Synthesis of a bulky nitroxide and its application in the nitroxide-mediated radical polymerization

Article abstract of DOI:10.1016/j.tet.2016.04.008

The synthesis of a sterically highly hindered morpholine-based nitroxide is described. Trapping of an α-ester radical with this novel nitroxide leads to an alkoxyamine which is used as an efficient initiator/regulator in the controlled nitroxide-mediated radical polymerization (NMP) of n-butyl acrylate and styrene. Controlled polymerization of n-butyl acrylate can be conducted at very low temperature (50 °C) convincingly documenting the efficiency of this nitroxide for acrylate polymerization.

Full text of DOI:10.1016/j.tet.2016.04.008

Tetrahedron xxx (2016) 1e7
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Synthesis of a bulky nitroxide and its application in the nitroxide-
mediated radical polymerization
*
Yuanyuan Jing, Matthias Tesch, Lin Wang, Constantin Gabriel Daniliuc, Armido Studer
€
€
€
€
Institute of Organic Chemistry, Department of Chemistry, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 40, Munster, 48149, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a sterically highly hindered morpholine-based nitroxide is described. Trapping of an a-
Received 14 January 2016
Received in revised form 31 March 2016
Accepted 5 April 2016
ester radical with this novel nitroxide leads to an alkoxyamine which is used as an efficient initiator/
regulator in the controlled nitroxide-mediated radical polymerization (NMP) of n-butyl acrylate and
styrene. Controlled polymerization of n-butyl acrylate can be conducted at very low temperature (50 ꢀC)
convincingly documenting the efficiency of this nitroxide for acrylate polymerization.
Ó 2016 Elsevier Ltd. All rights reserved.
Available online xxx
Keywords:
Radicals
Controlled polymerization
Nitroxides
Alkoxyamines
1. Introduction
a new polymeric radical (the C-radical generally adds to more
than one monomer before being trapped by the nitroxide). Since
The controlled/living radical polymerization (CLRP) that
emerged from the early 1980s has initiated a new research branch
in polymer science focusing on the synthesis of tailored polymers
with excellent control over their molecular architecture. Guided by
the pioneering work in the field, various CLPR technologies have
been established since then.1 Nitroxide-mediated polymerization
(NMP) is historically the earliest applied CLPR technology, and is
experimentally easy to conduct. Notably, NMP proceeds in the ab-
sence of any transition metal and colored compounds are not re-
quired. As a result, colorless polymers that are free of any transition
metal impurities bearing nitroxyl functional groups at the terminus
of the chains are obtained.
the equilibrium between free nitroxide/polymeric radical and
polymeric alkoxyamine lies far to the site of the closed shell
polymeric alkoxyamine, the concentration of free radicals is kept
low during the entire polymerization process, thereby sup-
pressing termination reactions. Hence, control of the polymeri-
zation depends on the equilibrium constant K between the
polymeric alkoxyamine and the macroradical/nitroxide. It is
known that the equilibrium constant K is strongly affected by
structural properties of the nitroxide such as internal H-bonding,
steric, electronic and polar effects.3 The structure of a nitroxide
influences both the polymerization rate and polydispersity of the
resulting macromolecules.
NMP is controlled by the persistent radical effect (PRE)2 and is
generally conducted with an alkoxyamine initiator under neat
conditions at elevated temperature (>100 ꢀC). NMP proceeds via
reversible CeON bond cleavage of a polymeric alkoxyamine
generated during the polymerization process. Upon thermolysis
of the CeON bond in an alkoxyamine initiator at an appropriate
temperature, a nitroxide and a transient C radical are generated.
Addition of the latter species to the alkene group of a monomer
and subsequent recombination with the nitroxide radical pro-
duces a polymeric alkoxyamine with extended chain, which un-
dergoes renewed thermolysis to generate the nitroxide and
The pioneering works on NMP were conducted with 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO) as the nitroxide compo-
nent. However, application of TEMPO as a mediator in NMP is
limited. It works well only for polymerization of styrene and its
derivatives. Moreover, high temperature (125e145 ꢀC) and a long
reaction time (1e3 days) are often required.1e,4 Considering these
limitations, various nitroxides have been developed in order to
achieve well-controlled polymerization of a broader range of
monomers at lower temperature. For instance, the readily prepared
acyclic nitroxides N-tert-butyl-N-(1-diethyl- phosphono-2,2-
dimethyl) propylnitroxyl radical (SG1)3h,i,5 and 2,2,5-trimethyl-4-
phenyl-3-azahexane-3-oxyl (TIPNO)6 were shown to be highly ef-
ficient mediators for well-controlled acrylate NMP. We found the
sterically hindered cyclic nitroxides 17 and 28 to be efficient regu-
lators for polymerization of styrene and n-butyl acrylate (Fig. 1).
* Corresponding author. Tel.: þ49 251 8333291; fax: þ49 251 8336523; e-mail
address: studer@uni-muenster.de (A. Studer).
http://dx.doi.org/10.1016/j.tet.2016.04.008
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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Y. Jing et al. / Tetrahedron xxx (2016) 1e7
Fig. 1. Known efficient cyclic six-membered nitroxides 1e3 and the novel congener 4.
