of the acyclic substrate 4–6 (1.0 equiv) in DMF (~ 0.06
M solution), under argon was cooled in a ice-water bath. NaH (60%
dispersion in mineral oil, 1.1 equiv) was added and the solution was
stirred at r.t. for 30 min. An anhyd solution of Pd(OAc)2 (5 mol%)
and DPPE (10 mol%) in DMF (~ 0.5 mL) was added. Afterwards
the mixture was heated at 110 °C for 2 h. The reaction was stopped
by the addition of NH4Cl (25 wt% aq solution) followed by extrac-
tion of the aqueous layer with Et2O (3 ×). The combined organic
layers were dried (MgSO4) and the solvent was removed in vacuo.
FC yielded the pure compounds.
Harom), 6.62 (d, J = 15.9 Hz, 1 H, CHPh, two isomers), 6.64 (d,
J = 15.9 Hz, 1 H, CHPh, two isomers), 6.22–6.05 (m, 1 H,
CH=CHPh), 5.57–5.38 (m, 1 H, CHOAc), 4.34 (m, 1 H, CHON,
two isomers), 4.19–3.99 (m, 2 H, OCH2, CHON two isomers),
3.98–3.63 (m, 2 H, CHOH, CHCO), 2.65–1.07 [m, 29 H, OH,
8 × CH2, CH2CH3, C(CH3)3], 2.08 (s, 3 H, COCH3, single isomer),
2.07 (s, 3 H, COCH3, single isomer), 2.06 (s, 3 H, COCH3, single
isomer), 2.04 (s, 3 H, COCH3, single isomer), 0.99–0.78 (m, 12 H,
4 × CH3).
13C NMR (100 MHz, CDCl3): d (all four isomers) = 210.0 (C),
209.9 (C), 209.1 (C), 209.0 (C), 170.1 (2 × C), 170.0 (2 × C), 169.6
(C), 169.5 (C), 169.4 (C), 169.3 (C), 136.4 (C), 136.3 (2 × C), 139.2
(C), 132.9 (CH), 132.8 (CH), 132.7 (CH), 132.5 (CH), 128.5
(2 × CH), 128.4 (CH), 127.9 (2 × CH), 127.8 (3 × CH), 127.7 (CH),
127.4 (CH), 127.2 (CH), 126.6 (3 × CH), 76.8 (CH), 76.5 (CH),
76.3 (CH), 75.4 (CH), 73.2 (CH), 72.8 (CH), 72.0 (CH), 71.9 (CH),
66.5 (2 × C), 62.7 (CH), 61.3 (2 × CH2), 61.1 (2 × CH2), 50.1 (CH),
49.9 (CH), 49.1 (CH), 48.9 (CH), 45.5 (2 × C), 45.3 (C), 45.2 (C),
40.9 (CH2), 40.8 (CH2), 40.5 (CH2), 38.3 (2 × CH2), 37.8 (CH2),
33.9 (CH2), 32.9 (CH2), 30.9 (2 × CH2), 30.8 (2 × CH2), 30.7
(2 × CH2), 30.6 (CH2), 27.3 (2 × CH2), 26.5 (2 × CH3), 26.3 (CH3),
26.2 (CH3), 21.3 (2 × CH3), 21.2 (2 × CH3), 14.0 (3 × CH3), 13.9
(CH3), 9.0 (CH3), 8.9 (CH3), 8.6 (CH3), 8.5 (CH3).
Dimethyl 2-[(1E)-Prop-1-enyl]cyclopentane-4-(2,2,6,6-tetra-
methylpiperidin-1-yloxy)-1,1-dicarboxylate (7a)
GP 5 was applied to the reaction of alkoxyamine 4a (110 mg, 250
mmol), NaH (11.2 mg, 280 mmol), Pd(OAc)2 (2.8 mg, 12.5 mmol)
and DPPE (10.0 mg, 25.0 mmol) in DMF (3 mL). FC (TBME–pen-
tane, 1:20) yielded 7a (63 mg, 66%) as a mixture of two diastereo-
isomers [dr (cis/trans) = 1:1].
IR (film): 2933, 1732, 1435, 1359, 1261, 1212, 968 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.59–5.26 (m, 2 H,
CH=CHCH3, CH=CHCH3), 4.46 (ddd, J = 11.1, 7.0, 4.2 Hz, 1 H,
CHON, single isomer), 4.27–4.15 (m, 1 H, CHON, single isomer),
3.73 (s, 3 H, OCH3, single isomer), 3.71 (s, 3 H, OCH3, single iso-
mer), 3.65 (s, 3 H, OCH3, single isomer), 3.63 (s, 3 H, OCH3, single
isomer), 3.49–3.39 (m, 1 H, CHCH=CH, single isomer), 3.07 (ddd,
J = 7.5, 7.5, 9.3 Hz, 1 H, CHCH=CH, single isomer), 2.80 (dd,
J = 7.0, 14.3 Hz, 1 H, CHH, single isomer), 2.60–2.45 (m, 1 H,
CHH), 2.39–2.28 (m, 1 H, CHH, single isomer), 2.23 (ddd,
J = 14.4, 4.5, 1.1 Hz, 1 H, CHH, single isomer), 2.17–2.08 (m, 1 H,
CHH, single isomer), 1.98–1.86 (m, 1 H, CHH, single isomer),
1.79–1.68 (m, 1 H, CHH, single isomer), 1.68–1.58 (m, 3 H, CH3),
1.52–1.22 (m, 6 H, 3 × CH2), 1.22–0.93 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 172.5 (C), 172.2
(C), 171.2 (C), 171.1 (C), 130.1 (CH), 129.8 (CH), 127.1 (CH),
126.9 (CH), 85.5 (CH), 85.0 (CH), 63.3 (C), 62.1 (C), 59.5 (2 × C),
52.6 (CH3), 52.5 (CH3), 52.4 (CH3), 52.0 (CH3), 46.5 (CH), 45.6
(CH), 41.4 (CH2), 40.1 (2 × CH2), 39.9 (CH2), 38.5 (CH2), 38.1
(CH2), 34.2 (CH3), 34.0 (CH3), 20.3 (CH3), 20.1 (CH3), 17.9
(2 × CH3), 17.2 (2 × CH2).
