Readily accessible oxazolidine nitroxyl radicals: Bifunctional cocatalysts for simplified copper based aerobic oxidation

Article abstract of DOI:10.1002/adsc.201000627

Using a two-step procedure a range of bifunctional oxazolidine nitroxyl radicals have been prepared. The application of these co-catalysts to the copper-based aerobic oxidation of alcohols was then investigated. From these studies it was found that the parent tetramethyloxazolidine nitroxyl radical L1 was competent for oxidation in the presence of 2,2′-bipyridine, and the bifunctional pyridyl-containing nitroxyl radicals L2 and L3 could be used in the absence of additional coordinating ligands. Following optimization, the scope of this simplified transformation was explored, demonstrating that a range of primary and secondary benzylic alcohols are readily oxidized. In addition, the oxidation of allylic alcohols and hydroquinone can be achieved. Copyright

Full text of DOI:10.1002/adsc.201000627

FULL PAPERS
DOI: 10.1002/adsc.201000627
Readily Accessible Oxazolidine Nitroxyl Radicals: Bifunctional
Cocatalysts for Simplified Copper Based Aerobic Oxidation
Christopher J. Gartshorea and David W. Luptona,*
a
Monash University, Clayton 3800, Melbourne, Victoria, Australia
Fax : (+61)-3-9905-4597; phone: (+61)-3-9902-0327; e-mail: david.lupton@monash.edu
Received: August 9, 2010; Revised: October 8, 2010; Published online: December 7, 2010
Abstract: Using a two-step procedure a range of bi- sence of additional coordinating ligands. Following
functional oxazolidine nitroxyl radicals have been optimization, the scope of this simplified transforma-
prepared. The application of these co-catalysts to the tion was explored, demonstrating that a range of pri-
copper-based aerobic oxidation of alcohols was then mary and secondary benzylic alcohols are readily
investigated. From these studies it was found that oxidized. In addition, the oxidation of allylic alcohols
the parent tetramethyloxazolidine nitroxyl radical L1 and hydroquinone can be achieved.
was competent for oxidation in the presence of 2,2’-
bipyridine, and the bifunctional pyridyl-containing Keywords: aerobic oxidation; aqueous conditions;
nitroxyl radicals L2 and L3 could be used in the ab- catalysis; copper; oxazolidine nitroxyl radicals
Introduction
oxygen,[5d,e,g] and other readily available terminal oxi-
dants,[4,5] have been developed, while chiral TEMPO
The chemoselective oxidation of alcohols is a ubiqui- derivatives have allowed kinetic resolutions and de-
tous transformation achieved using a variety of meth- symmetrizations to be realized.[9]
ods.[1] Catalytic protocols, using environmentally-
Recently we commenced studies into the use of
benign terminal oxidants, play a central role in in- chiral nitroxyl radicals as co-catalysts in transition
creasing the efficiency of this fundamental transfor- metal-based kinetic resolution and desymmetrization.
mation.[2–5] Pivotal to the success of a number of such While a number of asymmetric transition metal-based
methods has been 2,2,6,6-tetramethylpiperidyl-1-oxyl oxidation reactions have been developed,[10] the use
(TEMPO) and its derivatives. This stable nitroxyl rad- of chiral nitroxyl radicals has been neglected.[11] We
ical has been exploited in both catalytic transition envisaged the assembly of catalysts with coordinating
metal based oxidations[2,3] and in organocatalytic reac- groups adjacent to the nitroxyl radical centre.[12] In
tions.[4,5] In the former field copper[6]/TEMPO[7] has addition to introducing chirality such structures would
enjoyed significant attention, delivering valuable pro- display bifunctionality,[13] potentially increasing cata-
cedures exploiting oxygen as the terminal oxidant.[7,8] lytic activity. To deliver such structures it was decided
In the later field organocatalytic procedures using to
study
2,2,4,4-tetramethyloxazolidine-N-oxyl
Scheme 1. Strategy to access bifunctional TOXYL 2.