Although good results were obtained by using these nitroxides in
the polymerizations of styrene and acrylates, temperatures above
90 ꢀC are still required for well-controlled polymerizations within
a reasonable time frame. Very recently, we developed a chiral bulky
previously reported procedure,
L-(-)-menthone was diaster-
eoselectively transformed to the corresponding hydantoin 5 in
high yield by a Bucherer reaction.10 After hydrolysis with 60%
aqueous H2SO4 at 150 ꢀC, the corresponding amino acid was ob-
tained, which was directly reduced with NaBH4/I2 without any
further purification to give the amino alcohol 6 (84% yield over
two steps). Applying a method that was recently introduced by
Carreira and co-workers,11 the amino alcohol 6 was reacted with
3-oxetanone to form the N,O-ketal 7 in high yield. In the presence
of TMSCN and a catalytic amount of In(OTf)3, 7 further reacted via
a Strecker reaction with subsequent ring expansion to afford
morpholine 8 which was isolated as a single diastereoisomer. Ni-
trile reduction with LiAlH4 went along with silyl ether cleavage. N-
Bocylation by using Boc-anhydride provided bicycle 9. Treatment
of 9 with NaH and an excess of MeI led to protection of the pri-
mary alcohol as methyl ether and at the same time also BocNH-
methylation was achieved (see 10). Finally, oxidation of the sec-
ondary amine with AcOOH afforded the targeted bulky spiro
morpholine-based nitroxide 4. The corresponding alkoxyamine
Pro-4 was prepared in 92% yield according to a known literature
nitroxide 3 bearing a spiro-annellated six-membered ring in
a-
position of the nitroxyl functionality (Fig. 1).9 The isopropyl and
methyl groups at the cyclohexane ring are located in equatorial
position fixing the six-membered ring in a sterically shielding chair
conformation. Nitroxide 3 was found to be a highly efficient regu-
lator for NMP of styrene and n-butyl acrylate, and these polymer-
ꢀ
izations could be conducted even at 50 C.
Herein, we will present a straightforward synthesis of nitroxide
4 (Scheme 1). As compared to the highly efficient system 3, the
piperidinone core in 3 is replaced by a morpholine ring thereby
altering electronic effects of the nitroxide. Preparation of an
alkoxyamine derived from 4 is described and this alkoxyamine is
applied as an initiator/regulator to NMP of n-butyl acrylate and
styrene.
2. Results and discussions
procedure12 with methyl
a-bromopropiolate. Pro-4 was isolated
as a mixture of the two diastereoisomers. Due to the signal overlap
in the NMR spectra, the isomer ratio could not be unambiguously
determined.
2.1. Synthesis of nitroxide 4 and of alkoxyamine Pro-4
The synthesis commenced with the commercially available and
cheap enantiopure L-(-)-menthone (Scheme 1). According to a
Scheme 1. Synthesis of nitroxide 4 and the corresponding alkoxyamine Pro-4.
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Y. Jing et al. / Tetrahedron xxx (2016) 1e7
3
Unfortunately, nitroxide 4 and the alkoxyamine Pro-4 were
both isolated as oils and conformation analysis by X-ray structure
studies was not possible. To proof the relative configuration of 4
and to get an idea on the conformation of the two six-membered
rings we decided to prepare a crystalline derivative therefrom.
Cyclization of the Boc-protected amino alcohol 9 under basic con-
dition provided crystalline tricyclic carbamate 11 (Scheme 2).
(0.25e1 mol %). Conversion of NMP was determined gravimetri-
cally. Polydispersity index (PDI) and molecular weight (Mn,exp) of
the resulting polymers were analyzed by using size exclusion
chromatography (SEC).
Poly-n-butyl acrylate (PBA) synthesis was first investigated by
using alkoxyamine Pro-4 as initiator/regulator at 50e70 ꢀC and
results obtained are summarized in Table 1. All polymerizations
were well controlled delivering PBA with small PDIs (<1.30). At
70 ꢀC polymerizations proceeded rapidly and very high conversions
(94e98%) were obtained within 15 h (Table 1, entries 1e3). For
example, PBA with a molecular weight of 49,800 g/mol and small
PDI (1.24) was isolated by using 0.25 mol % of initiator Pro-4 (entry
3). As expected for a controlled living polymerization, at higher
initiator loading (0.5 and 1 mol %, respectively) PBA with smaller
molecular weight was formed. Reactions with Pro-4 proceeded
well also at 60 ꢀC and 75e93% conversions were achieved after 26 h
(Table 1, entries 4e6). PBA isolated in these experiments showed
small PDIs and the molecular weight was controlled by the initiator
concentration, clearly revealing that polymerization was well
controlled at 60 ꢀC. We then repeated BA-polymerizations at 50 ꢀC
(Table 1, entries 7e9). Pleasingly, polymerization was still occurring
albeit reaction time had to be increased to 125 h in order to get
conversions of 45e79%. PDI of the PBA isolated was small and
molecular weight was controlled by the initiator concentration.
Scheme 2. Synthesis of dispiro-annelated morpholine 11.
X-ray structure analysis allowed for assignment of the relative
configuration of the two fully substituted stereogenic centers in 11
(Fig. 2). The isopropyl group at the cyclohexane ring is located cis to
the oxygen atom of the carbamate ring. In analogy to nitroxide 3,
the cyclohexane ring in 11 lies in a chair conformation with the
isopropyl and methyl groups both oriented in equatorial positions.
We assume that also in the nitroxide 4 the six-membered carbo-
cycle will stay in the same fixed chair conformation that strongly
shields the N-oxyl radical. As expected, the morpholine ring also
lies in a chair conformation whereas the carbamate ring is distorted
from a chair due to the different hybridization of the carbonyl C-
atom and the two heteroatoms.