MS (ESI): m/z = 638 [M + Na]+, 616 [M + H]+.
HRMS (ESI): m/z calcd for C36H57NO7 [M + Na]+: 638.4027;
found: 638.4032.
Ethyl (7E)-6-Acetyloxy-2-(2,2-dimethylpropanoyl)-4-(2,2,6,6-
tetraethyl-4-hydroxypiperidin-1-yloxy)-9-methyldec-7-enoate
(6c)
According to GP 4, alkoxyamine 3b (72.7 mg, 182 mmol) and alk-
ene 1c (166 mg, 910 mmol) were reacted in DMF (182 mL). FC
(Et2O–pentane, 1:3 → 1:2) afforded 6c (87.2 mg, 82%) as a mixture
of four diastereoisomers (ratio = 1:1:1:1).
IR (film): 3410, 2962, 2879, 1738, 1708, 1464, 1369, 1236, 1163,
1039, 1019, 974, 733 cm–1.
1H NMR (400 MHz, CDCl3): d (all four isomers) = 5.71 (dd,
J = 6.1, 14.9 Hz, 1 H, CHvinylic), 5.56–4.98 (m, 2 H, CHvinylic, CHO-
Ac), 4.38–4.27 (m, 1 H, CHON, two isomers), 4.23–4.07 (m, 2 H,
OCH2), 4.05–3.95 (m, 1 H, CHON, two isomers), 3.90–3.57 (m, 2
H, CHOH, CHCO), 2.53–1.09 [m, 30 H, OH, 8 × CH2, CH(CH3)2,
C(CH3)3, CH2CH3], 2.05 (s, 3 H, COCH3, single isomer), 2.04 (s, 3
H, COCH3, single isomer), 2.02 (s, 3 H, COCH3, single isomer),
2.00 (s, 3 H, COCH3, single isomer), 0.98 [d, J = 6.6 Hz, 6 H,
CH(CH3)2], 0.94–0.84 (m, 12 H, 4 × CH3).
MS (ESI): m/z = 785 [2 M + Na]+, 404 [M + Na]+, 382 [M + H]+.
HRMS (ESI): m/z calcd for C21H35NO5 [M + Na]+: 404.2407;
found: 404.2433.
Anal. Calcd for C21H35NO5: C, 66.11; H, 9.25; N, 3.67. Found: C,
66.21; H, 9.23; N, 3.59.
13C NMR (100 MHz, CDCl3): d (all four isomers) = 209.6 (2 × C),
208.7 (2 × C), 169.7 (C), 169.6 (3 × CO), 169.3 (C), 169.2 (C),
169.0 (C), 168.9 (C), 141.2 (CH), 141.1 (CH), 140.9 (2 × CH),
125.2 (CH), 125.1 (CH), 124.8 (CH), 124.6 (CH), 76.5 (CH), 76.2
(CH), 76.1 (CH), 75.2 (CH), 72.9 (CH), 72.6 (CH), 71.8 (CH), 71.7
(CH), 66.1 (2 × C), 62.4 (CH), 62.3 (CH), 60.9 (2 × CH2), 60.7
(2 × CH2), 49.6 (2 × CH), 48.6 (CH), 48.5 (CH), 45.1 (2 × C), 45.0
(C), 44.9 (C), 40.9 (CH2), 40.6 (CH2), 40.5 (2 × CH2), 40.4 (CH2),
38.1 (CH2), 38.0 (4 × CH2), 37.7 (CH2), 34.7 (CH2), 33.6 (CH2),
Dimethyl 2-[(E)-2-Phenylvinyl]cyclopentane-4-(2,2,6,6-tetra-
methylpiperidin-1-yloxy)-1,1-dicarboxylate (7b)
GP 5 was applied to the reaction of alkoxyamine 4b (64.1 mg, 127
mmol), NaH (5.6 mg, 140 mmol), Pd(OAc)2 (1.4 mg, 6.35 mmol) and
DPPE (5.06 mg, 12.7 mmol) in DMF (3 mL). FC (TBME–pentane,
1:15) yielded 7b (53.4 mg, 95%) as a mixture of two diastereoiso-
mers [dr (cis/trans) = 1:1].
