The synthesis and evaluation of new α-hydrogen nitroxides for 'living' free radical polymerization

Article abstract of DOI:10.1055/s-2005-869894

Three N-alkoxyamines were synthesized for use in nitroxide-mediated radical polymerization. Upon thermolysis, they generate new acyclic α-hydrogen nitroxides: one adamantyl substituted and two diol-containing nitroxides. The initiators were tested in polymerization reactions in direct comparison with the initiator derived from the nitroxide TIPNO. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869894

1496
PAPER
The Synthesis and Evaluation of New a-Hydrogen Nitroxides for ‘Living’ Free
Radical Polymerization
S
ynthesis and Ev
e
aluation of
b
N
ew
a
-Hydr
e
ogen
N
itro
c
Laura Mueller, Jean Ruehl
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA
Fax +1(831)4592935; E-mail: braslau@chemistry.ucsc.edu
Received 8 February 2005
Dedicated to the illustrious career of Professor Bernd Giese and his influence on the chemical community
Thus all three methods constitute valuable options in the
Abstract: Three N-alkoxyamines were synthesized for use in ni-
troxide-mediated radical polymerization. Upon thermolysis, they
generate new acyclic a-hydrogen nitroxides: one adamantyl substi-
tuted and two diol-containing nitroxides. The initiators were tested
methodologies available for producing designed polymers
using free radical intermediates, yet there is room for im-
provement. With NMRP, an important achievement
in polymerization reactions in direct comparison with the initiator would be developing a system that would allow polymer-
derived from the nitroxide TIPNO.
izations to be carried out at temperatures lower than the
105–125 °C that are typically employed. The ability to po-
lymerize electron rich olefins in a controlled manner
would further extend the versatility of NMRP. For all of
these goals, the characteristics of the nitroxide end-cap are
key to improving the polymerization profile. Previously,
we4 and the group of Tordo5 have introduced a-hydrogen
nitroxides TIPNO 1 and SG-1 2, which are effective in the
polymerization of styrenes and a variety of electron poor
olefin monomers. Very recently a number of cyclic6 and
acyclic7 new nitroxides have been introduced for im-
proved efficacy in NMRP. Herein we present work on ini-
tiators based on several new acyclic a-hydrogen
nitroxides for NMRP, in which the N-tert-butyl has been
modified.
The synthesis of the adamantyl-based nitroxide8 was ini-
tially approached using the methodology previously de-
veloped in this laboratory for the preparation of TIPNO 1
(Figure 1).4 To prepare the starting nitro compound ni-
troadamantane 5, oxidation of adamantylamine was car-
ried out by preparing dimethyldioxirane in situ from
Oxone® and acetone under buffered conditions
(Scheme 1).9 This reaction appeared to proceed in reason-
able yield, however the product apparently contained the
nitroso compound as a contaminate, as indicated by a pale
blue tint to the solid product. As the next step involves in
situ reduction of the nitro compound to the hydroxyl-
amine, it seemed unimportant to remove the nitroso impu-
Key words: nitroxide, nitrone, free radicals, polymers, Grignard
reaction
Nitroxide-mediated ‘living’ free radical polymerization
(NMRP) has become a very attractive method for the con-
trolled polymerization of olefins, as monomers bearing a
wide variety of functionality can be tolerated under the
polymerization conditions. The resulting polymers gener-
ally display good control over both molecular weight and
polydispersity, and the ‘living’ nitroxide endcap allows
for the preparation of nanoscopic materials with highly
designed architecture.1 Other ‘living’ radical techniques
such as Atom Transfer Radical Polymerization (ATRP)
mediated by a metal complex,2 and Reversible Addition
Fragmentation Transfer (RAFT) mediated by a thiocar-
bonyl intermediate3 have also been developed. ATRP has
the advantage that it can be run at lower temperatures, and
it functions well with methacrylates, but amine containing
monomers sometimes coordinate to the metal catalyst, in-
terfering with the polymerization process. Polymers made
by ATRP contain traces of metal, derived from the metal
catalyst. RAFT polymerization is effective with a wider
range of monomers, including electron rich vinyl acetates,
which are not good substrates for NMRP and ATRP.
However sulfur-containing impurities may lead to unde-
sirable colored polymers prepared by the RAFT process.
R
N
O
N
O
N
O
N
HO
Ph
P(OEt)2
Ph
Ph
O
OH
O
R = Me
R = Ph
TIPNO
1
SG-1
2
AD
3
diol-Me 4a
diol-Ph 4b
Figure 1
SYNTHESIS 2005, No. 9, pp 1496–1506
x
x
.
x
x
.2
0
0
5
Advanced online publication: 11.05.2005
DOI: 10.1055/s-2005-869894; Art ID: C00405SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Evaluation of New a-Hydrogen Nitroxides
1497
O O
Zn, NH4Cl
NH2
NO2
5
N
O
Oxone®
O
6
O
33%
pH = 7–8
68%
+
O
N
1. PhMgBr
64%
blue
2. Cu(OAc)2, air
Mn(salen)*
NaBH4
air
N
O
N
O
Ph
7 = ‘AD’
Ph
Ph
3
76%
Ph
Scheme 1
rity, which is already one oxidation state closer to m-chloroperbenzoic acid to prepare the oxaziridine 9. The
hydroxylamine than the nitro compound. Thus the crude nitrone 10 was formed by thermal rearrangement in re-
nitroadamantane was treated with zinc and ammonium fluxing MeCN.11a Rearrangement induced by treatment
chloride in the presence of iso-butyraldehyde to give the with Lewis acid11b–d was also examined, however the mild
nitrone 6 in a disappointing 33% yield.
conditions of MeCN thermolysis give superior results.
Addition of iso-propyl Grignard in conjunction with tri-
methylsilyl chloride followed by copper catalyzed oxida-
tion provided the same adamantyl nitroxide 3 in good
yields (Scheme 2).
It is likely that the low yield of nitrone is due to inefficient
reduction of nitroadamantane due to the presence of resid-
ual oxidizing species derived from Oxone® and acetone
used in the previous step. This is supported by the 13C
NMR spectrum of the nitro compound, which shows three Polymerizations using this adamantyl initiator AD 7 were
peaks at d = 38.6, 36.0 and 30.2 ppm corresponding to the run side by side with polymerizations using TIPNO de-
three contaminants dimethyldioxirane, di-dimethyldiox- rived initiator for direct comparison. The results can be
irane, and tri-dimethyldioxirane (Figure 2).9 Addition of seen in Table 1. Polymerizations with and without added
phenyl Grignard to the nitrone, followed by Cu(II) cata- free nitroxide were examined. Addition of free nitroxide
lyzed oxidation of the resulting hydroxylamine gave the did not enhance the polymerization of styrene (St), consis-
adamantyl nitroxide 3 in 64% yield. Use of Hawker’s tent with previous observations.4 In polymerizations using
manganese catalyzed N-alkoxyamine preparation using dimethyl acrylamide (DMA), tert-butyl acrylate (TBA)
Jacobsen’s catalyst10 afforded the adamantyl initiator 7, and n-butyl acrylate (NBA), polydispersities were slightly
‘AD’ (Scheme 1).
improved by addition of 5% free nitroxide using either
initiator. In comparing the two initiators, the results of the
polymerization of styrene showed no significant differ-
ence, whereas with all three of the other monomers, the
new adamantyl initiator generally displayed slightly low-
er polydispersities and concurrently higher molecular
weights of the resulting polymers.
O
O
O
O
O
O
O
O
O
O
O
O
Figure 2
As TIPNO functions nicely at 125 °C, the real advantage
of a new nitroxide-based initiator would be in the ability
to conduct polymerizations at milder temperatures. Thus
polymerizations at 105 °C were conducted with both
TIPNO and the adamantyl initiators (Table 2). At this
lower temperature, polymerizations were run for 120
Unsatisfied with the low yields obtained at the beginning
of this sequence, we developed an alternative route to the
nitrone. Thus the imine 8 produced from the condensation
of adamantyl amine and benzaldehyde was oxidized with
O
mCPBA
74%
Ph
O
N
CH3CN
NH2
Ph
10
MgCl, TMS-Cl
N
tol
N
O–
Ph
reflux, 2 d
65%
Ph
Dean–Stark
8
9
81%
1.