Table 1
NMP of n-butyl acrylate under different conditions using alkoxyamines Pro-4, Mal-3
and Pro-3
Entry Alkoxyamine Temperature Time Conversion Mn,th
Mn,exp PDI
(mol %)
(oC)
(h)
(%)
(g/mol) (g/mol)
1
2
3
4
5
6
7
8
Pro-4 (1)
Pro-4 (0.5)
Pro-4 (0.25) 70
Pro-4 (1)
Pro-4 (0.5)
Pro-4 (0.25) 60
Pro-4 (1)
Pro-4 (0.5)
Pro-4 (0.25) 50
Mal-3 (1)
Mal-3 (0.5)
Mal-3 (0.25) 60
Pro-3 (1)
Pro-3 (0.5)
Pro-3 (0.25) 60
70
70
15 98
15 97
15 94
26 93
26 81
26 75
125 79
125 61
125 45
22 81
22 71
22 66
24 81
24 80
24 69
12,600 20,600 1.25
25,000 33,600 1.21
48,100 49,800 1.24
12,000 23,500 1.29
20,700 30,600 1.30
38,500 48,900 1.24
10,100 22,500 1.23
15,700 23,700 1.15
23,000 26,000 1.29
10,400 12,800 1.15
18,200 22,800 1.13
33,700 34,800 1.11
10,900 12,700 1.16
20,500 29,600 1.12
35,400 40,900 1.13
60
60
50
50
9
10a
11a
12a
13a
14a
15a
60
60
60
60
a
Data taken from Ref. 9.
Fig. 2. Crystal structure of compound 11 (Thermals ellipsoids are shown with 50%
probability.).
For comparison, results previously obtained9 for BA-polymer-
ization under identical conditions (neat, 60 ꢀC with 0.25e1 mol % of
initiator) with alkoxyamines Pro-3 and Mal-3 (Fig. 3), which are the
most efficient cyclic NMP-initiators/regulators known to date, are in-
cluded intoTable 1 (entries 10e15). Compared to Mal-3 and Pro-3, the
novel alkoxyamine Pro-4 is slightly more reactive (higher conver-
sions) but delivers PBA with slightly larger PDIs.
Cyclovoltammetry (CV) measurements confirmed a change of
the electronic properties of 4 when compared to 3. Both nitroxides
show a distinct reversible oxidation as well as an irreversible re-
duction (for spectra, see Supplementary data). With Eox¼þ0.1991 V
versus ferrocene (Fcþ/Fc) as internal standard, the oxidation po-
tential of 4 is significantly lower than the oxidation potential of 3
(Eox¼þ0.3695 V, versus Fcþ/Fc), indicating that 4 is less electro-
philic and more readily oxidized to the corresponding oxoammo-
nium ion. The electron-withdrawing lactam moiety in the
heterocycle of 3 shifts the oxidation potential to a higher value as
compared to 4. Notably, nitroxide 4 is even more readily oxidized
than the TEMPO radical which has an oxidation potential of
Eox¼þ0.2287 V (versus Fcþ/Fc).
2.2. Polymerization studies
Polymerizations were conducted in sealed tubes in neat styrene
or n-butyl acrylate using different initiator concentrations
Fig. 3. Alkoxyamines Mal-3 and Pro-3 included into this study for comparison.
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4
Y. Jing et al. / Tetrahedron xxx (2016) 1e7
Finally, styrene polymerizations were investigated by using Pro-
a highly efficient initiator/regulator for NMP of n-butyl acrylate.
Although known nitroxide 3 as compared to 4 afforded slightly
better results as initiator/regulator for styrene polymerization, it is
important to note that the herein introduced 4 outperforms almost
all existing known NMP regulators.
4 as an initiator/regulator at 70 and 60 ꢀC and different initiator
concentrations. Results obtained are depicted in Table 2. Polymer-
izations occurred smoothly at 70 ꢀC (Table 2, entries 1e3) and
55e72% conversion was achieved after 18 h providing polystyrene
(PS) with a narrow molecular weight distribution (PDIs¼1.13e1.17).
Decreasing the reaction temperature to 60 ꢀC led to a significant
reduction of the polymerization rate. Upon extending the reaction
time to 47 h, acceptable conversions (55e79%) were obtained
(Table 2, entries 4e6). Molecular weight was well-controlled based
on the initiator loading. However, only very little conversion (<5%)
was obtained at 50 ꢀC after 48 h. Again styrene polymerization
results obtained with Pro-4 are compared with those previously
obtained with initiator Pro-3 (Table 2, entries 7e9). For styrene, we
found a different reactivity trend. The novel nitroxide 4 is clearly
less active (lower conversion) as compared to 3 and also slightly
lower control over the molecular weight distribution (larger PDIs)
was achieved.