IR (film): 2972, 2935, 2872, 1729, 1435, 1263, 1206, 908, 730 cm–1.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

2136
B. Schulte, A. Studer
PAPER
Dimethyl 2-[(1E)-Prop-1-enyl]cyclopentane-4-(2,2,6,6-tetra-
ethyl-4-hydroxypiperidin-1-yloxy)-1,1-dicarboxylate (8a)
According to GP 4, alkoxyamine 5a (70.0 mg, 136 mmol,), NaH (6.0
mg, 150 mmol), Pd(OAc)2 (1.5 mg, 6.8 mmol) and DPPE (4.7 mg,
13.6 mmol) were reacted in DMF (3 mL). FC (Et2O–pentane, 1:3)
yielded 8a (61.2 mg, 99%) as a mixture of two diastereoisomers [dr
(cis/trans) = 1:1].
1H NMR (400 MHz, CDCl3): d (both isomers) = 7.34–7.27 (m, 4
arom), 7.24–7.16 (m, 1 Harom), 6.46 (d, J = 15.8 Hz, 1 H, CHPh, sin-
H
gle isomer), 6.44 (d, J = 15.8 Hz, 1 H, CHPh, single isomer), 6.22
(dd, J = 8.3, 15.8 Hz, 1 H, CH=CHPh, single isomer), 6.11 (dd,
J = 8.3, 15.8 Hz, 1 H, CH=CHPh, single isomer), 4.56–4.52 (m, 1
H, CHON, single isomer), 4.34–4.26 (m, 1 H, CHON, single iso-
mer), 3.76 (s, 3 H, OCH3, single isomer), 3.74 (s, 3 H, OCH3, single
isomer), 3.72–3.64 (m, 1 H, CHCH=CH, single isomer), 3.60 (s, 3
H, OCH3, single isomer), 3.59 (s, 3 H, OCH3, single isomer), 3.31
(ddd, J = 8.8, 7.4, 7.4 Hz, 1 H, CHCH=CH, single isomer), 2.88
(dd, J = 6.9, 14.3 Hz, 1 H, CHH, single isomer), 2.67–2.58 (m, 2 H,
CH2, single isomer), 2.48–2.41 (m, 1 H, CHH, single isomer), 2.33–
2.24 (m, 2 H, CH2, single isomer), 2.05 (ddd, J = 6.9, 9.1, 13.7 Hz,
1 H, CHH, single isomer), 1.90 (ddd, J = 8.6, 9.4, 12.8 Hz, 1 H,
CHH, single isomer), 1.66–0.95 (m, 18 H, 3 × CH2, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 172.4 (C), 172.0
(C), 171.0 (C), 170.8 (C), 137.3 (2 × C), 131.2 (CH), 131.1 (CH),
129.1 (CH), 128.9 (CH), 128.4 (4 × CH), 127.2 (CH), 127.1 (CH),
126.1 (4 × CH), 85.4 (CH), 85.1 (CH), 63.6 (C), 62.3 (C), 59.5
(2 × C), 52.7 (CH3), 52.5 (CH3), 52.3 (CH3), 52.2 (CH3), 46.8 (CH),
45.9 (CH), 41.6 (CH2), 40.1 (2 × CH2), 40.0 (2 × CH2), 39.9 (CH2),
38.3 (CH2), 38.0 (CH2), 34.0 (2 × CH3), 20.1 (2 × CH3), 17.2 (CH2).
IR (film): 3475, 2954, 2361, 1735, 1458, 1265, 1039 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.60–5.47 (m, 1 H,
CH=CHCH3), 5.43 (ddd, J = 15.2, 7.9, 1.1 Hz, 1 H, CH=CHCH3,
single isomer), 5.29 (ddd, J = 15.2, 8.1, 1.6 Hz, 1 H, CH=CHCH3,
single isomer), 4.50–4.41 (m, 1 H, CHON, single isomer), 4.26–
4.14 (m, 1 H, CHON, single isomer), 3.97–3.80 (m, 1 H, CHOH),
3.72 (s, 3 H, OCH3, single isomer), 3.71 (s, 3 H, OCH3, single iso-
mer), 3.65 (s, 3 H, OCH3, single isomer), 3.63 (s, 3 H, OCH3, single
isomer), 3.44–3.32 (m, 1 H, CHCH=CH, single isomer), 3.09–3.00
(m, 1 H, CHCH=CH, single isomer), 2.75 (dd, J = 7.2, 14.1 Hz, 1
H, CHH, single isomer), 2.53–2.45 (m, 1 H, CHH, single isomer),
2.35–2.23 (m, 1 H, CHH, single isomer), 2.15 (dd, J = 4.4, 14.1 Hz,
1 H, CHH, single isomer), 2.11–1.16 (m, 18 H, OH, 7 × CH2, CH3),
1.02–0.78 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 172.3 (C), 172.0
(C), 171.0 (C), 170.7 (C), 130.0 (CH), 129.7 (CH), 127.1 (CH),
127.0 (CH), 84.0 (CH), 83.5 (CH), 65.1 (CH), 63.3 (C), 62.6
(2 × C), 62.1 (C), 52.5 (CH3), 52.4 (CH3), 52.0 (2 × CH3), 46.4
(CH), 45.8 (CH), 41.8 (CH2), 40.3 (CH2), 40.0 (CH2), 39.9 (CH2),
39.8 (2 × CH2), 38.7 (CH2), 38.3 (CH2), 30.0 (CH2), 29.8 (CH2),
27.3 (CH2), 27.2 (CH2), 17.8 (2 × CH3), 10.1 (2 × CH3), 7.9
(2 × CH3).
MS (ESI): m/z = 909 [2 M + Na]+, 466 [M + Na]+, 444 [M + H]+.