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Christopher J. Gartshore and David W. Lupton
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(TOXYL 1)[14] as a scaffold. The assembly of bifunc- achieved under reverse or normal Dean–Stark condi-
tional TOXYLs 2 should be readily achievable in two tions with catalytic sulfonic acids. Purification of 5d–f
steps starting with an appropriate ketone (i.e., 4) was achieved by flash column chromatography on
(Scheme 1). Furthermore, their preparation in the silica gel, while 5a, b,[19] and c were more conveniently
enantiopure form, by resolution, or by use of chiral purified by distillation.
amino alcohol analogues of 3 in the oxazolidine for-
mation, should be relatively trivial.
Having accessed the requisite oxazolidines, their
oxidation to the corresponding nitroxyl radicals was
While the synthesis of TOXYLs is known,[15] they examined. In the case of amines 5a and 5e, this trans-
are yet to be studied as oxidation catalysts, hence it formation is known; achieved using 1.5 equivalents of
was essential to establish competence in this regard, mCPBA to provide L1 and L4.[16] Unfortunately,
prior to commencing studies with homochiral cata- when these conditions were applied to substrates 5b–
lysts. Herein we report the synthesis of a number of d oxidation of the pyridine residue led to pyridine N-
novel bifunctional TOXYL derivatives 2 and describe oxide, the desired nitroxyl radical, exhaustively oxi-
their application to the aerobic oxidation of alcohols. dized product, and starting material. To address these
difficulties sodium tungstate, in the presence of hy-
drogen peroxide as the stoichiometric oxidant, was
Results and Discussion
trialed.[20] Using these conditions, amines 5b and d
were converted to co-catalysts L2 and L3; however
the chemoselective oxidation of oxazolidine 5c could
not be achieved. Finally the preparation of the bisox-
Synthesis of Nitroxyl Radicals
Studies commenced with the preparation of the
ACHTUNGTRENaNUNG zolidine L5 was achieved using mCPBA, without the
parent TOXYL L1 and the bifunctional variants L2– formation of pyridine N-oxide.
L5. Although L1[14] and L4[16] have been prepared pre-
viously, the remaining nitroxyl radicals have not been
reported. The first step in the synthesis (Scheme 2) in- Oxidation Studies with Nitroxyl Radicals L1–L5
volved condensation of amino alcohol 3 with commer-
cial ketones 4a, b, c and e, and known ketones, 4d[17] Aerobic oxidation studies began using tetramethyl ni-
and 4f.[18] In our hands oxazolidine formation was troxyl radical L1. While L1, and indeed all nitroxyl
Scheme 2. Synthesis of oxazolidine nitroxyl radicals L1–L5. Reagents and conditions: (i) 10 mol% MeSO3H, DCM, reflux.
14–72 h. (ii) 10 mol% pTolSO3H, toluene, reflux, 14–72 h. (iii) 1.5 equiv. mCPBA, DCM, room temperature, 2 h. (iv) 3mol%
Na2WO3·2H2O, 3 equiv. H2O2, 1 equiv. NaHCO3/H2O, room temperature, 14 h. (v) 3 equiv. mCPBA, DCM, room tempera-
ture, 2 h.
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Readily Accessible Oxazolidine Nitroxyl Radicals: Bifunctional Cocatalysts
radicals in this study, were moderately unstable,[21]
The oxidation was subsequently trialled using bi-
they could be prepared, isolated, and used over the functional nitroxyl radical L2, without 2,2’-bipy and as
course of a week without special handling. It was de- hoped, the reaction was successful providing 74%
cided to explore copper-based oxidation reactions conversion of benzyl alcohol (Table 1, entry 2). At
analogous to those reported by Sheldon,[7a] owing to this juncture, a series of control reactions were con-
their extensive investigation,[7,8,13] thereby providing ducted. Replacement of L2 with amine 5b gave less
an appropriate benchmark. Specifically, the oxidation than 5% conversion (Table 1, entry 3); while the reac-
of benzyl alcohol to benzaldehyde, using nitroxyl radi- tion failed to proceed in the absence of either the
cal L1, in acetonitrile/water, with 5 mol% CuBr2, copper salt or the base.
