Imidazolidinone nitroxides as catalysts in the aerobic oxidation of alcohols, en route to atroposelective oxidative desymmetrization

Article abstract of DOI:10.1002/ejoc.201402324

New chiral nitroxides based on the imidazolidin-4-one skeleton, and the corresponding hydroxylamines, have been prepared from cyclic nitrones by a straightforward reaction sequence. They were evaluated as catalysts in the aerobic oxidation of benzyl alcohol using different co-catalysts. Both the imidazolidinone nitroxides and hydroxylamines were proven to catalyze the reaction, with the ring substituent having an effect depending on the co-catalytic system. In some cases, rapid oxidation to benzaldehyde was accomplished at room temperature under an atmospheric O₂ pressure. Moreover, atroposelective desymmetrization was achieved during the aerobic oxidation of a diol catalyzed by an enantiopure imidazolidinone nitroxide. Finally, the electrochemical behavior of the new hydroxylamines and nitroxides was investigated by cyclic voltammetry, which gave insights into the observed catalytic properties.

Full text of DOI:10.1002/ejoc.201402324

FULL PAPER
DOI: 10.1002/ejoc.201402324
Imidazolidinone Nitroxides as Catalysts in the Aerobic Oxidation of Alcohols,
en Route to Atroposelective Oxidative Desymmetrization
Marta Carbó López,[a,b] Guy Royal,[a,b] Christian Philouze,[a,b] Pierre Y. Chavant,[a,b] and
Véronique Blandin*[a,b]
Keywords: Aerobic oxidation / Nitroxyl radicals / Alcohols / Asymmetric catalysis / Atropisomerism
New chiral nitroxides based on the imidazolidin-4-one skel-
eton, and the corresponding hydroxylamines, have been pre-
pared from cyclic nitrones by a straightforward reaction se-
rapid oxidation to benzaldehyde was accomplished at room
temperature under an atmospheric O2 pressure. Moreover,
atroposelective desymmetrization was achieved during the
quence. They were evaluated as catalysts in the aerobic oxi- aerobic oxidation of a diol catalyzed by an enantiopure imid-
dation of benzyl alcohol using different co-catalysts. Both the
imidazolidinone nitroxides and hydroxylamines were proven
to catalyze the reaction, with the ring substituent having an
effect depending on the co-catalytic system. In some cases,
azolidinone nitroxide. Finally, the electrochemical behavior
of the new hydroxylamines and nitroxides was investigated
by cyclic voltammetry, which gave insights into the observed
catalytic properties.
tems have been reported,[3] as well as metal-free co-catalysts
that generally act as NOx sources.[4] Conversely, stable ni-
troxyl radicals other than piperidin-1-yloxyls have seldom
been investigated in the aerobic oxidation of alcohols (Fig-
ure 1): Iwabuchi and co-workers reported that several AZ-
ADO-type nitroxides (II) are highly active catalysts in the
presence of NaNO2 and acetic acid,[5] Stahl and co-workers
applied ABNO-type nitroxides (III) either with a Cu-
based[6] or a NOx[7] co-catalyst, and Gartshore and Lupton
studied the scope of TOXYL-type nitroxides (IV)[8] under
the oxidation conditions developed by Sheldon and co-
workers.[9] Several other types of nitroxides have been de-
scribed in the literature, some of which have been used as
catalysts in nonaerobic alcohol oxidation.[10] In addition,
chiral nitroxides have been employed in oxidative kinetic
resolutions and diol desymmetrizations.[11]
Introduction
The nitroxide-catalyzed oxidation of alcohols with mo-
lecular oxygen has received considerable attention over the
past decade.[1] The use of O2 in oxidation reactions is par-
ticularly advantageous in terms of cost, atom economy, and
environmental impact.[2] The combination of O2, TEMPO
[2,2,6,6-tetramethylpiperidin-1-yloxyl (I), Figure 1], and a
co-catalyst has rapidly emerged as the most sustainable oxi-
dation method.[2] Most of the work so far has been devoted
to the nature of the co-catalyst: Many Cu- or Fe-based sys-
Nitroxides of the general structure V with an imid-
azolidin-4-one skeleton were first prepared in the early
1970s (Figure 1).[12] Their use in various applications, in-
cluding nitroxide-mediated polymerization[13] and organic