HRMS (ESI): m/z calcd for C26H37NO5 [M + Na]+: 444.2744.
Found: 444.2743.
Anal. Calcd for C26H37NO5: C, 70.40; H, 8.41; N: 3.16. Found: C,
70.31; H, 8.64; N, 2.85.
Dimethyl 2-[(1E)-3-Methylbut-1-enyl]cyclopentane-4-(2,2,6,6-
tetramethylpiperidin-1-yloxy)-1,1-dicarboxylate (7c)
GP 5 was applied to the reaction of alkoxyamine 4c (126 mg, 269
mmol), NaH (11.9 mg, 296 mmol), Pd(OAc)2 (3.0 mg, 13.5 mmol)
and DPPE (10.7 mg, 26.9 mmol) in DMF (2 mL). FC (Et2O–pen-
tane, 1:15) yielded 7c (91.2 mg, 83%) as a mixture of two diastereo-
isomers [dr (cis/trans) = 1:1].
MS (ESI): m/z = 476 [M + Na]+, 454 [M + H]+.
HRMS (ESI): m/z calcd for C25H43NO6 [M + H]+: 454.3163; found:
454.3169.
Dimethyl 2-[(E)-2-Phenylvinyl]cyclopentane-4-(2,2,6,6-tetra-
ethyl-4-hydroxypiperidin-1-yloxy)-1,1-dicarboxylate (8b)
According to GP 5, alkoxyamine 5b (77.1 mg, 134 mmol) was react-
ed with NaH (5.9 mg, 147 mmol), Pd(OAc)2 (1.5 mg, 6.7 mmol) and
DPPE (5.3 mg, 13.4 mmol) in DMF (3 mL). FC (Et2O–pentane, 1:3)
afforded 8b (42.8 mg, 62%) as a mixture of two diastereoisomers
[dr (cis/trans) = 1:1].
IR (film): 2953, 2932, 2871, 1732, 1435, 1360, 1262, 1211, 972,
913, 732 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.60–5.51 (m, 1 H,
CHi-Pr), 5.46 (dd, J = 7.8, 15.4 Hz, 1 H, CH=CHi-Pr, single iso-
mer), 5.34 (dd, J = 8.0, 15.4 Hz, 1 H, CH=CHi-Pr, single isomer),
4.62–4.49 (m, 1 H, CHON, single isomer), 4.34–4.24 (m, 1 H,
CHON, single isomer), 3.82 (s, 3 H, OCH3, single isomer), 3.79 (s,
3 H, OCH3, single isomer), 3.73 (s, 3 H, OCH3, single isomer), 3.70
(s, 3 H, OCH3, single isomer), 3.58–3.48 (m, 1 H, CHCH=CHi-Pr,
single isomer), 3.25–3.12 (m, 1 H, CHCH=CHi-Pr, single isomer),
2.89 (dd, J = 7.1, 14.3 Hz, 1 H, CHH, single isomer), 2.67–2.58 (m,
1 H, CHH), 2.50–2.39 (m, 1 H, CHH, single isomer), 2.36–2.17 (m,
2 H, CH2), 2.06–1.99 [m, 1 H, CH(CH3)2, single isomer], 1.87–1.77
[m, 1 H, CH(CH3)2, single isomer], 1.72–1.10 (m, 18 H, 3 × CH2,
4 × CH3), 1.09–1.00 (m, 6 H, 2 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 172.5 (C), 172.2
(C), 171.0 (C), 170.8 (C), 139.4 (2 × CH), 126.0 (CH), 125.7 (CH),
85.6 (CH), 85.1 (CH), 63.4 (C), 62.2 (C), 59.4 (2 × C), 52.5 (CH3),
52.3 (CH3), 51.9 (2 × CH3), 46.3 (CH), 45.3 (CH), 41.3 (CH2), 40.1
(2 × CH2), 39.9 (CH2), 38.4 (CH2), 38.0 (CH2), 34.2 (CH2), 34.0
(CH2), 30.9 (2 × CH), 22.5 (2 × CH3), 22.4 (2 × CH3), 20.1
(2 × CH3), 17.2 (2 × CH2).
IR (film): 3458, 2953, 2878, 1731, 1450, 1436, 1263, 1218, 1058,
1038, 1017, 969, 744, 694 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 7.36–7.25 (m, 4
Harom), 7.24–7.16 (m, 1 Harom), 6.45 (d, J = 15.8 Hz, 1 H, CHPh, sin-
gle isomer), 6.43 (d, J = 15.8 Hz, 1 H, CHPh, single isomer), 6.21
(dd, J = 8.4, 15.8 Hz, 1 H, CH=CHPh, single isomer), 6.08 (dd,
J = 8.2, 15.8 Hz, 1 H, CH=CHPh, single isomer), 4.57–4.48 (m, 1
H, CHON, single isomer), 4.34–4.19 (m, 1 H, CHON, single iso-
mer), 3.95–3.80 (m, 1 H, CHOH), 3.75 (s, 3 H, OCH3, single iso-
mer), 3.74 (s, 3 H, OCH3, single isomer), 3.72–3.62 (m, 1 H,
CHCH=CH, single isomer), 3.60 (s, 3 H, OCH3, single isomer),
3.59 (s, 3 H, OCH3, single isomer), 3.32–3.22 (m, 1 H, CHCH=CH,
single isomer), 2.84 (dd, J = 14.1, 7.0 Hz, 1 H, CHH, single iso-
mer), 2.60–2.54 (m, 1 H, CHH, single isomer), 2.46–1.23 (m, 16 H,
OH, 7 × CH2, CHH), 1.04–0.81 (m, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d (both isomers) = 172.2 (C), 171.8
(C), 170.9 (C), 170.6 (C), 137.2 (C), 131.4 (CH), 131.2 (CH), 129.0
(CH), 128.7 (CH), 128.5 (2 × CH), 127.3 (CH), 126.2 (2 × CH),
84.0 (CH), 83.6 (CH), 65.1 (3 × C), 63.4 (C), 62.7 (CH), 62.3 (C),
52.7 (CH3), 52.6 (CH3), 52.4 (2 × CH3), 46.7 (CH), 46.2 (CH), 42.0
(CH2), 40.4 (CH2), 39.8 (CH2), 39.7 (CH2), 38.5 (CH2), 38.2 (CH2),
30.0 (CH2), 29.8 (CH2), 27.4 (CH2), 27.3 (2 × CH2), 26.9 (CH2),
10.2 (CH3), 10.1 (CH3), 8.0 (CH3), 7.9 (CH3).