4. Experimental section
4.1. General
All reactions involving air- or moisture-sensitive reagents or
intermediates were carried out in heat gun-dried glassware under
an argon atmosphere and were performed using standard Schlenk
techniques. All solvents for extraction and flash chromatography
(FC) were distilled before use. Benzene was distilled from Na, THF
was distilled from K, and CH2Cl2 was distilled from P2O5. All the
other solvents and chemicals were used as received from the
suppliers (Alfa, Acros, Aldrich, ABCR, Fluka). Styrene (Acros, 99%)
and n-butyl acrylate (Acros, 99%) were distilled under reduced
pressure from CaH2 to remove stabilizer. Thin layer chromatogra-
phy (TLC) was carried out on Merck silica gel 60 F254 plates; de-
tection by UV or dipping into a solution of KMnO4 (1.5 g), NaHCO3
(5.0 g) in H2O (400 mL), followed by heating. Flash chromatography
Table 2
NMP of styrene under different conditions using alkoxyamine Pro-4 and Pro-3
Entry Alkoxyamine Temperature Time Conversion Mn,th
Mn,exp PDI
(g/mol) (g/mol)
7500 8500 1.17
12,900 14,600 1.13
23,000 25,500 1.14
(mol %)
(oC)
(h)
(%)
(FC) was carried out on Merck or Fluka silica gel 60 (40e63 mm) at
1
2
3
4
5
6
Pro-4 (1)
Pro-4 (0.5)
Pro-4 (0.25) 70
Pro-4 (1)
Pro-4 (0.5)
Pro-4 (0.25) 60
Pro-3 (1)
Pro-3 (0.5)
70
70
18
18
18
47
47
47
24
24
24
72
62
55
79
64
55
64
53
41
about 1.4 bar. 1H NMR and 13C NMR spectra were recorded on
a Bruker DPX-300 (1H: 300 MHz; 13C: 75 MHz), a Varian Inova 500
(1H: 500 MHz; 13C: 125 MHz), or a Varian Unity plus 600 (1H:
60
60
8200
8300 1.23
13,000 12,800 1.16
23,000 23,200 1.22
600 MHz; 13C: 150 MHz). Chemical shifts
d in ppm are referenced to
7a
8a
9a
60
60
6600
7500 1.12
the solvent residual peak. IR spectra were recorded on a Varian
3100 FT-IR equipped with an MKII Golden Gate Single Reflection
ATR unit. ESI-MS (m/z) and HRMS (m/z) were performed using
a Bruker MicroTof and a Waters-Micromass Quattro LCZ (ESI-MS).
Cyclovoltammetry (CV) was conducted in a non-separated micro
cell (6 mL, Metrohm) using a Ag/AgCl reference electrode (0.1 M n-
BuBF4 in MeCN: þ0.21 V versus SHE), a glassy carbon counter
electrode and a round Pt electrode (d¼3 mm) used as working
electrode. A PG-STAT 20 in combination with a VA 663 (Metrohm)
was used as power source. The data were collected with GPES 4.6
(Eco-Chemie B.V.) software and analyzed with Origin Pro 2015.
11,000 14,000 1.13
17,000 18,600 1.09
Pro-3 (0.25) 60
a
Data obtained from Ref. 9.
The livingness of the Pro-4-mediated polymerization of styrene
was proved by plotting ln(M0/M) as a function of time as well as Mn
as a function of conversion (Fig. 4). The data set shows the typical
behavior for controlled radical polymerizations.
Fig. 4. a) Pseudo-first order kinetic plot for the Pro-4 (0.5 mol %) mediated NMP of neat styrene at 70 ꢀC and corresponding PDI values plotted as a function of time. b) Number
average molecular weight Mn as a function of conversion.
3. Conclusions
Ferrocene was used as internal standard. Size exclusion chroma-
tography (SEC) was carried out with degassed THF as eluent at
a flow rate of 1.0 mL/min at rt on a system consisting of a L6200A
We presented the synthesis of a novel sterically highly hindered
nitroxide 4. The developed multi-step approach allows preparing 4
in large amounts. The chiral nitroxide 4 carries a spiro anellated
doubly substituted cyclohexane ring which is fixed in a highly
shielding chair conformation. The corresponding alkoxyamine Pro-
4 was readily prepared in excellent yield and was found to be
Intelligent Pump (Merck Hitachi), a set of two PLgel 5 mm MIXED-C
columns (300ꢁ7.5 mm, Polymer Laboratories), and a Knauer RI
differential refractometer detector. Data were analyzed with PSS
WinGPC Compact V.7.20 software (Polymer Standards Service)
based on calibration curves built upon polystyrene and poly(methyl
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Y. Jing et al. / Tetrahedron xxx (2016) 1e7
5
methacrylate) standards (Polymer Laboratories Polystyrene Me-
dium MW Calibration Kit S-M-10 to determine the molecular
weight of styrene and Poly(methyl methacrylate) Medium MW
Calibration Kit M-M-10 to determine the molecular weight of
poly(n-butyl acrylate)) with peak molecular weights ranging from
1660 to 1,000,000 g/mol.
the reaction mixture was concentrated under reduced pressure.
Subsequent purification by FC (pentane: Et2O, 3:1) afforded the
pure product 7 as a colorless oil (2.18 g, 9.1 mmol, 91%). 1H NMR
(300 MHz, CDCl3):
d
4.80 (dd, J¼7.0, 1.0 Hz, 1H), 4.75e4.66 (m, 2H),
4.57 (d, J¼6.4 Hz, 1H), 3.84 (d, J¼8.3 Hz, 1H), 3.37 (d, J¼8.3 Hz, 1H),
2.10 (br s, 1H, NH), 1.90 (pd, J¼6.9, 1.5 Hz, 1H), 1.82e1.62 (m, 2H),
1.58 (dq, J¼13.2, 3.4 Hz, 1H), 1.45e1.26 (m, 2H), 1.11 (ddd, J¼12.7,
3.5, 1.6 Hz, 1H), 1.03e0.81 (m, 11H). 13C NMR (75 MHz, CDCl3):
4.2. Synthesis of nitroxide 4 and alkoxyamine Pro-4
d
95.62 (Cq), 86.74 (CH2), 83.51 (CH2), 75.75 (CH2), 65.44 (Cq), 48.06
4.2.1. (5S,6S,9R)-6-Isopropyl-9-methyl-1,3-diazaspiro[4.5] decane-
(CH2), 47.89 (CH), 35.22 (CH2), 29.41 (CH), 25.89 (CH), 24.84 (CH3),
23.24 (CH2), 22.40 (CH3), 18.90 (CH3). IR (neat): 3334, 2948, 2928,
2866, 1454, 1356, 1212, 1041, 976, 838 cmꢂ1. HRMS (ESI): calculated
for C14H25NO2Na [MþNa]þ m/z 262.1778, found 262.1773.