98%
2. cat. CuII, air
Ph
N
O
3
Scheme 2
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

1498
R. Braslau et al.
PAPER
Table 1 Polymerization Using Adamantyl Initiator 7 vs. TIPNO-Based Initiator at 125 °C
Entry
1
Monomer
St
Initiator
TIPNO
TIPNO
AD
Added Nitroxide
5% BV
Equiv of Monomer Time (h)
Mw (GPC)
61,000
69,000
85,000
122,000
55,000
25,000
24,000
51,000
36,000
27,000
46,000
53,000
84,000
111,000
115,000
115,000
71,000
PD (GPC)
1000
1000
1000
1000
1000
1000
200
20
20
20
20
19
19
24
19
19
24
39
39
39
39
92
92
16
1.19
1.20
1.22
1.19
1.27
1.30
1.48
1.25
1.31
1.19
1.18
1.22
1.17
1.17
1.36
1.42
1.45
2
St
None
3
St
5% AD
None
4
St
AD
5
DMA
DMA
DMA
DMA
DMA
DMA
TBA
TBA
TBA
TBA
NBA
NBA
NBA
TIPNO
TIPNO
TIPNO
AD
5% TIPNO
None
6
7
5% TIPNO
5% AD
None
8
1000
1000
200
9
AD
10
11
12
13
14
15
16
17
AD
5% AD
5% TIPNO
None
TIPNO
TIPNO
AD
1000
1000
1000
1000
1000
1000
200
5% AD
None
AD
TIPNO
TIPNO
TIPNO
5% TIPNO
None
5% TIPNO
St = styrene, DMA = N,N-dimethyl acrylamide, TBA = tert-butyl acrylate, NBA = n-butyl acrylate.
AD = adamantyl initiator 7, TIPNO = N-tert-butyl isopropylphenyl nitroxide-based initiator.
Note: in some cases, a portion of the monomer was lost during the freeze/pump/thaw procedure.
hours (5 d). With acrylate monomers, the adamantyl initi- the synthesis is not as straightforward, as it requires pro-
ator was clearly superior to TIPNO-based initiator, where- tection of the hydroxy group by trimethylsilyl or THP12
as with dimethyl acrylamide, both initiators demonstrated during the entire reaction sequence. During polymeriza-
poor control. However, neither initiator showed good con- tion, it is believed that hydrogen bonding between the hy-
trol at 105 °C.
droxy group and the nitroxide oxygen13 in a six-
membered ring 12 stabilizes the nitroxide. This is reflect-
ed in a lower BDE of the key carbon-oxygen bond and an
associated faster Kd of the N-alkoxyamine growing chain-
In 1999, we introduced the monohydroxy analogue of
TIPNO 11.4 It functions slightly better than TIPNO, but
Table 2 Polymerization Using Adamantyl Initiator 7 vs. TIPNO Initiator at 105 °C
Entry
Monomer
DMA
DMA
NBA
Initiator
AD
Added Nitroxide
5% AD
Time (h)
120
M
w (NMR)
Mw (GPC)
13,000
PD (GPC)
1.99
1
2
3
4
5
6
97,200
95,800
52,600
26,200
119,400
115,500
TIPNO
AD
5% TIPNO
5% AD
120
10,300
1.76
120
96,000
1.29
NBA
TIPNO
AD
5% TIPNO
5% AD
120
28,300
1.15
TBA
120
140,000
91,000
1.48
TBA
TIPNO
5% TIPNO
120
1.97
SDMA = N,N-dimethyl acrylamide, TBA = tert-butyl acrylate, NBA = n-butyl acrylate.
Note: All of these polymerizations were carried out with 1000 equiv of monomer.
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

PAPER
Synthesis and Evaluation of New a-Hydrogen Nitroxides
1499
end. There is also a weak contribution by polar ground trones 16 and 18, respectively (Scheme 3). Grignard
state effects that destabilize the N-alkoxyamine with the addition followed by CuII catalyzed air oxidation gave
addition of hydroxy substituents.14 Recently Studer7b and protected diol nitroxide 19. Conversion to the N-
Hawker7c have developed the triol-substituted analogue of alkoxyamine 20, followed by deprotection with ten equiv-
TIPNO 13, with the idea that three hydrogen bonds should alents of trifluoroacetic acid (TFA) gave the diol-Me ini-
be better than one in stabilizing the nitroxide intermediate. tiator 21 in 71% yield. Use of fewer equivalents of TFA
This triol initiator does have a lower BDE and faster Kd at resulted in significantly lower yields.
120 °C (BDE = 125.1 kJ/mol, Kd = 5.6 × 10–3 s–1)14,15 than
In initial polymerization screens (Table 3), Me-diol initi-
ator 21 showed slightly less control than the TIPNO-based
the TIPNO based initiator (BDE = 129.6 kJ/mol, Kd =
3.3 × 10–3 s–1),15,16 and it does indeed function effectively
initiator. Since the free nitroxide Me-diol 4a could not be
in effecting polymerization at lower temperatures than
obtained, 2.5% of the nitroxide TIPNO was added in the
TIPNO. However, the synthesis requires the use of an
n-butyl acrylate polymerizations. Although it is clear that
ortho ester as a triol protection group, and is somewhat
nitroxides are free to exchange during the polymerization
challenging. We felt that the diol analogue would be eas-
reaction,18 any significant excess of free a-hydrogen ni-
ier to protect and deprotect, and would likely afford a sim-
troxide is expected to decompose19 at 124 °C. Thus incor-
ilar hydrogen-bonding advantage in lowering the BDE of
poration of TIPNO into the growing polymer chains
the N-alkoxyamine initiator and macroinitiators during
would at most be 2.5%, but is likely significantly less. The
role of the added nitroxide is to prevent undesired radical
chain termination reactions from occurring at the onset of
polymerization. Thus we prepared N-alkoxyamine initia-
tors based on nitroxide diols 4a and 4b (Figure 3). In the
latter, the extra steric bulk of the neopentyl phenyl group
the polymerization before the Persistent Radical Effect20
might also help to lower the BDE to allow for polymeriza-
can establish a steady state concentration of free nitroxide.
tion to proceed at lower temperatures.
By spiking the polymerization with a small amount of ni-
To prepare an initiator based on methyl substituted nitrox- troxide, the system is forced to ‘livingness’ and thus to
ide diol 4a, the hydroxy groups of 2-nitro-2-methyl-1,3- control in the early moments of the polymerization.21
propanediol (14) were protected as acetal 15 using benzal-
The second diol starting material, phenyl substituted 22,
dehyde following the procedure of Piotrowska et al.17 Al-
was protected as the acetonide, which was then converted
though our general procedure for nitrone formation
usually involves a one-pot reaction involving reduction of
the nitro compound to the hydroxylamine, followed by in
situ condensation with an aldehyde, with this substrate, a
two-step procedure gave superior results. Both benzalde-
hyde and isobutyroaldehyde were utilized to prepare ni-
to the N-alkoxyamine 26 following a similar procedure
(Scheme 4). Final deprotection using trifluoroacetic acid
provided the phenyl substituted N-alkoxyamine diol 27.
HO
HO
Ph
N
O
N
O
N
O
N
O
N
HO
HO
Ph
12
Ph
Ph
Ph
Ph
O
OH
OH
O
OH
OH
H
11
13
4a
4b
Figure 3
3 equiv
1. activated Zn, NH4Cl
i-PrMgCl
N
HO
N
O
Ph
2. 2 equiv
Ph
Ph
O
O
O
O
99%
O
O
Cu(OAc)2,
NH4OH,
Ph
89%
16
Ph
17
Ph
NO2
NO2
p-TsOH
PhH
Dean–Stark
HO
73%
O
air
OH
14
O
80%
1. activated Zn,
NH4Cl
Ph
1. 2 equiv PhMgBr
15
N
O
75%
N
O
O
Ph
19
O
O
2. Cu(OAc)2,
NH4OH, air
2. 2 equiv
O
18
O
Ph
Ph
Ph
83%
Mn(salen)*
NaBH4, air
88%
N
O
10 equiv TFA
71%
N
O
Ph
Ph
20
HO
HO
Ph
O
O
Ph
Ph
21
Scheme 3
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

1500
R. Braslau et al.
PAPER
Table 3 Polymerizations Using Diol Initiator 21 vs. TIPNO-Based Initiator
Entry
Initiator
TIPNO
21
Monomer
St
Temp. (°C)
Time (h)
Mw (NMR)
71,000
Mw (GPC)
63,900
62,600
63,500
69,300
97,600
184,000
25,100
96,600
PD (GPC)
1
2
3
4
5
6
7
8
124
124
90
8
8
1.24
1.27
1.19
1.25
1.39
1.57
1.42
5.03
St
71,100
TIPNO
21
St
72
72
120
8
53,400
St
90
49,200
TIPNOa
21a
NBA
NBA
NBA
NBA
124
124
90
97,600
Not determined
27,200
TIPNOa
21a
140
17
90
95,100
NBA = n-butyl acrylate, St = styrene
1000 equivalents of monomer were used.
a In all NBA polymerizations, 2.5% of the nitroxide TIPNO was added.