MS (ESI): m/z = 432 [M + Na]+, 410 [M + H]+.
HRMS (ESI): m/z calcd for C23H39NO5 [M + H]+: 410.2901. Found:
410.2902.
Anal. Calcd for C23H39NO5: C, 67.45; H, 9.60; N, 3.42. Found: C,
67.46; H, 9.66; N, 3.26.
MS (ESI): m/z = 1053 [2 M + Na]+, 538 [M + Na]+, 516 [M + H]+.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

PAPER
Regioselective Intermolecular Radical Carboaminoxylation
2137
HRMS (ESI): m/z calcd for C30H45NO6 [M + Na]+: 538.3139;
HRMS (ESI): m/z calcd for C29H51NO5 [M + H]+: 494.3851; found:
found: 538.3113.
494.2851.
Dimethyl 2-[(1E)-3-Methylbut-1-enyl]cyclopentane-4-(2,2,6,6-
tetraethyl-4-hydroxypiperidin-1-yloxy)-1,1-dicarboxylate (8c)
According to GP 5, alkoxyamine 5c (78.3 mg, 145 mmol), NaH (6.4
mg, 159 mmol), Pd(OAc)2 (1.6 mg, 7.2 mmol) and DPPE (5.8 mg,
14.5 mmol) were reacted in DMF (3 mL). FC (Et2O–pentane, 1:3)
afforded 8c (43.3 mg, 62%) as a mixture of two diastereoisomers [dr
(cis/trans) = 1:1].
Ethyl 1-(2,2-Dimethylpropanoyl)-2-[(E)-2-phenylvinyl]cyclo-
pentane-4-(2,2,6,6-tetraethyl-4-hydroxypiperidin-1-yloxy)car-
boxylate (9b)
GP 5 was applied to the reaction of alkoxyamine 6b (178 mg, 290
mmol) with NaH (12.8 mg, 319 mmol), Pd(OAc)2 (3.3 mg,
14.5 mmol) and DPPE (11.5 mg, 29.0 mmol) in DMF (3 mL). FC
(Et2O–pentane, 1:4) yielded 9b (20.1 mg, 13%) as a mixture of four
diastereoisomers. The isomers could not be separated.
IR (film): 3463, 2956, 2878, 2362, 2337, 1730, 1461, 1435, 1264,
1219, 1037, 910, 731 cm–1.
IR (film): 3376, 2963, 2878, 1736, 1694, 1463, 1366, 1212, 1192,
1061, 1038, 1014, 970, 909, 732, 694 cm–1.
1H NMR (400 MHz, CDCl3): d (both isomers) = 5.46 (ddd,
J = 15.4, 6.6, 0.7 Hz, 1 H, CH=CHi-Pr, single isomer), 5.45 (dd,
J = 15.4, 6.3 Hz, 1 H, CH=CHi-Pr, single isomer), 5.36 (dd,
J = 15.5, 7.6 Hz, 1 H, CH=CHi-Pr, single isomer), 5.22 (ddd,
J = 15.4, 8.0, 1.1 Hz, 1 H, CH=CHi-Pr, single isomer), 4.50–4.40
(m, 1 H, CHON, single isomer), 4.24–4.13 (m, 1 H, CHON, single
isomer), 3.95–3.81 (m, 1 H, CHOH), 3.71 (s, 3 H, OCH3, single iso-
mer), 3.70 (s, 3 H, OCH3, single isomer), 3.63 (s, 3 H, OCH3, single
isomer), 3.61 (s, 3 H, OCH3, single isomer), 3.42-3.33 (m, 1 H,
CHCH=CHi-Pr, single isomer), 3.10–3.00 (m, 1 H, CHCH=CHi-
Pr), 2.76 (dd, J = 7.2, 14.2 Hz, 1 H, CHH, single isomer), 2.49 (d,
J = 8.0 Hz, 1 H, CHH, single isomer), 2.37–1.22 [m, 17 H, 7 × CH2,
CH(CH3)2, OH, CHH], 1.01–0.74 [m, 18 H, CH(CH3)2, 4 × CH3].