5 mol% 2,2’-bipy, 5 mol% KOH,[22] and oxygen in air
The bipyridyl-containing nitroxyl radical L3 did not
as the stoichiometric oxidant was attempted. Gratify- result in significant improvement over results ob-
ingly, co-catalyst L1 was a suitable replacement for tained with L2 (Table 2, entry 2 cf. 4), while its
TEMPO providing the aldehyde in good yield, al- pseudo isomer L4 was unsuitable for this reaction
though requiring longer reaction time (Table 1, (Table 1, entry 5). We,[23] and others,[16] have found
entry 1a). Furthermore, and as observed with related that L4 is a useful tridentate species capable of form-
studies using TEMPO, removal of the 2,2’-bipyridine ing Cu(II)(L4)2 complexes. Under the described reac-
from the system resulted in loss of activity (Table 1, tion conditions, we presume this complex forms and is
entry 1b).
catalytically inactive. Finally, bisnitroxyl radical L6
gave only minor amounts of the oxidized product
(Table 1, entry 6).
Table 1. Oxidations with nitroxyl radicals L1–L5.
Optimization of Oxidation with L2
Results obtained with both co-catalysts L2 and L3
demonstrate the capacity of bifunctional oxazolidine
nitroxyl radicals to elicit aerobic oxidations, in the ab-
Entry Nitroxyl radical
Additive
Yield[%][a]
1a
1b
2,2’-bipy[b] 95
Table 2. Optimization with nitroxyl radical L2.
–
–
2
3
4
–
74
Entry MXn
Base
CH3CN/H2O Yeld [%][a,b]
1
2
3
4
5
6
7a
7b[c]
7c[d]
8
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
KOH
KOH
KOH
KOH
NaOH
K2CO3
K-t-OBu 3:1
K-t-OBu 3:1
K-t-OBu 3.1
2:1
74
1:1
63
–
–
<5%
3:1
86
100:0
3:1
–
51
3:1
71
95 (91)
(95)[e]
(93)[e]
65
76
Cu
Cu
ACHTUNGTRENNUNG
9
A
40
10
11
12
13[d,f]
14[g]
CuSO4
CuCl2
FeCl3
CuBr2
CuBr2
K-t-OBu 3:1
K-t-OBu 3:1
K-t-OBu 3:1
K-t-OBu 3:1
K-t-OBu 3:1
87
83
trace
<5
trace
5
–
–
4
7
[a]
1
Conversion as calculated by H NMR analysis.
Isolated yield in parentheses.
Conducted at 708C.
20 mol% of all catalytic components.
7 h.
[b]
[c]
[d]
[e]
[f]
6
[a]
1
Conversion calculated by H NMR analysis.
5 mol%.
Conducted with TEMPO in place of nitroxyl L2.
Conducted with no nitroxyl radical.
[b]
[g]
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sence of additional ligand. Building upon these condi- pared in 63% isolated yield (Table, entry 12). We next
tions we set about optimization with nitroxyl radical examined compounds containing more than one oxi-
L2. The reaction shows significant sensitivity to sol- dizable alcohol. In the case of naphthalene-2,6-dime-
vent, with most organic solvents leading to low con- thanol the expected dialdehyde formed in acceptable
version and acetonitrile/water mixtures giving optimal yield (Table 3, entry 13); however the oxidation of
results. Changing from a 2:1 ratio to equal parts water benzene-1,3,5-trimethanol provided the corresponding
and acetonitrile, decreased the yield, while increasing trialdehyde in low isolated yield (Table 3, entry 14).
the organic component (3:1) improved it (Table 2, en-
The oxidation of secondary alcohols was investigat-
tries 1–3). When the reaction was conducted in neat ed, and while diphenylmethanol was oxidized to ben-
acetonitrile, none of the product was observed zophenone in good yield (Table 3, entry 15), the oxi-
(Table 2, entry 4). In respect to the base, we found dation of 1-phenylethanol to acetophenone failed
that many are suitable; including NaOH and K2CO3 (Table 3, entry 16). The oxidation of primary non-ben-
(Table 2, entries 5 and 6), although K-t-OBu gave the zylic alcohol systems also failed to deliver the expect-
best outcome, allowing benzaldehyde to be formed in ed aldehyde (Table 3, entry 17).