Ph
Ph
N
MeO
OMe
Ph
NO2
Zn, NH4Cl
NO2
O
O
O
O
O
HO
p-TsOH
71%
OH
24
23
22
O
67%
1. PhMgBr
34%
Ph
2. Cu(OAc)2, air
Mn(salen)*
NaBH4
air
Ph
Ph
TFA
N
O
N
N
O
O
Ph
aq THF
32%
HO
HO
O
O
Ph
Ph
O
O
Ph
26
25
44%
27
Ph
Ph
Scheme 4
Polymerizations using the diol-Ph initiator 27 (Table 4) Table 4 Polymerizations Using Diol 27 vs. TIPNO-Based Initiator
at 124 °C
showed significantly poorer control than those using the
TIPNO-derived N-alkoxyamine, particularly with tert-bu-
Entry
Initiator
TIPNO
27
Monomer
ST
Mw (GPC) PD (GPC)
tyl acrylate and dimethyl acrylamide monomers. This was
surprising, as the increased steric bulk of the phenyl group
in diol-Ph 4b compared to the methyl group in diol-Me 4a
was expected to help destabilize the parent N-alkoxy-
amine, and thus lower the BDE.
1
2
3
4
5
6
7
8
108,700
143,100
105.100
54,100
55,200
44,400
36,800
19,400
1.18
1.22
1.39
1.44
1.20
2.37
1.19
1.53
ST
TIPNO
27
NBA
NBA
TBA
TBA
DMA
DMA
A clue to the poor behavior of 4b in polymerizations
might be provided by MOPAC calculations of the confor-
mation of nitroxides 4a and 4b (Figure 4). Energy mini-
mization predicts the diols to be proximal to the nitroxide
oxygen in 4a, but distal to the nitroxide oxygen in 4b, pre-
venting H-bonding (Figure 4).
TIPNO
27
TIPNO
27
OH
OH
O
N
O
N
St = styrene, NBA = n-butyl acrylate, TBA = tert-butyl acrylate,
DMA = N,N-dimethyl acrylamide Note: All of these polymerizations
were carried out with 1000 equiv of monomer for 24 h. No free ni-
troxide was added.
Me
4a
H
HO
H
HO
4b
Figure 4
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

PAPER
Synthesis and Evaluation of New a-Hydrogen Nitroxides
1501
solid; mp 226–235 °C (decomp); Rf 0.23 [TLC: EtOAc–MeOH
(10:1), UV detection].
Compared to TIPNO, each contains a modified tert-butyl IR (neat): 1583, 1181 cm–1.
In summary, three novel nitroxides for use in Nitroxide
Mediated Radical Polymerization were synthesized.
1H NMR (250 MHz, CDCl3): d = 6.55–6.52 (d, J = 7.6 Hz, 1 H),
3.21–3.18 (m, 1 H), 2.19 (br s, 3 H), 2.1 (m, 6 H), 1.74–1.69 (m, 6
H), 1.07 (d, J = 7.0 Hz, 6 H).
13C NMR (63 MHz, CDCl3): d = 139.36, 99.29, 68.78, 40.75, 36.06,
29.63, 25.72, 19.10.
group. For adamantyl nitroxide 3, thermally induced rear-
rangement of oxaziridine 9 provided a much more effi-
cient route to the requisite nitrone intermediate than our
conventional route. The corresponding N-alkoxyamines
were screened against TIPNO in free radical polymeriza-
tions: AD 7 performed slightly better than the well-estab-
lished TIPNO initiator, whereas both diol initiators 21 and
27 were not as effective at controlling free radical poly-
merization.
1-Adamantyl-3-methyl-2-phenylazabutane-1-nitroxide (3)
Under an atmosphere of N2, N-adamantyl-a-propylnitrone (6; 500
mg, 2.26 mmol) was dissolved in anhyd THF (4 mL) and cooled to
0 °C; then phenylmagnesium bromide (1.51 mL, 3 M in Et2O, 4.52
mmol) was added dropwise over 5 min. The reaction was allowed
to stir for 3 h and then quenched with sat. NH4Cl (1.5 mL) solution
followed by addition of H2O (10 mL) to dissolve all solids. The or-
ganic layer was separated and the aqueous layer extracted with Et2O
(4 × 12.5 mL). The organic layers were combined, dried over
MgSO4, filtered, and concentrated, and the residue was treated with
a mixture of MeOH (11 mL), concd NH4OH (0.90 mL), and copper
acetate (23.04 mg, 0.08 mmol), producing a yellow solution. A
stream of air was bubbled through the mixture until the color
changed to dark blue (ca 20 min). The mixture was dissolved in
CHCl3 (15 mL), concd sodium hydrogen sulfate (3 mL), and water
(15 mL). The organic layer was separated and the aqueous layer ex-
tracted with CHCl3 (30 mL). The organic layers were combined and
washed with sat. NaHCO3 solution (20 mL), dried over MgSO4, fil-
tered, and concentrated to give crude nitroxide (637.7 mg). The ni-
troxide was then purified by flash column chromatography
[hexanes → hexanes–EtOAc (5:1)] to afford 3 as an orange oil
(432.4 mg, 64%); Rf 0.38 [TLC: hexanes–EtOAc (5:1), UV detec-
tion].
THF was distilled from sodium/benzophenone. All other reagents
were used as received. Flash chromatography was performed using
EM Science Silica Gel 60. FTIR spectra were recorded on a Perkin–
Elmer 1600 FTIR spectrometer in CDCl3 solution unless otherwise
noted. NMR spectra were recorded on either a Bruker ACF dual
probe 250 MHz or a Varian 500 MHz spectrometer as specified,
with TMS as internal standard for 1H NMR and the CDCl3 triplet as
an internal standard for 13C NMR. Mass spectra were obtained on
either a Fisons Instruments VG Quattro II Mass Spectrometer or a
Mariner Biospectrometry Workstation Mass Spectrometer from
Applied Biosystems with a TOF detector. Melting points are uncor-
rected.
1-Nitroadamantane22 (5)
Following the general procedure of Murray and Jeyaraman,9 a sus-
pension of 1-aminoadamantane (5.00 g, 33.1 mmol), acetone (10.3
g, 179 mmol), and a pH = 8 phosphate buffer (131 mL) was cooled
to 8 °C. A solution of Oxone® (48.79 g, 79.4 mmol) in H2O (260
mL) was added dropwise with vigorous stirring while maintaining
the pH between 7–8 by careful addition of 6 M aq KOH. Following
the addition of Oxone®, the pH was monitored until stable at ca. 8,
then the reaction was allowed to slowly return to r.t., and stirred for
an additional 20 h. The reaction mixture was then extracted with
CH2Cl2 (4 × 200 mL), and the combined extracts were washed with
sat. NaCl (300 mL), dried over solid MgSO4, filtered and concen-
trated under vacuum to give the crude product as a pale blue solid
(5.19 g, 87%). This material was used without purification in the
next step. The blue color is from a small amount of nitrosoadaman-
tane by-product. If desired, the nitroso compound can be removed
chromatographically by elution with hexanes, and the nitro com-
pound can then be obtained by elution with hexanes–acetone (5:1);
mp 157–162 °C; Rf 0.89 (TLC: EtOAc, visible by UV, brown with
I2).
IR (neat): 2906, 2851, 1453, 1306, 1095, 701 cm–1.
HRMS: m/z [M+] calcd for C20H28NO: 298.217; found: 298.218.
For purposes of characterization, the nitroxide was reduced with
phenyl hydrazine in the NMR tube to form the corresponding N-hy-
droxylamine.