1H NMR (400 MHz, CDCl3): d (all four isomers) = 7.36–7.23 (m, 4
Harom), 7.22–7.15 (m, 1 Harom), 6.42–6.32 (m, 1 H, CHPh), 6.18–
6.03 (m, 1 H, CH=CHPh), 4.55 (tt, J = 4.3, 7.5 Hz, 1 H, CHON, sin-
gle isomer), 4.36–3.94 (m, 2 H, OCH2, CHON three isomers), 3.92–
3.83 (m, 1 H, CHOH), 3.81–3.71 (m, 1 H, CHCH=CHPh, single
isomer), 3.56–3.35 (m, 1 H, CHCH=CHPh, two isomers), 3.32–
3.23 (m, 1 H, CHCH=CHPh, single isomer), 3.06 (dd, J = 7.5, 14.0
Hz, 1 H, CHH, single isomer), 2.94 (dd, J = 7.9, 14.6 Hz, 1 H, CHH,
single isomer), 2.74–1.17 [m, 40 H, 7 × CH2, CHH, OCH2CH3,
C(CH3)3, OH, 4 × CH3, CHH-two isomers].
13C NMR: Due to the complexity, 13C NMR spectrum is not provid-
ed.
13C NMR (100 MHz, CDCl3): d (both isomers) = 172.4 (C), 172.1
(C), 170.9 (C), 170.6 (C), 139.6 (CH), 139.5 (CH), 126.0 (CH),
125.6 (CH), 84.1 (CH), 83.6 (CH), 65.1 (C), 65.0 (C), 63.4 (C), 62.7
(CH), 62.4 (C), 52.5 (CH3), 52.4 (CH3), 52.0 (CH3), 51.9 (CH3),
46.1 (CH), 45.5 (CH), 41.7 (CH2), 40.2 (CH2), 39.9 (2 × CH2), 39.8
(2 × CH2), 38.8 (CH2), 38.3 (CH2), 30.9 (2 × CH), 30.0 (2 × CH2),
29.8 (2 × CH2), 27.4 (2 × CH2), 27.3 (CH2), 27.2 (CH2), 22.5 (CH3),
22.4 (CH3), 10.1 (3 × CH3), 10.0 (CH3), 7.9 (2 × CH3).
MS (ESI): m/z = 578 [M + Na]+, 556 [M + H]+.
HRMS (ESI): m/z calcd for C34H53NO5 [M + H]+: 556.4007; found:
556.3990.
Ethyl 1-(2,2-Dimethylpropanoyl)-2-[(1E)-3-methylbut-1-
enyl]cyclopentane-4-(2,2,6,6-tetraethyl-4-hydroxypiperidin-1-
yloxy)carboxylate (9c)
GP 5 was applied to the reaction of alkoxyamine 6c (66.8 mg, 115
mmol) with NaH (5.1 mg, 126 mmol), Pd(OAc)2 (1.3 mg, 5.7 mmol)
and DPPE (4.6 mg, 11.5 mmol) in DMF (2 mL). FC (Et2O–pentane,
1:3) yielded 9c (48.5 mg, 81%) as a mixture of four diastereoiso-
mers. The isomers could not be separated.
MS (ESI): m/z = 504 [M + Na]+, 482 [M + H]+.
HRMS (ESI): m/z calcd for C27H47NO6 [M + Na]+: 482.3476;
found: 482.3471.
Anal. Calcd for C27H47NO6: C, 67.33; H, 9.84; N, 2.91. Found: C,
66.91; H, 9.86; N, 2.82.
IR (film): 3376, 2960, 2876, 1737, 1696, 1464, 1366, 1216, 1190,
1038, 1014, 978, 733 cm–1.
Ethyl 1-(2,2-Dimethylpropanoyl)-2-[(1E)-prop-1-enyl]cyclo-
pentane-4-(2,2,6,6-tetraethyl-4-hydroxypiperidin-1-yloxy)car-
boxylate (9a)
GP 5 was applied to the reaction of alkoxyamine 6a (132 mg, 239
mmol) with NaH (10.5 mg, 262 mmol), Pd(OAc)2 (2.7 mg,
11.9 mmol) and DPPE (23.9 mg, 9.5 mmol) in DMF (3 mL). FC
(Et2O–pentane, 1:3) yielded 9a (46.1 mg, 39%) as a mixture of four
diastereoisomers. The isomers could not be separated.
1H NMR (300 MHz, CDCl3): d (all four isomers) = 5.50–5.16 (m, 2
H, CH=CHi-Pr, CH=CHi-Pr), 4.53–4.42 (m, 1 H, CHON, single
isomer), 4.34–3.96 (m, 2 H, OCH2, CHON three isomers), 3.95–
3.80 (m, 1 H, CHOH), 3.55–3.43 (m, 1 H, CHCH=CHi-Pr, single
isomer), 3.28–3.18 (m, 1 H, CHCH=CHi-Pr, two isomers), 3.14–
3.05 (m, 1 H, CHCH=CHi-Pr, single isomer), 3.00 (dd, J = 7.8, 14.0
Hz, 1 H, CHH, single isomer), 2.90 (dd, J = 7.9, 14.6 Hz, 1 H, CHH,
single isomer), 2.66–0.76 [m, 47 H, 7 × CH2, CHH, OCH2CH3,
C(CH3)3, OH, CH(CH3)2, CH(CH3)2, 4 × CH3, CHH, two isomers].
13C NMR: Due to the complexity, 13C NMR spectrum is not provid-
ed.
MS (ESI): m/z = 544 [M + Na]+, 522 [M + H]+.