91% isolated yield following chromatography
The application of the reaction to aliphatic and aro-
(Table 1, entry 7a). Next the Cu(II) salt was investi- matic allylic alcohols was investigated; both proved to
gated, with CuBr2 giving the best outcome (Table 2, be suitable substrates providing the corresponding
entries 7–11). Finally, use of FeCl3 afforded only a enals in good yield (Table 3, entries 18 and 19). Final-
trace of benzaldehyde (Table 2, entry 12).[24]
ly, the oxidation of hydoquinone to para-quinone was
Although the optimized conditions (Table 2, entry 7a) attempted. This transformation can be achieved with
allowed high yielding oxidation and good catalyst load- alternate copper-based systems,[25] and preceded
ing, the reaction time was long, requiring 3.5 days to smoothly under our reaction conditions (Table 3,
reach completion. Gratifyingly, this could be addressed entry 20).
by raising the temperature to 708C; providing full con-
version in under 7 h (Table 2, entry 7b). Similarly per-
forming the reaction with 20 mol% catalyst increased Mechanistic Aspects
the rate of the reaction (Table 2, entry 7c).
Having developed conditions optimized for bifunc- The mechanism of related Cu/TEMPO-based aerobic
tional nitroxyl radicals it was pertinent to test oxidations has been investigated using kinetic isotope
TEMPO in place of L2. When this experiment was and Hammett investigations,[7b] as well as computa-
conducted, using 20 mol% of each catalytic compo- tional approaches.[26] From these studies it appears
nent, less than 5% conversion of the benzyl alcohol that formation of oxoammonium intermediates is un-
was observed (Table 2, entry 13). This result is in favourable. Furthermore, it is known that TOXYL de-
keeping with the observations of Sheldon,[7] and oth- rivatives decompose upon oxidation to the oxoammo-
ers,[8f] who found that TEMPO requires coordinating nium cation.[27] Finally, the chemoselectivity observed
ligands to be effective in this type of oxidation. Final- in these studies is incongruous with oxoammonium-
ly, background oxidation of benzyl alcohol was mea- based oxidations. Together these lines of evidence
sured by removal of the nitroxyl radical catalyst, in suggest a mechanism involving copper-centred dehy-
this case only a trace of benzaldehyde was observed drogenation by intramolecular hydrogen abstraction
(Table 2, entry 14). While TEMPO and bipyrdine are resulting in the reduced nitroxyl radical intermediate
both commercially available, the development of cata- II. Reduction at copper would then provide the alde-
lysts that are active in the absence of the latter offer hyde complex III which, following aerobic oxidation
fundamental improvement to this type of system.
and substrate association, would regenerate I, and
complete the cycle (Scheme 3).
Scope of Aerobic Oxidation
Conclusions
Using the optimized conditions (Table 2, entry 7a, see
Experimental Section), the scope of this reaction was The application of TEMPO, and derivatives, in oxida-
investigated (Table 3). Studies commenced with the tion reactions has been extensively investigated. Sur-
oxidation of benzylic alcohols of various electronic prisingly, the application of the related oxazolidine ni-
character. All reactions reached 100% conversion, as troxyl radicals (i.e., L1–L5) had not been studied. The
1
judged by H NMR, allowing a host of aldehydes to potential utility of these nitroxyl radicals relates to
be isolated in good to excellent yields (Table 3, en- their ease of synthesis, thus allowing access to cata-
tries 1–11). There was no evidence of over oxidation lysts with readily tunable features, for example, bi-
to the carboxylic acid. Oxidation of heteroaromatic functionality. In these studies we found that the bi-
alcohols could also be achieved, with furaldehyde pre- functional catalysts L2 and L3, performed well in
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Readily Accessible Oxazolidine Nitroxyl Radicals: Bifunctional Cocatalysts
Table 3. Scope of the aerobic oxidation with Cu(II) and oxazolidine nitroxyl radical L2.
Entry Starting material Product[a]
Yield [%][b] Entry Starting material
Product[a]
Yield [%][b]
95
1
91
92
68
11
12
13
2
3
63
54
4
64
14
6
5
6
7
8
86
94
77
96
15
88
[c]
16
–
–
-
[c]
17
-
18[d]
92
76
9
75
73
19
20
10
60
[a]
All products prepared using the procedure described in Table 2 entry 7a and purified by flash column chromatography.
See Experimental Section.
Yield of isolated material.
No reaction observed.