1H NMR (250 MHz, CDCl3; after addition of phenylhydrazine): d =
7.25–7.46 (m, 5 H, partially obscured by phenylhydrazine), 3.45 (d,
J = 10 Hz, 1 H), 2.25 (m, 1 H), 1.99 (m, 3 H), 1.68 (m, 6 H), 1.56
(m, 6 H), 1.15 (d, J = 6.5 Hz, 3 H), 0.61 (d, J = 6.5 Hz, 3 H).
13C NMR (63 MHz, CDCl3; after addition of phenylhydrazine): d =
129.6, 127.3, 126.2, 73.4, 69.6, 39.0, 36.4, 31.0, 29.2, 21.3, 20.2.
N-Adamantyl Phenyl Imine23 (8)
1-Adamantylamine (2.00 g, 13.23 mmol) was dissolved in toluene
(25 mL) and refluxed for a period of 2 h with a Dean–Stark trap to
remove residual water. Benzaldehyde (14.04 g, 132.30 mmol) was
added and the mixture was refluxed with a Dean–Stark trap for 18
h. The reaction was allowed to cool to r.t. and MgSO4 was added to
remove any residual water. The mixture was filtered and most of the
excess benzaldehyde was removed under vacuum. The product was
obtained as a slightly yellow wet solid (3.35 g) contaminated with
24% benzaldehyde as indicated by H NMR (81% yield); Rf 0.60
(TLC: CH2Cl2, visible in UV, no stain with I2).
1H NMR (500 MHz, CDCl3): d = 8.29 (s, 1 H), 7.73–7.77 (m, 2 H),
7.38–7.41 (m, 3 H), 2.17 (br s, 3 H), 1.82 (d, J = 2.8 Hz, 6 H), 1.74
(br s, 6 H).
IR (nujol): 1540, 1342, 1250 cm–1.
13C NMR (63 MHz, CDCl3): d = 84.5, 40.6, 29.5, 35.3.
N-Adamantyl-a-propylnitrone (6)
Crude 1-nitroadamantane (5; 1.3204 g, 7.99 mmol), NH4Cl (427.9
mg, 8.0 mmol), and isobutyraldehyde (0.38 mL, 7.3 mmol) were
suspended in H2O (15 mL). Et2O (7.3 mL) was added to dissolve all
solids. The solution was cooled to 0 °C in an ice bath, and zinc pow-
der (1.9036 g, 29.12 mmol) was added in multiple small portions
over the period of 30 min. After stirring for 24 h, the mixture was
filtered through Celite®, and the filter cake was washed with Et2O
(3 × 20 mL). The two-phase filtrate was extracted with Et2O (4 × 50
mL). The combined organic layers were washed with brine (100
mL), dried over MgSO4, filtered, and concentrated to give crude ni-
trone (845.5 mg). The nitrone was then purified twice by flash col-
umn chromatography [hexanes → hexanes–EtOAc (5:1), and
hexanes–acetone (5:1)] to afford 6 (527.7 mg, 32.7%) as a white
1
N-Adamantylphenyloxaziradine (9)
N-Adamantyl phenyl imine (8; 3.00 g, 12.53 mmol) was dissolved
in a minimum amount of CHCl3 and chilled in an ice bath. A solu-
tion of m-chloroperbenzoic acid (3.71 g of 70% mCPBA, 15.04
mmol) in CHCl3 (120 mL) was dried over MgSO4, and then added
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

1502
R. Braslau et al.
PAPER
dropwise with vigorous stirring over a period of 1.5 h. The reaction
mixture was stirred at 0 °C for 3 h and then filtered through a plug
of basic alumina. The filtrate was washed with a sat. NaHCO3 solu-
tion (50 mL). The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo to give a light orange wet solid (2.61 g). 1H
NMR indicated that the product was contaminated with 9% benzal-
dehyde, resulting in a final yield of 74%. A very pure sample was
obtained by recrystallization from pentane; mp 62–66 °C; Rf 0.80
(TLC: CH2Cl2, visible in UV).
IR (CDCl3): 3156, 2906, 1794, 1456, 1396, 1308, 1256, 1084 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.34–7.50 (m, 5 H), 4.93 (s, 1 H),
2.15 (br s, 3 H), 1.79 (br s, 6 H), 1.70 (br s, 6 H).
mL). The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and
the organic layers were combined and evaporated to dryness to pro-
vide crude product (493.2 mg), which was purified twice by flash
column chromatography [hexanes followed by hexanes–EtOAc
(16:1)] to give 7 (421.1 mg, 76.5%) as a thick, colorless oil, as a
mixture of two diastereomers; Rf 0.81 [TLC: hexanes–EtOAc
(16:1), UV detection].
IR (CDCl3): 2852, 1453, 1383, 1061 cm–1.
1H NMR (500 MHz, CDCl3, major diastereomer): d = 7.53–7.02 (m,
10 H), 4.93 (m, 1 H), 3.55 (d, J = 11.0 Hz, 1 H), 2.37 (m, 1 H), 2.05
(m, 3 H), 1.83 (m, 6 H), 1.61 (m, 6 H), 1.61 (d, J = 7.0 Hz, 3 H),
1.33 (d, J = 6.0 Hz, 3 H), 0.58 (d, J = 6.0 Hz, 3 H).
13C NMR (63 MHz, CDCl3): d = 135.8, 129.6, 128.4, 127.4, 72.3,
1H NMR (500 MHz, CDCl3, minor diastereomer): d = 7.53–7.02
(m, 10 H), 4.93 (m, 1 H), 3.44 (d, J = 10.5 Hz, 1 H), 2.05 (m, 3 H),
1.83 (m, 6 H), 1.68 (d, J = 7.0 Hz, 3 H), 1.61 (m, 6 H), ca 1.4 [m, 1
H (note: this CHi-Pr is buried)], 0.95 (d, J = 6.5 Hz, 3 H), 0.22 (d,
J = 6.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3, major + minor diastereomers): d =
146.0, 145.2, 143.2, 143.0, 131.2, 131.1, 128.22, 128.18, 127.5,
127.4, 127.3, 127.2, 126.8, 126.5, 126.4, 126.2, 83.8, 83.1, 70.65,
70.60, 61.4, 61.3, 40.9, 40.6, 37.0, 36.8, 32.3, 31.9, 30.1, 29.9, 24.8,
23.4, 22.4, 22.2, 21.4, 21.3.
58.4, 38.7, 36.5, 29.1.
N-Adamantyl-a-phenylnitrone8b (10)
N-Adamantyl-a-phenyloxaziridine (9; 0.114 g, 0.45 mmol) was dis-
solved in MeCN (10 mL). The mixture was refluxed for 48 h. It was
concentrated in vacuo, and the crude product was purified by flash
column chromatography using hexanes–EtOAc (16:1) to give an
amber-colored solid (0.074 g, 65% yield); Rf 0.59 [TLC: hexanes–
EtOAc (1:1), UV].
1H NMR (250 MHz, CDCl3): d = 8.24 (m, 2 H), 7.43 (s, 1 H), 7.37–
7.40 (m, 3 H), 2.25 (s, 3 H), 2.20 (s, 6 H), 1.73 (s, 6 H).
HRMS: m/z [M + 1] calcd for C28H38NO: 404.295; found: 404.294.
13C NMR (125 MHz): d = 131.2, 130.1, 129.6, 129.0, 128.5, 70.9,
5-Methyl-5-nitro-2-phenyl-1,3-dioxane (15)
40.1, 36.1, 29.9.
Following the procedure of Piotrowska,17 benzaldehyde (0.2124 g,
2.0 mmol), 2-methyl-2-nitro-propane-1,3-diol (0.2702 g, 2.0 mmol)
and p-toluenesulfonic acid were heated in benzene (5 mL) with a
Dean–Stark trap until no further water was produced. After cooling,
the reaction mixture was washed with sat. NaHCO3 solution (3 ×
10 mL), dried over MgSO4 and filtered. After the product was con-
centrated in vacuo, the crude product was recrystallized with cold
EtOH to give the product 15 (0.3337 g, 75%) as a white solid; mp
119–120 °C (recrystallized from EtOH, Lit.17 mp 121–122 °C); Rf
0.52 [TLC: EtOAc–hexanes (3:10), UV, p-anisaldehyde].
HRMS: m/z [M + 1] calcd for C17H21NO: 256.16959; found:
256.16791.