HRMS (ESI): m/z calcd for C31H55NO5 [M +H]+: 522.4164; found:
522.4149.
IR (film): 3376, 2962, 2879, 1737, 1695, 1462, 1366, 1214, 1191,
1062, 1038, 1014, 974 cm–1.
1H NMR (400 MHz, CDCl3): d (all four isomers) = 5.54–4.92 (m, 2
H, CH=CHCH3, CH=CHCH3), 4.46 (tt, J = 4.6, 7.4 Hz, 1 H,
CHON, single isomer), 4.36–3.99 (m, 2 H, OCH2, CHON three
isomers), 3.96–3.82 (m, 1 H, CHOH), 3.57–3.47 (m, 1 H,
CHCH=CHCH3, single isomer), 3.31–3.20 (m,
1 H,
CHCH=CHCH3, two isomers), 3.16–3.07 (m, 1 H, CHCH=CHCH3,
single isomer), 2.99 (dd, J = 7.6, 14.0 Hz, 1 H, CHH, single iso-
mer), 2.90 (dd, J = 7.9, 14.6 Hz, 1 H, CHH, single isomer), 2.64–
1.16 [m, 31 H, 7 × CH2, CHH, OCH2CH3, CHCH3, C(CH3)3, OH,
CHH-two isomers], 1.05–0.76 (m, 12 H, 4 × CH3).
13C NMR: Due to the complexity, 13C NMR spectrum is not provid-
ed.
Dimethyl 2-[(1E)-3-Methylbut-1-enyl]cyclohexane-5-(2,2,6,6-
tetraethyl-4-hydroxypiperidin-1-yloxy)-1-1-dicarboxylate (10)
According to GP 5, alkoxyamine 5d (109 mg, 197 mmol,) was react-
ed with NaH (8.7 mg, 217 mmol), Pd(OAc)2 (2.2 mg, 9.8 mmol) and
DPPE (7.8 mg, 19.7 mmol) in DMF (3 mL). FC (Et2O–pentane, 1:5
→ 1:3) yielded 10 (56.0 mg, 57%) as a mixture of two diastereoiso-
mers [dr (cis/trans) = 1:1].
MS (ESI): m/z = 516 [M + Na]+, 494 [M + H]+.
IR (film): 3372, 2953, 2879, 1732, 1453, 1436, 1252, 1211, 1149,
1008, 911, 732 cm–1.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York

2138
B. Schulte, A. Studer
PAPER
1H NMR (300 MHz, CDCl3): d (both isomers) = 5.73 (ddd,
J = 1.5, 9.0, 15.2 Hz, 1 H, CH=CHi-Pr, single isomer), 5.61–5.47
(m, 1 H, CH=CHi-Pr), 5.46–5.34 (m, 1 H, CH=CHi-Pr, single iso-
mer), 3.95–3.81 (m, 1 H, CHON), 3.78–3.55 (m, 1 H, CHOH), 3.70
(s, 3 H, OCH3, single isomer), 3.69 (s, 3 H, OCH3, single isomer),
3.65 (s, 3 H, OCH3, single isomer), 3.61 (s, 3 H, OCH3, single iso-
mer), 3.60 (s, 3 H, OCH3, single isomer), 3.59 (s, 3 H, OCH3, single
isomer), 3.47–3.33 (m, 1 H, CHCH=CHi-Pr, single isomer), 2.99–
2.90 (m, 1 H, CHCH=CHi-Pr, single isomer), 2.61–0.76 [m, 38 H,
OH, 9 × CH2, CH(CH3)2, CH(CH3)2, 4 × CH3].
13C NMR (75 MHz, CDCl3): d = 171.7 (C), 171.2 (C), 170.7 (C),
170.2 (C), 140.6 (CH), 139.4 (CH), 127.1 (CH), 124.5 (CH), 77.8
(CH), 77.2 (CH), 65.6 (C), 65.5 (C), 65.3 (C), 65.1 (C), 62.6
(2 × CH), 59.5 (2 × C), 52.3 (CH3), 52.1 (CH3), 52.0 (CH3), 51.8
(CH3), 46.2 (CH), 40.8 (CH), 40.1 (CH2), 39.9 (2 × CH2), 39.8
(CH2), 34.1 (CH2), 33.3 (CH2), 31.1 (CH), 31.0 (CH), 30.0 (CH2),
29.9 (CH2), 29.7 (2 × CH2), 28.0 (CH2), 27.7 (CH2), 27.3 (CH2),
27.2 (CH2), 27.0 (2 × CH2), 22.6 (2 × CH3), 22.5 (CH3), 22.3
(CH3), 10.1 (CH3), 8.2 (3 × CH3).
(3) (a) Wetter, C.; Jantos, K.; Woithe, K.; Studer, A. Org. Lett.
2003, 5, 2899. (b) Wetter, C.; Studer, A. Chem. Commun.
2004, 174. (c) Herrera, A. J.; Studer, A. Synthesis 2005,
1389. (d) Uenoyama, Y.; Tsukida, M.; Doi, T.; Ryu, I.;
Studer, A. Org. Lett. 2005, 7, 2985.
(4) Molawi, K.; Schulte, T.; Siegenthaler, K. O.; Wetter, C.;
Studer, A. Chem. Eur. J. 2005, 11, 2335.
(5) Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett.
2004, 6, 3477.
(6) (a) Fischer, H. Chem. Rev. 2001, 101, 3581. (b) Studer, A.