[b]
[c]
[d]
Reaction complete in 48 h.
copper-based aerobic oxidation reactions in the ab-
sence of additives. Using these reaction conditions it
These studies constitute the first application of ox-
AHCTUNGTREGaNNNU zolidine nitroxyl radicals in oxidation reactions. On-
was possible to achieve room temperature oxidation going studies are aimed at increasing the scope of this
of alcohols with oxygen in air as the stoichiometric reaction, and accessing homochiral oxazolidine nitrox-
oxidant. Raising the temperature, or increasing cata- yl radicals suitable for enantioselective oxidative
lyst loading, accelerated the reaction, allowing com- transformations.
plete conversion to be achieved in less than 7 h. The
scope of the aerobic oxidation was explored, demon-
strating that a range of benzylic and allylic alcohols
can be oxidized, as can hydroquinone. Unfortunately,
Experimental Section
the oxidation of unactivated primary alcohols, and
partially activated secondary alcohols, was not viable
General Remarks
using our reaction conditions, a limitation shared by a
number of aerobic Cu/TEMPO oxidations.
Starting materials and reagents were purchased from
Sigma–Aldrich and used as supplied. Tetrahydrofuran
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Scheme 3. Key intermediates in a plausible mechanism
(THF) was distilled from sodium benzophenone ketyl. Tolu-
ene was purified using solvent purification system
(mBraum) and degassed. Acetone was dried over CaH2 and
distilled. Unless stated otherwise all reactions were conduct-
ed in flame-dried glassware under an inert atmosphere (N2).
The preparations of ketones 4d[17] and 4f,[18] oxazolidine
5a,[14] 5b,[19] 5e,[16] and nitroxyl radicals L1[14] and L4[16] were
achieved as described in Scheme 2 and associated text and
gave data in accord with the literature.
480 mg (72%); Rf 0.4 (1:1 hexane/EtOAc). 1H NMR
(400 MHz): d=8.67 (dt, J=4.8, 0.8 Hz, 1H), 8.47 (d J=
8.0 Hz, 1H), 8.34 (dd, J=8.0, 0.8 Hz, 1H), 7.83 (t, J=
8.0 Hz, 1H), 7.80 (td, J=8.0, 1.6 Hz, 1H), 7.66 (dd, J=8.0,
0.8 Hz, 1H), 7.30 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 3.77 (d, J=
8.0 Hz, 1H), 3.34 (d, J=8.0 Hz, 1H), 2.40 (bs, 1H), 1.74 (s,
3H), 1.37 (s, 3H), 1.19 (s, 3H); 13C NMR (100 MHz): d=
163.6, 156.2, 154.7, 149.2, 138.0, 137.0, 123.9, 121.4, 119.8,
119.4, 97.3, 59.5, 30.2, 28.6, 26.2; FT-IR (neat): nmax =3301,
2970, 2930, 2867, 1581, 1428, 1197, 1045, 781 cmÀ1; HR-MS
(ESI+, MeOH): m/z=270.1601 [M+H]+, C16H20N3O+ re-
quires 270.1601.
Synthesis of Oxazolidine Nitroxyl Radicals: 2,4,4-
Trimethyl-2-(pyridin-3-yl)oxazolidine (5c)
p-TsOH (785 mg, 4.13 mmol) was added to a stirred solution
of 3-acetylpyridine (4c) (4.54 mL, 41.3 mmol) and 2-amino-
2-methylpropanol (7.88 mL, 82.6 mmol) in toluene (30 mL).
The reaction was heated to reflux and water was removed
using a Dean–Stark apparatus. After 3 days the reaction was
cooled and concentrated in vacuo the residue was taken up
in dichloromethane (DCM) (15 mL) and washed with
NaHCO3 (10 mL of a saturated solution). The organic was
dried (MgSO4), filtered and concentrated under vacuum to
give a brown oil. Distillation (56–598C at 0.1 mbar) afforded
the title compound as a colorless oil; yield: 6.1 g (76%).