2,4-dione (5).10b According to literature protocols reported by
Munday10a] and Edwards,10c
L-(-)-menthone (17.3 mL, 100 mmol,
1.0 equiv) was added to a suspension of KCN (7.16 g, 110 mmol,
1.1 equiv) and (NH4)2CO3 (46.12 g, 480 mmol, 4.8 equiv) in EtOH/
H2O (1:1, 310 mL). The mixture was stirred at 60 ꢀC for 17 h and was
then cooled to 0 ꢀC. The white precipitate formed was filtered and
rinsed with H2O to afford the crude product, which was further
purified by recrystallization from 200 mL hot EtOH. The pure
product 5 was obtained as colorless needles as a single di-
astereoisomer (20.3 g, 90.7 mmol, 90% yield). 1H NMR (300 MHz,
4.2.4. tert-Butyl
(((2R,6S,7S,10R)-2-(hydroxymethyl)-7-isopropyl-
10-methyl-4-oxa-1-aza-spiro[5.5]undecan-2-yl)methyl)carbamate
(9). According to a modified procedure developed by Carreira
et al.,11 TMSCN (507
m
L, 4.05 mmol, 1.5 equiv) was added to a so-
lution of the compound 7 (647 mg, 2.70 mmol, 1.0 equiv) and
In(OTf)3 (30 mg, 54 mol, 2 mol %) in CH3CN (6 mL). The reaction
m
DMSO-d6):
(m, 6H, 3ꢁCH2), 1.31 (m, 2H, 2ꢁCH), 0.99e0.77 (m, 10H, 3ꢁCH3,
CH). 13C NMR (75 MHz, DMSO-d6):
178.42 (CO), 156.50 (CO), 67.00
(Cq), 45.65 (CH), 44.24 (CH2), 34.02 (CH2), 27.80 (CH), 27.24 (CH),
23.16 (CH3), 21.82 (CH3), 21.38 (CH2), 18.19 (CH3).
d
10.54e10.35 (br s, 1H, NH), 8.29 (s, 1H, NH), 1.76e1.41
mixture was stirred at rt overnight. An aqueous NaHCO3 (sat.) was
added and the resulting mixture was extracted with CH2Cl2. The
combined organic phase was then dried over MgSO4 and concen-
trated under vacuum to afford the crude product 8 (915 mg), which
was used without further purification. Under argon, LAH (512 mg,
13.5 mmol, 5.0 equiv) was slowly added to a solution of crude 8 in
THF (5 mL) at 0 ꢀC. The reaction mixture was allowed to warm to rt
and was then stirred for further 30 min. Next, the reaction mixture
was heated under reflux overnight. After cooling to 0 ꢀC, H2O
(0.5 mL), aqueous NaOH (15%, 0.5 mL) and H2O (1.5 mL) were added
successively. The resulting suspension was filtered through Celite
and washed with EtOAc. After concentration of the filtrate under
vacuum, the crude amino alcohol (730 mg) was obtained. The crude
d
4.2.2. ((1S,2S,5R)-1-Amino-2-isopropyl-5-methylcyclohexyl) metha-
nol (6).13 According to a modified protocol of Munday,10a the
hydantoin 5 (20.3 g, 90.7 mmol, 1.0 equiv) was added to an aqueous
H2SO4 solution (60%, 240 mL). The reaction mixture was stirred for
ꢀ
2 days at 150 C. Then the dark solution was cooled to room tem-
perature, filtered and washed with H2O. After neutralization of the
filtrate with NaOH, the water in the solution was removed by
freeze-drying technology. Methanol was added to the resulting
white solid toꢀextract the product (amino acid). The suspension was
stirred at 40 C for 30 min and then filtered. After repeating this
procedure three times, the combined filtrate was concentrated. The
crude amino acid was obtained by removal of methanol, and was
used without any further purification. The crude amino acid (16 g)
and NaBH4 (10.7 g, 284 mmol, 3.5 equiv) were suspended in THF
(250 mL) under argon. A solution of I2 (24.7 g, 97.2 mmol, 1.2 equiv)
in THF (80 mL) was added dropwise to the reaction mixture. After
ceasing of gas formation, the reaction mixture was heated to reflux.
After refluxing for 18 h, the reaction mixture was cooled to rt and
treated with methanol. The mixture was concentrated under vac-
uum and then redissolved with an aqueous KOH solution (20%,
260 mL). The resulting solution was refluxed for 3 h and then
cooled to rt. After extraction with CH2Cl2, the collected organic
phase was dried over MgSO4 and concentrated under vacuum.