1-Adamantyl-3-methyl-2-phenylazabutane-1-nitroxide (3)
N-Adamantyl-a-phenylnitrone (10; 0.2 g, 0.78 mmol) was dis-
solved in THF (5 mL) and the mixture was cooled to 0 °C in an ice-
bath. Distilled trimethylsilyl chloride (0.2 mL, 1.56 mmol) was add-
ed, and the mixture was allowed to stir for 5 min. Isopropyl magne-
sium chloride (1.18 mL, 2.35 mmol) was then added, and the
mixture was stirred at r.t. for 2 h. To decompose the excess Grignard
reagent, concd NH4Cl (5 mL) was added, followed by deionized
water (15 mL). The organic layer was separated and extracted with
Et2O (25 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to give an orange oil.
This product was purified by flash column chromatography using
hexanes–EtOAc (16:1) to yield the product (0.1523 g). This collect-
ed product was dissolved in THF (5 mL) and Cu(OAc)2 (3.64 mg,
0.02 mmol), and concd NH4OH (2 drops) were added to give a pale
yellow-green solution. MeOH was added dropwise until the copper
compound dissolved. Air was bubbled through the solution for
about 30 min, but only a slight color change was observed: from
pale yellow-green to a pale forest green. The reaction was concen-
trated, CHCl3 (5 mL) and aq KHSO4 (5 mL) and deionized water (3
mL) were added. The organic layer was separated, washed with
concd NaHCO3 solution (5 mL), dried over MgSO4, filtered, and
concentrated in vacuo to give an orange oil (0.117 g, 98% yield).
Treatment of a small sample with phenylhydrazine in an NMR tube
gave a sample identical to that formed by the alternative method
above.
IR (CDCl3): 3006, 2944, 2902, 1554 (NO2), 1226 (CO), 1111 (CO)
cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50–7.30 (m, 5 H, ArH), 5.52 (s,
1 H, CHPh), 4.99 (d, J = 12.0, Hz, 2 H, CH2O), 3.94 (d, J = 12.0 Hz,
2 H, CH2O), 1.44 (s, 3 H, CH3).
13C NMR (63 MHz, CDCl3): d = 136.7 (Cq of Ar), 129.4 (CH of Ar),
128.3 (2 × CH of Ar), 126.1 (2 × CH of Ar), 101.7 (CHPh), 82.8
[C(CH2O)2], 71.6 [2 × CH2O], 19.4 (CH3).
N-(5-Methyl-2-phenyl[1,3]dioxan-5-yl)phenylnitrone (16)
Zinc powder was activated by washing sequentially with 5% HCl
(3 ×), H2O (3 ×), MeOH (3×), and Et2O (3×) in a Büchner funnel,
and then dried under vacuum. To a flask containing 5-methyl-5-ni-
tro-2-phenyl-1,3-dioxane (15; 0.4465 g, 2.0 mmol) in EtOH (15
mL) was added a solution of NH4Cl (0.1177 g, 2.2 mmol) in H2O
(5.0 mL) and then THF (15 mL) was added until all solids dissolved.
Activated zinc powder (0.5230 g, 8.0 mmol) was added over a peri-
od of 15 min with stirring. The reaction mixture was allowed to
warm to r.t. and stirred for an additional 4 h. The zinc salts were fil-
tered off and washed with hot 95% EtOH (20 mL) and hot CHCl3
(20 mL). The filtrate was concentrated to 5 mL in vacuo and used
directly in the next step. Benzaldehyde (0.4248 g, 4.0 mmol) was
added, and the reaction mixture was refluxed for 2 h. After concen-
tration by rotary evaporation, the residue was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers was dried over MgSO4,
filtered and concentrated in vacuo. Purification by flash column
chromatography (eluent: hexanes → EtOAc–hexanes (7:10)] gave
product 16 (0.4662 g, 89%) as a white solid; mp (recrystallized from
1-Adamantyl-3-methyl-1-(1¢-phenylethoxy)-2-phenyl-1-azabu-
tane ‘AD’ (7)
To a solution of styrene (302.04 mg, 2.90 mmol) and 1-adamantyl-
3-methyl-2-phenyl-azabutane-1-nitroxide (3; 432.4 mg, 1.45
mmol) in toluene–EtOH (11 mL, 1:1) was added [N,N-bis(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediaminato] manganese(II)
chloride (184.21 mg, 0.29 mmol) followed by NaBH4 (164.56 mg,
4.35 mmol). The reaction mixture was stirred for 48 h, evaporated
to dryness, and partitioned between CH2Cl2 (11 mL) and H2O (15
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

PAPER
Synthesis and Evaluation of New a-Hydrogen Nitroxides
1503
EtOH) 149–150 °C (Lit.24 mp 150–152 °C); Rf 0.22 [TLC: EtOAc–
hexanes (4:5), UV, p-anisaldehyde].
mmol) and isobutyraldehyde (0.1134 g, 1.6 mmol) were employed.
The reaction mixture was stirred at r.t. overnight (16 h). Purification
with flash column chromatography [eluent: hexanes → EtOAc →
MeOH–EtOAc (1:5)] gave product 18 (0.1657 g, 80%) as a white
solid; mp 115–116 °C; Rf 0.29 [TLC: MeOH–EtOAc (1:5), UV, p-
anisaldehyde].
IR (CDCl3): 2964, 2905, 2867, 1643, 1563 (C=N), 1266 (CO), 1223
(CO) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.37–8.34 (m, 2 H, ArH), 8.07 (s,
1 H, N=CH), 7.46–7.26 (m, 8 H, ArH), 5.61 (s, 1 H, CHPh), 4.82
(d, J = 12.8 Hz, 2 H, CH2O), 4.02 (d, J = 12.8 Hz, 2 H, CH2O), 1.45
(s, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 137.3 (Cq of Ar), 134.9 (N=CH),
131.0 (Cq of Ar), 130.6 (CH of Ar), 129.5 (3 × CH of Ar), 128.6
(2 × CH of Ar), 128.5 (2 × CH of Ar), 126.3 (2 × CH of Ar), 102.5
(CHPh), 72.4 (2 × CH2O), 68.5 [CH3C(CH2O)2], 19.5 (CH3).
IR (CDCl3): 2977, 2902, 2869, 1563 (C=N), 1468 (NO), 1364
(NO), 1266 (CO), 1223 (CO) 1101 (CO) cm–1.
1H NMR (250 MHz, CDCl3): d = 7.40–7.30 (m, 5 H, ArH), 7.14 (d,
J = 7.3 Hz, 1 H, N=CH), 5.52 (s, 1 H, CHPh), 4.67 (d, J = 12.5 Hz,
2 H, CH2O), 3.90 (d, J = 12.5 Hz, 2 H, CH2O), 3.35–3.27 [m, 1 H,
CH(CH3)2], 1.43 (s, 3 H, CH3), 1.16 [d, J = 6.8 Hz, 6 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 145.3 (N=CH), 137.3 (Cq of Ar),
129.4 (CH of Ar), 128.4 (2 × CH of Ar), 126.2 (2 × CH of Ar), 102.2
(CHPh), 71.9 (2 × CH2O), 66.7 [CH3C(CH2O)2], 26.3 [CH(CH3)2],
19.13 (CH3), 19.10 [CH(CH3)2].
N-(5-Methyl-2-phenyl[1,3]dioxan-5-yl)-N-(2-methyl-1-phenyl-
propyl)nitroxide (19)
N-(5-Methyl-2-phenyl[1,3]dioxan-5-yl)phenylnitrone (16; 0.5048,
1.92 mmol) was dissolved in THF (20 mL) and the solution cooled
to 0 °C. A 2.0 M solution of isopropylmagnesium chloride (2.9 mL,
5.76 mmol) in THF was added by syringe over 5 min. The mixture
was allowed to warm to r.t. After 16 h, excess Grignard reagent was
decomposed by the addition of concd NH4Cl solution (5 mL) fol-
lowed by H2O (10 mL) until all solids had dissolved. The organic
layer was separated, and the aqueous layer was extracted with Et2O
(3 × 10 mL). The organic layers were combined, dried over MgSO4,
and filtered. Removal of solvent in vacuo gave hydroxylamine 17
(0.6528 g, 99%). This hydroxylamine 17 was treated with a mixture
of MeOH (10 mL), concd NH4OH (0.3 mL) and Cu(OAc)2H2O
(0.0192 g, 0.10 mmol) to give a pale yellow solution. A steam of air
was bubbled through the yellow solution until it became dark blue
(5–10 min). This mixture was concentrated and the residue dis-
solved in a mixture of CHCl3 (10 mL), concd NaHSO4 solution (5
mL) and water (10 mL). The organic layer was separated and the
aqueous layer was extracted with CHCl3 (3 × 10 mL). The organic
layers were combined, washed with sat. NaHCO3 solution (10 mL),
dried over MgSO4 and filtered. The filtrate was concentrated in vac-
uo to give the crude product. Purification by flash column chroma-
tography [eluent: hexanes → EtOAc–hexanes (1:10)] provided
nitroxide 19 (0.0.4769 g, 73%) as an orange solid; mp 116–117 °C;
Rf 0.41 [TLC: EtOAc–hexanes (3:10), UV, p-anisaldehyde].