1H NMR (400 MHz): d=8.82 (dd, J=2.0, 1.2 Hz, 1H), 8.48
(dd, J=4.8, 1.3 Hz, 1H), 7.86 (dt, J=8.0, 2.0 Hz, 1H), 7.21
(ddd, J=8.0, 4.8, 0.8 Hz, 1H), 3.62 (d, J=8.0 Hz, 1H), 3.45
(d, J=8.0 Hz, 1H), 2.08 (bs, 1H), 1.59 (s, 3H), 1.30 (s, 3H),
0.88 (s, 3H); 13C NMR (100 MHz): d=148.6, 148.0, 133.6,
2,6-Bis(2,4,4-trimethyloxazolidin-2-yl)pyridine (5f)
Methanesulfonic acid (0.12 mL, 1.9 mmol) was added to a
stirred solution of 1,1’-(pyridine-2,6-diyl)diethanone (3.1 g,
19 mmol)
and
2-amino-2-methylpropanol
(7.26 mL,
76 mmol) in DCM (50 mL). The reaction was heated to
reflux and water was removed using a reverse Dean–Stark
apparatus. After 3 days methanesulfonic acid (0.12 mL,
1.9 mmol) was added and the reaction stirred at reflux for a
further 2 days before being cooled and washed with
NaHCO3 (20 mL of a saturated aqueous solution). The or-
ganic phase was dried (MgSO4), filtered and concentrated
under vacuum to give a yellow oil. Purification via flash
column chromatography (SiO2; 3:1 Hexane/EtOAc) gave
the title compound as a yellow solid; yield: 3.5 g (60%); Rf
1
0.3 (3:1 hexane/EtOAc); mp 77–818C. H NMR (400 MHz):
d=7.71 (td, J=7.8, 2.1 Hz, 1H), 7.52 (d, J=7.6 Hz, 2H),
3.72 (dd J=6.0, 1.6 Hz, 2H), 3.41 (bs, 2H), 3.27 (dd, J=
16.0, 7.8 Hz, 2H), 1.65 (d, J=4.4 Hz, 6H), 1.31 (d, J=
2.4 Hz, 6H), 1.12 (d, J=2.4 Hz, 6H); 13C NMR (100 MHz):
d=162.7, 138.0, 118.3, 96.6, 77.6, 59.3, 30.1, 28.7, 26.3; FT-IR
(KBr): nmax =3327, 2976, 2932, 2843, 1584, 1369, 1168, 1048,
817 cmÀ1; HR-MS (ESI+, MeOH): m/z=306.2176 [M+H]+,
122.9, 96.3, 77.5, 60.2, 31.2, 28.7, 27.5; FT-IR (neat): nmax
=
3275, 2972, 2929, 2865, 1690, 1414, 1041, 717 cmÀ1; HR-MS
(ESI+, MeOH): m/z=193.1336 [M+H]+, C11H17N2O+ re-
quires 193.1335.
2-([2,2’-Bipyridin]-6-yl)-2,4,4-trimethyloxazolidine
(5d)
+
C17H29N3O2 requires 306.2176.
Methanesulfonic acid (0.1 mL, 0.94 mmol) was added to a
stirred solution of 3-acetyl-(2,2’-bipyridine) (4d) (1.85 g,
2,4,4-Trimethyl-2-(pyridin-2-yl)oxazolidine N-Oxide
(L2)
9.4 mmol)
and
2-amino-2-methylpropanol
(8.9 mL,
93.3 mmol) in DCM (30 mL). The reaction was heated to
reflux and water was removed using a reverse Dean–Stark
apparatus. After 2 days the reaction mixture was cooled
then concentrated under vacuum to give a brown oil. Purifi-
cation via flash column chromatography (SiO2; 1:1 hexane/
EtOAc) gave the title compound as a yellow oil; yield:
To a solution of 2,4,4-trimethyl-2-(pyridin-2-yl)oxazolidine
(5b) (350 mg, 1.82 mmol) in MeOH:MeCN (30 mL of a 14:1
mixture) was added sodium hydrogen carbonate (120 mg,
1.4 mmol), sodium tungstate dihydrate (21 mg, 0.056 mmol)
and hydrogen peroxide (0.75 mL of a 30% aqueous solution,
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Readily Accessible Oxazolidine Nitroxyl Radicals: Bifunctional Cocatalysts
5.46 mmol). The suspension was stirred at room temperature
for 16 h before being diluted with Et2O (20 mL) and washed
with water (10 mL). The organic layer was separated, dried
(MgSO4), filtered and concentrated under vacuum to give
an orange oil. Purification via flash column chromatography
(SiO2; 2:1 hexane/EtOAc) afforded the title compound as a
yellow oil; yield: 260 mg (69%); Rf 0.45 (2:1 hexane/
EtOAc). FT-IR (neat): nmax =3582, 2978, 2935, 2874, 1586,
1465, 1364, 1045, 782 cmÀ1; HR-MS (ESI+, MeOH): m/z=
208.1200 [M+H]+, C11H15N2O2C requires 208.1206.