Upon bulb to bulb distillation under reduced pressure, the pure
amino alcohol 6 was obtained as a colorless oil (12.6 gꢀ, 68 mmol,
84% yield over two steps), which slowly crystallized at 0 C. 1H NMR
amino alcohol and NEt3 (565 mL, 4.00 mmol, 1.5 equiv) were dis-
solved in a mixture of CH2Cl2/MeOH (1:4, 20 mL). A solution of
Boc2O (766 mg, 3.50 mmol, 1.3 equiv) in MeOH (4.0 mL) was then
added and the reaction mixture was stirred at rt overnight. After
removal of the solvent under reduced pressure, the crude product
was purified by FC (CH2Cl2: Et2O, 6:1) to afford 9 as a colorless oil
(790 mg, 2.13 mmol, 79% yield over three steps). 1H NMR (300 MHz,
CDCl3):
d
4.86 (t, J¼6.7 Hz,1H), 3.62 (t, J¼10.7 Hz, 2H), 3.38e3.18 (m,
5H), 3.08 (d, J¼11.3 Hz, 1H), 2.22e1.99 (m, 2H), 1.75 (dp, J¼12.8,
3.2 Hz, 1H), 1.55e1.36 (m, 12H), 1.36e1.23 (m, 1H), 0.92e0.71 (m,
12H). 13C NMR (75 MHz, CDCl3):
d 157.50, 80.27, 76.02, 71.21, 66.07,
54.88, 53.94, 48.28, 47.23, 44.40, 35.39, 28.46, 28.17, 26.02, 24.84,
22.60, 21.45, 19.43. IR (neat): 3372, 2953, 2868, 1691, 1504, 1458,
1367, 1252, 1171, 1115, 1086, 1047, 666 cmꢂ1. HRMS (ESI): calculated
for C20H38N2O4H [MþH]þ m/z 371.2904, found 371.2901.
4.2.5. tert-Butyl (((2R,6S,7S,10R)-7-isopropyl-2-(methoxy methyl)-
10-methyl-4-oxa-1-aza-spiro[5.5]undecan-2-yl)methyl) (methyl)car-
bamate (10). NaH (690 mg, 17.3 mmol, 5.0 equiv) was added to
a solution of compound 9 (1.28 g, 3.45 mmol, 1.0 equiv) in THF
(30 mL) at 0 ꢀC. The reaction mixture was stirred for 30 min at the
same temperature and then MeI (1.08 mL,17.3 mmol, 5.0 equiv) was
added dropwise. The resulting solution was allowed to warm to rt
and stirring was continued overnight. H2O was added and the
resulting mixture was extracted with EtOAc (three times). The
combined organic phase was dried over MgSO4 and concentrated
under vacuum. Purification by FC (pentane: Et2O, 3:1) afforded the
product 10 as a colorless oil (1.19 g, 3.10 mmol, 90%). 1H NMR
(300 MHz, CDCl3):
d
3.53 (d, J¼10.5 Hz, 1H, CHH), 3.32 (d, J¼10.5 Hz,
1H, CHH), 2.06 (pd, J¼6.9, 1.9 Hz, 1H), 1.85 (br s, 3H, NH2, OH), 1.76
(dq, J¼12.7, 3.2 Hz, 1H), 1.61e1.50 (m, 3H), 1.35 (qd, J¼12.9, 3.5 Hz,
1H), 1.17 (ddd, J¼12.7, 3.4, 1.9 Hz, 1H), 1.04e0.93 (m, 1H), 0.93e0.76
(m, 10H). 13C NMR (75 MHz, CDCl3):
d 70.80 (CH2), 56.30 (Cq), 47.84
(CH), 46.45 (CH2), 35.41 (CH2), 28.00 (CH), 25.92 (CH), 24.60 (CH3),
22.65(CH3), 21.39 (CH2), 18.81 (CH3).
4.2.3. (6S,7S,10R)-7-Isopropyl-10-methyl-2,13-dioxa-5-aza- dispiro
[3.1.56.24]tridecane (7). According to a modified procedure de-
veloped by Carreira et al.,11 the amino alcohol 6 (1.85 g, 10.0 mmol,
1.0 equiv) was added to a solution of 3-oxetanone (792 mg,
(300 MHz, CDCl3):
d
3.94e3.79 (m, 1H), 3.74 (d, J¼11.4 Hz, 1H),
3.60e3.51 (m, 1H), 3.33e3.24 (m, 4H), 3.20e3.08 (m, 2H),
3.04e2.98 (m, 1H), 2.93e2.80 (m, 4H), 2.26 (dt, J¼13.9, 2.7 Hz, 1H),
2.12e1.97 (m, 1H), 1.72e1.63 (m, 2H), 1.49e1.35 (m, 12H), 0.92e0.81
11.0 mmol, 1.1 equiv), acetic acid (58
4 A MS (1.0 g) in CH2Cl2 (20 mL). After being stirred at rt for 4 days,
m
L, 0.10 mmol, 10 mol %) and
(m, 11H), 0.75e0.63 (m, 1H). 13C NMR (75 MHz, CDCl3):
d 156.73,
ꢀ
Please cite this article in press as: Jing, Y.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.04.008

6
Y. Jing et al. / Tetrahedron xxx (2016) 1e7
77.23, 75.75, 59.06, 53.78, 53.39, 48.73, 47.01, 36.99, 35.69, 28.54,
27.26, 25.85, 25.02, 22.53, 21.14, 18.97. IR (neat): 2952, 2869, 1697,
1457, 1389, 1255, 1161, 1108, 876, 773 cmꢂ1. HRMS (ESI): calculated
for C22H42N2O4H [MþH]þ m/z 399.3217, found 399.3221.
CDCl3): d 153.81, 76.26, 74.09, 71.67, 54.43, 49.91, 48.03, 46.47,
46.45, 35.23, 29.82, 28.05, 26.02, 24.61, 22.45, 20.93, 19.19. IR
(neat): 3324, 3248, 2953, 2869, 1700, 1491, 1283, 1119, 1090, 1036,
736, 706 cmꢂ1. HRMS (ESI): calculated for C16H28N2O3Na [MþNa]þ
m/z 319.1992, found 319.1997.