LRMS: m/z (% relative intensity) = 286 (40) [M+ + Na], 264 (70)
[M+ + H], 158 (20), 102 (100).
HRMS: m/z [M+ + H] calcd for C15H21NO3: 264.15942; found:
264.15799.
Alternate Procedure for N-(5-Methyl-2-phenyl[1,3]dioxan-5-
yl)-N-(2-methyl-1-phenylpropyl)nitroxide (19)
According to the procedure described above, 5-methyl-2-phenyl-N-
(isopropylene)-1,3-dioxan-5-amin-N-oxide (18; 0.0511 g, 0.19
mmol), phenylmagnesium bromide (3.0 M in Et2O, 0.13 mL, 0.38
mmol), Cu(OAc)2H2O (0.0020 g, 0.0097 mmol), THF (2 mL),
MeOH (3 mL) and concd NH4OH (0.1 mL) were employed. Purifi-
cation by flash column chromatography [eluent: hexanes →
EtOAc–hexanes (1:10)] yielded the same nitroxide 19 (0.0545 g,
83%) as an orange solid.
N-(5-Methyl-2-phenyl[1,3]dioxan-5-yl)-N-(2-methyl-1-phenyl-
propyl)-O-(1-phenylethyl)hydroxylamine (20)
To a solution of styrene (0.2916 g, 2.8 mmol) and N-(5-methyl-
2-phenyl[1,3]dioxan-5-yl)-N-(2-methyl-1-phenylpropyl)nitroxide
(19; 0.4769 g, 1.4 mmol) in toluene–EtOH (15 mL, 1:1) were added
(R,R)-Jacobsen’s catalyst (0.1779 g, 0.28 mmol) and NaBH4
(0.1589 g, 4.2 mmol). The reaction mixture was stirred open to air
at r.t. for 16 h. The reaction mixture was concentrated in vacuo to
dryness and filtered through a plug of silica gel using EtOAc as the
eluent. The filtrate was concentrated and the residue was purified by
flash column chromatography [eluent: hexanes → CH2Cl2–hexanes
(2:5)] to give the desired product 20 (0.3009 g, 88%) as a colorless
oil as a 1:1 mixture of diastereomers; Rf 0.36 [TLC: EtOAc–hexanes
(1:10), UV, p-anisaldhyde].
IR (CDCl3): 2984, 2902, 1561 (NO), 1469 (NO), 1366 (NO), 1225
(CO), 1093 (NO) cm–1.
LRMS: m/z (% relative intensity) = 364 (25) [M+ + Na + H], 364
(100) [M+ + Na], 341 (65) [M+ + H], 310 (25), 298 (20), 235 (38).
1H NMR (250 MHz, CDCl3, in the presence of phenylhydrazine):
d = 7.60–7.20 (m, 10 H, 2 × ArH), 5.51 (s, 1 H, CHPh), 4.90 (br s,
1 H, OH), 4.45 (d, J = 12.5 Hz, 1 H, CH2O), 4.35 (d, J = 12.5 Hz, 1
H, CH2O), 3.64 (d, J = 12.5 Hz, 1 H, CH2O), 3.60 (d, J = 12.5 Hz,
1 H, CH2O), 3.36 (d, J = 11.8 Hz, 1 H, NCHPh), 2.50–2.30 [m, 1 H,
CH(CH3)2], 1.34 [d, J = 6.5 Hz, 3 H, CH(CH3)2], 0.65 [d, J = 6.5 Hz,
3 H, CH(CH3)2], 0.32 (s, 3 H, CH3).
13C NMR (63 MHz, CDCl3, in the presence of phenylhydrazine):
d = 142.2 (Cq of Ar), 138.3 (Cq of Ar), 129.7 (CH of Ar), 129.1
(2 × CH of Ar), 127.9 (2 × CH of Ar), 126.9 (CH of Ar), 126.4 (2 ×
CH of Ar), 102.2 (CHPh), 74.2 (NCHPh), 72.8 (CH2O), 70.6
(CH2O), 58.3 [CH3C(CH2O)2], 31.9 [CH(CH3)2], 21.5 (CH3), 20.6
[CH(CH3)2], 14.0 [CH(CH3)2].
IR (CDCl3): 3025, 2931, 2959, 2869, 1602, 1560 (NO), 1469 (NO),
1281 (CO), 1100 (CN) cm–1.
1H NMR (500 MHz, CDCl3, two diastereomers in a 1:1 ratio): d =
7.70–7.05 (m, 30 H, ArH), 5.60 (s, 1 H, CHPh), 5.42 (s, 1 H, CHPh),
5.21 (q, J = 6.5 Hz, 1 H, CH3CHPh), 5.17 (q, J = 6.5 Hz, 1 H,
CH3CHPh), 4.56–4.39 (m, 4 H, CH2O), 3.72–3.49 (m, 4 H, CH2O),
3.45 (d, J = 11.5 Hz, 1 H, NCHPh), 2.98 (d, J = 12.5 Hz, 1 H, NCH-
Ph), 2.26–2.24 [m, 1 H, CH(CH3)2], 1.68 (d, J = 6.5 Hz, 3 H,
CH3CHPh), 1.61 (d, J = 6.5 Hz, 3 H, CH3CHPh), 1.50 [d, J = 6.0
Hz, 6 H, CH(CH3)2], 1.14 [d, J = 6.0 Hz, 6 H, CH(CH3)2], 0.60 [d,
J = 6.5 Hz, 3 H, CH(CH3)2], 0.60 [d, J = 6.5 Hz, 3 H, CH(CH3)2],
0.45 (s, 3 H, CH3), 0.29 [d, J = 6.5 Hz, 3 H, CH(CH3)2].
HRMS (after treatment with phenylhydrazine): m/z [M+ + H] calcd
for C21H26NO3: 342.20637; found: 342.20825.
13C NMR (125 MHz, CDCl3, two diastereomers in a 1:1 ratio): d =
144.8 (Cq of Ar), 144.2 (Cq of Ar), 142.5 (Cq of Ar), 142.2 (Cq of
Ar), 139.0 (Cq of Ar), 138.7 (Cq of Ar), 129.1 (CH of Ar), 128.8 (CH
of Ar), 128.5 (2 × CH of Ar), 128.4 (5 × CH of Ar), 128.2 (2 × CH
of Ar), 127.8 (2 × CH of Ar), 127.7 (2 × CH of Ar), 127.4 (CH of
Ar), 127.0 (2 × CH of Ar), 126.9 (3 × CH of Ar), 126.8 (5 × CH of
5-Methyl-2-phenyl-N-(isopropylen)-1,3-dioxan-5-amin-N-ox-
ide (18)
Following the procedure outlined above for the formation of the ni-
trone 16, 2-phenyl-5-methyl-5-nitro-1,3-dioxane (15; 0.1756 g, 0.8
mmol), activated zinc (0.2057 g, 3.2 mmol), NH4Cl (0.0463 g, 0.9
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

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R. Braslau et al.
PAPER
Ar), 126.6 (CH of Ar), 126.1 (2 × CH of Ar), 102.7 (CHPh), 102.6
(CHPh), 83.7 (OCHPh), 82.8 (OCHPh), 74.8 (CH2O), 74.6 (CH2O),
74.3 (CH2O), 71.9 (NCHPh), 71.7 (NCHPh), 59.6 [CH3C(CH2O)2],
59.3 [CH3C(CH2O)2], 32.5 [CH(CH3)2], 31.9 [CH(CH3)2], 24.9
(CH3), 23.5 (CH3), 22.2 (CH3), 22.0 (CH3), 21.2 (2 × CH3), 15.1
(CH3), 15.0 (CH3).
HRMS: m/z [M+ + H] calcd for C22H31NO3: 358.23766; found:
358.23438.