Procedure for the Aerobic Oxidation (Table 3)
The appropriate alcohol (1 mmol) was added to a vigorously
stirred solution of the KO-t-Bu (5.6 mg, 0.05 mmol) in aceto-
nitrile/water (3 mL of a 3:1 mixture). To this was added
CuBr2 (11 mg, 0.05 mmol) followed by the oxazolidine ni-
troxyl radical L2 (10.4 mg, 0.05 mmol) and the reaction
stirred at room temperature. Once the reaction was com-
plete the mixture was extracted with CH2Cl2 (10 mL) then
dried (MgSO4), filtered, concentrated under vacuum and pu-
rified via flash column chromatography (silica gel; hexane/
EtOAc).
2-[(2,2’-Bipyridin)-6-yl]-2,4,4-trimethyloxazolidine
N-Oxide (L4)
To a solution of 2-[(2,2’-bipyridin)-6-yl]-2,4,4-trimethyloxa-
zolidine (5c) (100 mg, 0.34 mmol) in methanol/acetonitrile
(15 mL of a 14:1 mixture) was added sodium hydrogen car-
bonate (22.6 mg, 0.27 mmol), sodium tungstate dihydrate
(3.5 mg, 0.03 mmol) and hydrogen peroxide (0.2 mL of a
30% aqueous solution, 2.04 mmol). The reaction was al-
lowed to stir at room temperature for 16 h before being di-
luted with Et2O (20 mL) and washed with water (10 mL).
The organic layer was separated, dried (MgSO4), filtered
and concentrated under vacuum to give an orange oil. Pu-
rification via flash column chromatography (SiO2; 1:1
hexane/EtOAc) afforded the title compound as an orange
solid; yield: 60 mg (62%); Rf 0.4 (1:1 hexane/EtOAc); mp.
59–638C. FT-IR (KBr): nmax =3449, 2974, 2936, 2875, 1701,
1581, 1430, 1260, 1047, 786 cmÀ1; HR-MS (ESI+, MeOH):
m/z=285.1477 [M+H]+, C16H19N3O2C requires 285.1472.
Acknowledgements
The authors would like to acknowledge the ARC for finan-
cial support (DP0881137), Monash University for Early
Career Researcher grants and a Deans scholarship (CJG). Fi-
nally the authors acknowledge the preliminary studies of Jane
Octavia Junaidi on this topic.
References
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2,6-Bis(2,4,4-trimethyloxazolidin-2-yl)pyridine
N-Oxide (L5)
m-CPBA (874 mg, 4.91 mmol) was added in portions to a
stirred solution of 2,6-bis(2,4,4-trimethyloxazolidin-2-yl)pyri-
dine (500 mg, 1.64 mmol) in Et2O (20 mL) at 08C. The solu-
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3449, 2976, 2937, 2878, 1701, 1584, 1459, 1364, 1224, 1046,
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C17H26N3O4C requires 336.1918.
Typical Procedure for Aerobic Oxidation
Optimization (Table 1 and Table 2)
Benzyl alcohol (108 mg, 1 mmol) was added to a vigorously
stirred solution of the base (0.05 mmol) in acetonitrile/water
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the reaction was complete the mixture was extracted with
CH2Cl2 (10 mL) then dried (MgSO4), filtered, concentrated
under vacuum and purified via flash column chromatogra-
phy (silica gel; hexane/EtOAc).
Adv. Synth. Catal. 2010, 352, 3321 – 3328
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3327

Christopher J. Gartshore and David W. Lupton
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3328
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Adv. Synth. Catal. 2010, 352, 3321 – 3328