4.2.6. tert-Butyl (((2R,6S,7S,10R)-7-isopropyl-2-(methoxy methyl)-
10-methyl-4-oxa-1-aza-spiro[5.5]undecan-2-yl)methyl) (methyl)car-
bamate-1-oxyl (4). Peroxoacetic acid (39% in AcOH, 1.1 mL,
6.3 mmol, 2.5 equiv) was slowly added to a solution of compound
10 (1.0 g, 2.5 mmol, 1.0 equiv) in EtOAc (25 mL). The resulting
mixture was then stirred at 50 ꢀC for 2 days. H2O was added to
hydrolyze the excess oxidant, and the aqueous phase was extracted
by EtOAc (three times). The combined organic layer was washed
with aqueous sat. NaHCO3, and dried over MgSO4. After filtration
and concentration under vacuum, purification by FC (CH2Cl2: Et2O,
6:1) provided the nitroxide 4 as an orange oil (592 mg, 1.40 mmol,
57%). IR (neat): 2952, 2925, 2870,1698,1455,1389,1367, 1312,1254,
1155, 1121, 1096, 876, 774 cmꢂ1. HRMS (ESI): calculated for
4.3. Nitroxide mediated polymerization
4.3.1. General procedure for the polymerization of n-butyl acryl-
ate. Under argon atmosphere, the alkoxyamine Pro-4 and n-butyl
acrylate (0.50 mL, 3.5 mmol) were added into a heat gun dried
Schlenk tube. The reaction mixture was subjected to freeze-thaw
cycles for three times and was then heated to the given tempera-
ture (see Table 1, 50e70 ꢀC) for a specified time. The reaction
mixture was cooled to room temperature, dissolved in CH2Cl2, and
transferred into a vial. Solvent was evaporated under reduced
pressure and the polymer was obtained after removing the
unreacted monomer in a vacuum-drying cabinet at 60 ꢀC overnight.
The conversion of the polymerization was determined gravimetri-
cally, and molecular weight and polydispersity index (PDI) were
determined by GPC.
C
22H41N2O5Na [MþNa]þ m/z 436.2908, found 436.2911.
4.2.7. Methyl 2-(((2R,6S,7S,10R)-2-(((tert-butoxycarbonyl) (methyl)
amino)methyl)-7-isopro-pyl-2-(methoxymethyl)-10-methyl-4-oxa-
1-azaspiro[5.5]undecan-1-yl)oxy)propanoate
a modified procedure reported by Matyjaszewski12a and Kiriy,12b
pentamethyl-diethylenetriamine (PMDETA, 336 L, 1.60 mmol,
2.0 equiv) was slowly added to a suspension of methyl 2-
bromopropanoate (267 mg, 1.60 mmol, 2.0 equiv), CuBr (230 mg,
(Pro-4). Following
4.3.2. General procedure or the polymerization of styrene. Under
argon, the alkoxyamine Pro-4 and styrene (0.50 mL, 4.4 mmol)
were added into a heat gun dried Schlenk tube. The reaction mix-
ture was subjected to freeze-thaw cycles for three times, and was
then heated to given temperature (see Table 2, 60 or 70 ꢀC) for
a specified time. The reaction mixture was cooled to room tem-
perature, dissolved in CH2Cl2, and transferred into a vial. Solvent
was evaporated under reduced pressure and the polymer was ob-
m
1.60 mmol, 2.0 equiv) and the nitroxide 4 (331 mg, 800
mmol,
1.0 equiv) in benzene under argon. After stirring at rt for 1 h, the
product was isolated by FC (pentane: Et2O, 3:1). The solvent after
the column was rapidly removed at 10 ꢀC under vacuum to provide
the alkoxyamine Pro-4 as a colorless oil as a mixture of the two
tained after removing the unreacted monomer in a vacuum-drying
ꢀ
cabinet at 60 C overnight. The conversion of the polymerization
diastereoisomers (367 mg, 730
m
mol, 92% yield). The ratio of the
was determined gravimetrically, and molecular weight and PDI
were determined by GPC.
two isomers could not be determined due to signal overlap in the
1H NMR spectrum. 1H NMR (300 MHz, CDCl3): one isomer:
d
4.67e4.46 (m, 1H), 4.09e3.86 (m, 2H), 3.85e3.47 (m, 7H),
4.4. X-ray diffraction
3.33e3.19 (m, 4H), 3.15e2.87 (m, 4H), 2.59e2.41 (m, 1H), 2.30e2.04
(m, 2H), 1.79e1.68 (m, 1H), 1.60e1.23 (m, 15H), 0.99e0.90 (m, 6H),
Data sets for the compound 11 were collected with a D8 Venture
Dual Source 100 CMOS diffractometer. Programs used: data col-
lection: APEX2 V2014.5e0;14 cell refinement: SAINT V8.34A
(Bruker AXS Inc., 2013); data reduction: SAINT V8.34A (Bruker AXS
Inc., 2013); absorption correction, SADABS V2014/2 (Bruker AXS
Inc., 2014); structure solution SHELXT-2014;15 structure refinement
SHELXL-2014.15 R-values are given for observed reflections, and
wR2 values are given for all reflections. Thermals ellipsoids are
shown with 50% probability. R-values are given for observed re-
flections, and wR2 values are given for all reflections.