2,2-Dimethyl-5-nitro-5-phenyl[1,3]dioxane (23)
To a solution of 2-nitro-2-phenylpropane-1,3-diol (22; 5.21 g, 26.4
mmol) and para-toluenesulfonic acid monohydrate (5.02 g, 26.4
mmol) in THF (25 mL) with 4 Å activated molecular sieves (5 g),
was added 2,2-dimethoxypropane (11.0 g, 106 mmol) over 10 min
with stirring. The reaction mixture was refluxed for 12 h, quenched
with water (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried with MgSO4, filtered and con-
centrated in vacuo to give a white resin. Flash chromatography
[hexanes–EtOAc (1:1)] afforded a white solid (4.45 g, 71% yield);
mp 95 °C; Rf 0.42 [TLC: hexanes–EtOAc (1:1), UV].
IR (CDCl3): 2902, 1557, 1450, 1376, 1348, 1136, 1093 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.4–7.3 (m, 5 H), 5.0 (d, J = 14.4
Hz, 2 H), 4.3 (d, J = 14.4 Hz, 2 H), 1.5 (s, 3 H), 1.4 (s, 3 H).
13C NMR (63 MHz, CDCl3): d = 133.1, 130.2, 129.4, 125.1, 98.8,
87.1, 64.5, 28.2, 18.8.
LRMS: m/z (% relative intensity) = 468 (14) [M+ + Na], 446 (23)
[M+ + H], 365 (20), 337 (16), 314 (22), 102 (100).
HRMS: m/z [M+ + H] calcd for C29H35NO3: 446.26897; found:
446.26389.
2-Methyl-2-[(2-methyl-1-phenylpropyl)-(1-phenylethoxy)ami-
no]propane-1,3-diol (21)
To a solution of N-(5-methyl-2-phenyl[1,3]dioxan-5-yl)-N-(2-
methyl-1-phenylpropyl)-O-(1-phenylethyl)hydroxylamine
(20;
0.5661 g, 1.27 mmol) in THF (8 mL) and H2O (2 mL) was added
trifluoroacetic acid (0.94 mL, 12.7 mmol) at 0 °C. The reaction mix-
ture was allowed to warm to r.t. and then refluxed (66 °C) overnight.
After quenching with sat. NaHCO3 solution (10 mL), the organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The organic layers were combined, washed
with sat. NaHCO3 solution (3 × 5 mL), dried with MgSO4 and fil-
tered. Removal of volatiles in vacuo followed by flash column chro-
matography [eluent: hexanes → EtOAc–hexanes (3:10)] gave the
product 21 (0.3238 g, 71%) as a colorless oil as a mixture of two di-
2,2-Dimethyl-5-nitrone-N-(2-methyl-1-propene)-5-phe-
nyl[1,3]dioxane (24)
To 2,2-dimethyl-5-nitro-5-phenyl[1,3]dioxane (23; 5.339 g, 22.5
mmol) were added isobutyraldehyde (3.245 g, 4.09 mL, 45.0 mmol)
and NH4Cl (1.324 g, 24.75 mmol) in H2O (40 mL) and Et2O (13
mL). Zn powder (5.88 g, 90.0 mmol) was added batchwise over 20–
25 min at 0 °C. The reaction mixture was allowed to slowly warm
to r.t. and stirred overnight. The solution was filtered and the zinc
residues were washed with CH2Cl2. The solution was extracted with
CH2Cl2 (2 × 100 mL) and the combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The product ni-
trone 24 was purified by flash chromatography [hexanes–EtOAc
(1:2)] yielding an oil (4.1903 g, 67%); Rf 0.16 [TLC: hexanes–
EtOAc (1:1), UV].
1
astereomers. The H NMR spectrum was complex: D2O exchange
removed the coupling from the hydroxy protons, giving a somewhat
simplified spectrum; Rf 0.29 [TLC: EtOAc–hexanes (2:5), UV, p-
anisaldehyde].
IR (CDCl3): 3539 (OH), 2982, 2902, 1602, 1561 (NO), 1469 (NO),
1223 (CO), 1094 (CN), 1052 (CO) cm–1.
1H NMR (500 MHz, CDCl3, with addition of D2O, two diastereo-
mers): d = 7.60–7.10 (m, 20 H, ArH), 4.97 (q, J = 6.5 Hz, 1 H,
OCHPh, major isomer), 4.93 (q, J = 6.5 Hz, 1 H, OCHPh, minor iso-
mer), 3.86 (d, AB-system, J = 11.5 Hz, 2 H, CH2OH, minor isomer),
3.70 (d, AB-system, J = 11.5 Hz, 2 H, CH2OH, minor isomer), 3.57
(d, AB-system, J = 12.0 Hz, 2 H, CH2OH, minor isomer), 3.55 (d,
AB-system, J = 12.0 Hz, 2 H, CH2OH, minor isomer), 3.48 (d, AB-
system, J = 11.5 Hz, 1 H, CH2OH, major isomer), 3.40 (d, AB-sys-
tem, J = 11.5 Hz, 1 H, CH2OH, major isomer), 3.31 (d, AB-system,
J = 11.5 Hz, 1 H, NCHPh, minor isomer), 3.30 (d, J = 10.0 Hz, 1 H,
NCHPh, major isomer), 3.02 (d, AB-system, J = 11.5 Hz, 1 H,
CH2OH, major isomer), 2.92 (d, AB-system, J = 11.5 Hz, 1 H,
CH2OH, major isomer), 2.50–2.38 [m, 1 H, CH(CH3)2, major iso-
mer], 1.69 (d, J = 6.5 Hz, 3 H, CH3CHPh, major isomer), 1.61 (d,
J = 6.5 Hz, 3 H, CH3CHPh, minor isomer), 1.56–1.43 [m, 1 H,
CH(CH3)2, minor isomer], 1.40 [d, J = 6.5 Hz, 3 H, CH(CH3)2, ma-
jor isomer], 0.90 [d, J = 6.5 Hz, 3 H, CH(CH3)2, minor isomer], 0.89
(s, 3 H, CH3, major isomer), 0.60 [d, J = 6.5 Hz, 3 H, CH(CH3)2, ma-
jor isomer], 0.52 (s, 3 H, CH3, minor isomer), 0.25 [d, J = 6.5 Hz, 3
H, CH(CH3)2, minor isomer].
13C NMR (125 MHz, CDCl3, two diastereomers): d = 143.7 (Cq of
Ar), 143.6 (Cq of Ar), 141.5 (Cq of Ar), 141.0 (Cq of Ar), 130.5 (CH
of Ar), 128.8 (3 × CH of Ar), 128.5 (2 × CH of Ar), 128.3 (2 × CH
of Ar), 128.0 (2 × CH of Ar), 127.9 (3 × CH of Ar), 127.2 (2 × CH
of Ar), 127.0 (2 × CH of Ar), 126.6 (3 × CH of Ar), 84.0 (OCHPh),
83.7 (OCHPh), 72.8 (NCHPh), 72.4 (NCHPh), 68.7 (CH2O), 68.4
(CH2O), 67.7 (CH2O), 67.4 (CH2O), 66.9 [CH3C(CH2O)2], 66.0
[CH3C(CH2O)2], 32.1 [CH(CH3)2], 31.5 [CH(CH3)2], 23.7 (CH3),
23.2 (CH3), 22.1 (CH3), 22.0 (CH3), 21.4 (CH3), 21.0 (CH3), 18.7
(CH3), 17.0 (CH3).
IR (CDCl3): 2942, 1698, 1556, 1450, 1375, 1308, 1151, 1091, 972
cm–1.
1H NMR (250 MHz, CDCl3): d = 7.5–7.2 (m, 5 H), 7.0 (d, J = 7.5
Hz, 1 H), 4.5 (AB system, J = 13.5 Hz, 2 H), 3.9 (AB system, J =
13.5 Hz, 2 H), 3.3 (m, 1 H), 1.5 (s, 3 H), 1.4 (s, 3 H), 1.2 (d, J = 6.8
Hz, 6 H).
13C NMR (63 MHz, CDCl3): d = 147.2, 140.0, 128.8, 128.0, 125.6,
99.2, 98.4, 69.6, 28.8, 19.2, 18.4.
LRMS: m/z = 486.4, 485.4, 292.3, 278.2, 264.2, 209.2, 208.2,
150.16.