Chem. Eur. J. 2001, 7, 1159. (c) Studer, A. Chem. Soc. Rev.
2004, 33, 267. (d) Studer, A.; Schulte, T. Chem. Rec. 2005,
5, 27.
(7) Other applications of the PRE: (a) Daikh, B. E.; Finke, R. G.
J. Am. Chem. Soc. 1992, 114, 2938. (b) Allen, A. D.;
Fenwick, M. F.; Henry-Riyad, H.; Tidwell, T. T. J. Org.
Chem. 2001, 66, 5759. (c) Leroi, C.; Fenet, B.; Couturier, J.-
L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 1079.
(d) Leroi, C.; Bertin, D.; Dufils, P.-E.; Gigmes, D.; Marque,
S.; Tordo, P.; Couturier, J.-L.; Guerret, O.; Ciufolini, M. A.
Org. Lett. 2003, 5, 4943. (e) Alajarín, M.; Vidal, A.; Ortín,
M.-M.; Bautista, D. Synlett 2004, 991. (f) Alajarín, M.;
Vidal, A.; Ortín, M.-M.; Bautista, D. New J. Chem. 2004, 28,
570.
MS (ESI): m/z = 518 [M + Na]+, 496 [M + H]+.
HRMS (ESI): m/z calcd for C28H49NO6 [M + H]+: 496.3633; found:
496.3622.
(8) (a) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron:
Asymmetry 1992, 3, 1089. (b) Helmchen, G. J. Organomet.
Chem. 1999, 576, 203. (c) Tsuji, J. Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Ed.; Wiley: New York, 2002, 1669.
(9) For sequential radical addition Trost–Tsuji allylation, see:
Miyabe, H.; Asada, R.; Takemoto, Y. Tetrahedron 2005, 61,
385.
(10) Janza, B.; Studer, A. Org. Lett. 2006, 8, 1875.
(11) Review on microwave chemistry: Kappe, C. O. Angew.
Chem. Int. Ed. 2004, 43, 6250; Angew. Chem. 2004, 116,
6408.
(12) Microwave induced radical chemistry: (a) Olofsson, K.;
Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org.
Chem. 1999, 64, 4539. (b) Lamberto, M.; Corbett, D. F.;
Kilburn, J. D. Tetrahedron Lett. 2003, 44, 1347.
(c) Ericsson, C.; Engman, L. J. Org. Chem. 2004, 69, 5143.
(d) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. J.
Eur. J. Org. Chem. 2006, 1547.
Radical Carboaminoxylation of Alkoxyamines 2, 3a with Subse-
quent Pd-Catalyzed Intramolecular Allylation; General Proce-
dure (GP 6)
The alkoxyamine 2, 3a (1.0 equiv) was dissolved in DMF (1 M so-
lution) and the alkene 1a–3d (5.0 equiv) was added under argon.
The solution was heated to 125 °C for 2 h. The mixture was allowed
to cool to r.t. and diluted with DMF (~ 0.06 M solution). After ad-
dition of NaH (60% dispersion in mineral oil, 1.1 equiv) at 0 °C, the
mixture was stirred for 20 min at 0 °C. An anhyd solution of
Pd(OAc)2 (5 mol%) and DPPE (10 mol%) in DMF (~ 0.5 mL) was
added. Afterwards the mixture was heated at 110 °C for 2 h. The re-
action was stopped by the addition of NH4Cl (25 wt% aq solution)
followed by extraction of the aqueous layer with Et2O (3 ×). The
combined organic layers were dried (MgSO4) and the solvent was
removed in vacuo. FC yielded the pure compounds 7a, 7b, 8a, 8b,
10.
Acknowledgment
(13) Diene 1d turned out to be unstable under the reaction
We thank the Deutsche Forschungsgemeinschaft DFG (STU/5-1)
and the Fonds der Chemischen for support. DEGUSSA AG is ack-
nowledged for donation of chemicals. We thank Anne Mumm and
Marius Strunk for conducting some experiments.
conditions.
(14) Compounds 5a–d were isolated as 1:1 mixture of
diastereoisomers. The isomers could not be separated. For
6a–c all four isomers (ratio 1:1:1:1) were formed. These
isomers could not be separated.
(15) Trost B. M., Verhoeven T. R.; J. Am. Chem. Soc.; 1977, 99:
3867.
References
(16) Lemaire, S.; Prestat, G.; Giambastiani, G.; Madec, D.;
Pacini, B.; Poli, G. J. Organomet. Chem. 2003, 687, 291.
(17) The isomers could not be separated. Due to the complexity
of the NMR spectra, the determination of the
(1) Studer, A. Angew. Chem. Int. Ed. 2000, 39, 1108; Angew.
Chem. 2000, 112, 1157.
(2) Reviews on tin-free radical chemistry: (a) Baguley, P. A.;
Walton, J. C. Angew. Chem. Int. Ed. 1998, 37, 3072; Angew.
Chem. 1998, 110, 3272. (b) Studer, A.; Amrein, S. Synthesis
2002, 835.
diastereoisomeric ratio for compounds 9a and 9c was not
possible. For 9b the product was formed as a 30:12:3:1
mixture of isomers.
(18) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew.
Chem. Int. Ed. 1998, 37, 152; Angew. Chem. 1998, 110, 160.
Synthesis 2006, No. 13, 2129–2138 © Thieme Stuttgart · New York