0.87e0.70 (m, 5H); the other isomer:
d
4.62 (q, J¼6.9 Hz, 1H), 4.18
(d, J¼14.6 Hz, 1H), 3.95 (dd, J¼11.8, 2.2 Hz, 1H), 3.87e3.65 (m, 4H),
3.59 (d, J¼11.3 Hz, 1H), 3.42e3.23 (m, 3H), 3.20 (s, 3H), 3.03 (d,
J¼10.0 Hz, 1H), 2.91 (s, 3H), 2.54 (d, J¼14.8 Hz, 1H), 2.28e2.01 (m,
2H), 1.80 (d, J¼13.1 Hz, 1H), 1.72e1.53 (m, 3H), 1.52e1.35 (m, 12H),
1.02e0.92 (m, 6H), 0.89e0.72 (m, 5H). The 13C NMR of the two
isomers of Pro-4 couldn’t be assigned due to the complexity of the
spectrum. IR (neat): one isomer: 2954, 2871, 1755, 1696, 1454, 1391,
1159, 1105, 973, 878, 774 cmꢂ1; the other isomer: 2953, 2870, 1749,
1694, 1453, 1390, 1367, 1158, 1104, 973, 877, 731 cmꢂ1. HRMS (ESI)
calculated for C26H48N2O7Na [MþNa]þ m/z 523.3354, found one
isomer: 523.3361; the other isomer: 523.3365.
X-ray crystal structure analysis of 11: A colorless plate-like
specimen of
C16H28N2O3$CH4O, approximate dimensions
0.084 mmꢁ0.090 mmꢁ0.254 mm, was used for the X-ray crystal-
lographic analysis. The X-ray intensity data were measured. A total
of 1078 frames were collected. The total exposure time was 19.01 h.
The frames were integrated with the Bruker SAINT software pack-
age using a wide-frame algorithm. The integration of the data using
a monoclinic unit cell yielded a total of 10,240 reflections to a
4.2.7. (6S,8S,9S,12R)-9-Isopropyl-12-methyl-2,15-dioxa-4,7-
dia-
zadispiro[5.1.58.36]hexa-decan-3-one (11). The Boc-protected amino
alcohol 9 (503 mg, 1.36 mmol, 1.0 equiv) was dissolved in THF
(10 mL) and the reaction mixture was cooled to 0 ꢀC. Potassium tert-
butoxide (229 mg, 2.04 mmol,1.5 equiv) was then added slowly and
the reaction mixture was allowed to warm to rt. After stirring
overnight, aqueous NH4Cl (sat.) was added. The resulting mixture
was extracted with EtOAc (three times) and the combined organic
phase was dried over MgSO4 and concentrated. The pure carbamate
11 was obtained by FC (CH2Cl2: Et2O, 1:2) as a white solid (374,
ꢀ
ꢀ
maximum q angle of 68.46 (0.83 A resolution), of which 3268 were
independent (average redundancy 3.133, completeness¼98.3%,
Rint¼2.60%, Rsig¼2.69%) and 3125 (95.62%) were greater than
2
ꢀ
ꢀ
2
s
(F ). The final cell constantsꢀof a¼8.3182(2) A, b¼9.6473(2) A,
3
ꢀ
ꢀ
c¼11.6026(3) A, ¼99.9790(10) , volume¼917.00(4) A , are based
b
upon the refinement of the XYZ-centroids of 7487 reflections above
1.26 mmol, 93%). 1H NMR (600 MHz, CDCl3):
d
6.10 (br s, 1H), 4.01
20
s
(I) with 7.736ꢀ<2 <136.9ꢀ. Data were corrected for absorption
q
(d, J¼11.5 Hz, 1H), 3.90e3.77 (m, 3H), 3.70 (d, J¼11.0 Hz, 1H), 3.39
(d, J¼11.0 Hz, 1H), 3.31 (d, J¼11.6 Hz, 1H), 3.23e3.09 (m, 1H),
2.13e1.98 (m, 2H), 1.78e1.69 (m, 1H), 1.57e1.48 (m, 1H), 1.48e1.37
(m, 1H), 1.29e1.08 (m, 2H), 0.95e0.78 (m, 12H). 13C NMR (150 MHz,
effects using the multi-scan method (SADABS). The ratio of mini-
mum to maximum apparent transmission was 0.915. The calculated
minimum and maximum transmission coefficients (based on
crystal size) are 0.8470 and 0.9450. The final anisotropic full-matrix
Please cite this article in press as: Jing, Y.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.04.008

Y. Jing et al. / Tetrahedron xxx (2016) 1e7
7
least-squares refinement on F2 with 227 variables converged at
R1¼2.70%, for the observed data and wR2¼6.70% for all data. The
goodness-of-fit was 1.032. The largest peak in the final difference
€
Encyclopedia of Polymeric Nanomaterials; Kobayashi, S., Mullen, K., Eds.;
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3
ꢂ ꢀ
electron density synthesis was 0.157 e /A and the largest hole was
3
ꢂ ꢀ
3
ꢂ ꢀ
ꢂ0.121 e /A with an rms deviation of 0.030 e /A . On the basis of
the final model, the calculated density was 1.190 g/cm3 and F(000),
360 eꢂ.
Acknowledgments
This work was financially supported by the Chinese Scholarship
Council (stipend to Y.J.).
Supplementary data
Supplementary data (Crystallographic data (excluding structure
factors) for compound 11 in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC1445405. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: þ44 (0)1223-336033 or e-mail: depos-
it@ccdc.cam.ac.Uk.)) associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2016.04.008.
€
dEur. J. 2004, 10, 1156e1166; (b) Chang, C.-C.; Studer, A. Macromolecules 2006,
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Please cite this article in press as: Jing, Y.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.04.008