2,2-Dimethyl-5-nitroxide-N-(2-methyl-1-phenylpropyl)-5-phe-
nyl[1,3]dioxane (25)
To 2,2-dimethyl-5-nitrone-N-(2-methyl-1-propene)-5-phenyl[1,3]di-
oxane (24; 1.40 g, 5.05 mmol) and THF (5 mL) was added phenyl-
magnesium bromide (3.4 mL, 10.1 mmol) dropwise over 5 min at
0 °C. The reaction mixture was allowed to warm to r.t. and was
stirred for 2 h. Excess Grignard reagent was quenched with sat.
NH4Cl solution (7 mL). To this was added H2O (5 mL) and the
aqueous layer was extracted with CHCl3 (3 × 20 mL). The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was dissolved in MeOH (20 mL), and
concd NH4OH (0.7 mL) and copper acetate monohydrate (51 mg,
0.253 mmol) were added with stirring. Air was bubbled into the so-
lution for 30–40 min, and then the solution was concentrated in vac-
uo. To this was added 2 M NH4OH (35 mL) and CHCl3 (35 mL) and
the aqueous layer was extracted with CHCl3 (3 × 20 mL). The com-
bined organic layer was dried over MgSO4, filtered, and concentrat-
ed in vacuo. The product was purified by flash chromatography
[hexanes, hexanes–EtOAc (16:1)] to afford the product as a dark or-
LRMS: m/z (% relative intensity) = 380 (48) [M+ + Na], 359 (24)
[M+ +2 H], 358 (100) [M+ + H], 275 (13), 254 (5), 226 (14), 133
(27), 102 (56).
Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York

PAPER
Synthesis and Evaluation of New a-Hydrogen Nitroxides
1505
ange oil (610 mg, 34% yield); Rf 0.22 [TLC: 6% EtOAc in hexanes,
HRMS: m/z [M+ + H] calcd for C27H34NO3: 420.25658; found:
UV].
420.25332.
IR (CDCl3): 2960, 2874, 1682, 1554, 1450, 1385, 1090 cm–1.
Polymerization; General Procedure
1H NMR (250 MHz, CDCl3, with addition of phenyl hydrazine):
d = 7.6–6.8 (m, 10 H), 4.4–3.4 2.3 (m, 4 H), 2.97 (d, J = 7.4 Hz,
1 H), 2.23 (m, 1 H), 1.39 (s, 3 H), 1.22 (s, 3 H), 0.92 (d, J = 7 Hz,
3 H), 0.41 (d, J = 7 Hz, 3 H).
A mixture of N-alkoxyamine initiator (0.0192 mmol, 1 equiv) olefin
monomer (19.2 mmol, 1000 mol equiv unless otherwise specified)
and nitroxide (if added: 0.00096 mmol, 0.05 mol equiv) was de-
gassed in an ampoule by three consecutive freeze-pump-thaw cy-
cles and sealed under Ar. The mixture was heated to the specified
temperature in an oil bath for the amount of time indicated. After
cooling to r.t., a small sample of the crude polymer was collected for
1H NMR analysis, and the remaining product was dissolved in
CH2Cl2 (6–10 mL) and poured into the specified precipitation sol-
vent (300 mL) at 0 °C. The precipitated polymer was separated by
decantation, re-dissolved in CH2Cl2 (ca. 6 mL) and mixed with the
specified solvent (300 mL). The precipitated polymer was separated
LRMS: m/z = 356.4, 341.4, 340.4, 284.2, 208.1, 150.2, 134.1,
133.1.
N-(2,2-Dimethyl-5-phenyl[1,3]dioxan-5-yl)-N-(2-methyl-1-phe-
nylpropyl)-O-(1-phenylethyl)hydroxylamine (26)
To 2,2-dimethyl-5-nitroxide-N-(2-methyl-1-phenylpropyl)-5-phe-
nyl[1,3]dioxane (25; 611 mg, 1.72 mmol) were added [N,N¢-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato]man-
ganese(III) chloride (Jacobsen’s catalyst) (164 mg, 0.258 mmol),
styrene (215 mg, 2.06 mmol), and NaBH4 (130 mg, 3.44 mmol) in
toluene–EtOH (11 mL, 1:1). The reaction mixture was stirred over-
night at r.t. The product was concentrated in vacuo and H2O (55
mL) was added. The aqueous layer was extracted with CH2Cl2 (3 ×
30 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The product was purified by
flash chromatography [hexanes–EtOAc, (32:1)] yielding the prod-
uct as a white opaque oil (350 mg, 44% yield); Rf 0.62 (TLC: 6%
EtOAc in hexanes, UV).
1
by decantation, allowed to air dry, and analyzed by H NMR and
GPC. Polymers were precipitated as follows: St with MeOH, DMA
with hexanes, TBA with 50% aq MeOH, and NBA with 70% aq
MeOH.
Acknowledgment
We thank the National Science Foundation (CHE-0078852, INT-
0123857 and REU grants CHE-0243786 and CHE-9987824), and
equipment grants from NSF BIR-94-19409 (NMR) and supplement
grant to NIH CA52955 (ESITOFMS) for providing financial sup-
port for this project. J.R. (née Waldbieser) thanks the NSF for a
graduate fellowship.
IR (CDCl3): 2957, 1683, 1494, 1453, 1373, 1086 cm–1.
1H NMR (500 MHz, CDCl3, two isomers): d = 7.7–7.1 (m, 15 H),
5.06 (q, J = 6.6 Hz, 1 H), 5.00 (q, J = 6.6 Hz, 1 H), 4.12 (d, J = 10.5
Hz, 1 H), 3.85 (d, J = 10.5 Hz, 1 H), 3.65 (d, J = 10.5 Hz, 1 H), 3.50
(d, J = 10.5 Hz, 1 H), 2,99 (dd, J = 10.5 Hz, 1 H), 2.30 (m, 1 H), 1.75
(2 × d, J = 6.6 Hz, 6 H), 1.45 (s, 3 H), 1.31 (d, J = 7.0 Hz, 6 H), 1.20
(s, 3 H), 1.00 (s, 3 H), 0.91 (d, J = 7.0 Hz, 6 H), 0.86 (s, 3 H), 0.33
(d, J = 7.0 Hz, 6 H), 0.30 (d, J = 7.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3): d = 144.2, 141.9, 141.6, 128.5, 128.3,
128.1, 127.9, 127.7, 127.5, 127.1, 126.8, 126.6, 97.6, 84.4, 71.8,
68.8, 61.3, 31.8, 28.2, 27.3, 23.7, 22.9, 21.8, 21.7, 21.0, 20.5, 19.1.
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2-[(2-Methyl-1-phenylpropyl)-(1-phenylethoxy)amino]-2-phe-
nylpropane-1,3-diol (27)
To a solution of N-(2,2-dimethyl-5-phenyl[1,3]dioxan-5-yl)-N-(2-
methyl-1-phenylpropyl)-O-(1-phenylethyl)hydroxylamine (26; 180
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hexanes, UV).
IR (CDCl3): 2956, 1683, 1453, 1384, 1306, 1140, 1072 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.5–7.1 (m, 15 H), 5.03 (q, J = 6.6
Hz, 1 H), 4.46 (d, J = 10.5 Hz, 1 H), 4.09 (d, J = 10.5 Hz, 1 H), 3.84
(d, J = 10.5 Hz, 1 H), 3.75 (d, J = 10.5 Hz, 1 H), 3.69 (d, J = 10.5
Hz, 1 H), 3.47 (d, J = 10.5 Hz, 1 H), 3.09 (d, J = 10.5 Hz, 1 H), 3.03
(d, J = 10.5 Hz, 1 H), 2.52 (br s, 2 H), 2.32 (m, 1 H), 1.72 (d, J = 7
Hz, 3 H), 1.59 (d, J = 7 Hz, 3 H), 1.25 (d, J = 7 Hz, 6 H), 0.94 (d,
J = 7 Hz, 6 H), 0.37 (d, J = 7 Hz, 6 H), 0.13 (d, J = 7 Hz, 6 H).
13C NMR (63 MHz, CDCl3): d = 143.0, 141.3, 140.2, 128.6, 128.4,
128.3, 128.1, 128.0, 127.8, 127.7, 127.0, 126.7, 84.2, 72.8, 67.8,
63.7, 32.2, 23.1, 22.5, 22.0, 21.8, 21.1, 21.0.
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Synthesis 2005, No. 9, 1496–1506 © Thieme Stuttgart · New York