batteries,[14] has been investigated.[15] To the best of our
knowledge, however, the properties of imidazolidin-4-one-
based nitroxides as oxidation catalysts have never been re-
ported.
Our work on imidazolidinone-based nitrones of general
formula 1[16] led us to report the direct C–H arylation of
cyclic nitrones.[17] This reaction allows the preparation of a
variety of new α,α,αЈ,αЈ-tetrasubstituted hydroxylamines in
only two steps. In particular, when this transformation was
applied to the chiral nitrone MiPNO (1a; R1 = Me, R2 =
iPr), available in both enantiopure forms,[18] enantiopure
hydroxylamines 4a were readily obtained (Scheme 1).
Figure 1. Nitroxides I–IV employed in the aerobic oxidation of
alcohols and imidazolidin-4-one-based nitroxide V.
[a] Université Grenoble Alpes, DCM UMR-5250,
38000 Grenoble, France
E-mail: Veronique.Blandin@ujf-grenoble.fr
www.dcm.ujf-grenoble.fr
[b] CNRS, DCM UMR-5250,
38000 Grenoble, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402324.
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Imidazolidinone Nitroxide Catalysts in Alcohol Oxidation
Arylnitrones 3 and hydroxylamines 4 were synthesized
according to Scheme 1 and the relevant reaction data are
presented in Table 1. The palladium-catalyzed coupling of
nitrones 1 with p-tolyl bromide (2a) in the presence of
20 mol-% pivalic acid (Method A), and with 2-bromopyr-
idine (2b) in the presence of 5 mol-% copper bromide[17]
(Method B), provided arylnitrones 3 in excellent yields.
Methylation with excess methyl Grignard reagents
(Method C or D) then gave access to hydroxylamines 4 in
yields of 40–89%. In the case of chiral nitrones 3aa and
3ab, the diastereoselectivity of the addition reactions was
excellent, as previously encountered:[17] Only one dia-
Scheme 1. Direct arylation of nitrones 1 and synthesis of α,α,αЈ,αЈ-
tetrasubstituted hydroxylamines 4.
1
stereomer was detected by H NMR analysis of the crude
reaction mixtures. The relative configurations of 4aa[17] and
4ab[19] (Figure 2) were determined by X-ray diffraction
analysis: The methyl group was transferred anti to the bulky
isopropyl group.
We wondered, i. whether these imidazolidinone-based
hydroxylamines 4 could be used as nitroxide precursors for
the catalysis of the aerobic oxidation of alcohols, ii. what
would be the effect of the nature of the α,αЈ-substituents,
and iii. whether enantiodifferentiation could be achieved.
We herein present our first investigations on this subject,
combining synthesis, catalytic oxidation experiments, and
electrochemical characterization of the species involved.
Table 1. Preparation of arylnitrones 3 and hydroxylamines 4.
Results and Discussion
Synthesis of Nitroxide Precursors
In addition to the chiral nitrone MiPNO (1a) with iso-
propyl/methyl substitution,[18] we selected two other imid-
azolidinone-based nitrones to investigate the influence of
substituents at the α position of the nitroxide: 1b bearing
two methyl substituents and 1c with a spiro-cyclohexane
moiety (Scheme 1).
At the αЈ position of the nitroxide, we chose to have one
methyl group in all cases, together with either an aryl ring
(p-tolyl or 2-pyridyl in compounds 3 and 4, Scheme 1, and
nitroxides 7) or a second methyl group (compounds 5 and
6, Scheme 2, and nitroxides 8).
[a] Isolated yield. [b] Reagents and conditions for direct arylation:
ArBr (1.1 equiv.), K2CO3 (1.5 equiv.), anisole (1 m), 150 °C, 0.5–
2 h. Method A: Pd (2 mol-%), PPh3 (2 mol-%), PivOH (20 mol-%).
Method B: Pd (2 mol-%), PPh3 (2 mol-%), CuBr·DMS (5 mol-%),
1,10-phenanthroline (5 mol-%). [c] Reagents and conditions for
methylation, Method C: MeMgCl (1.5–2.0 equiv.), THF, 15 min.
Method D: MeMgI (2.0–3.5 equiv.), diethyl ether, 0 °C, 30 min.
The bis-methylated analogues 6a and 6b were prepared in
moderate yields by an addition/oxidation/addition reaction
sequence (Scheme 2).
There are literature precedents for the direct use of hy-
droxylamines as oxidation catalysts in place of their ni-
troxide counterparts.[20] Nevertheless, nitroxides 7aa, 7ab,
7ba, and 8b were prepared quantitatively by MnO2 or
mCPBA oxidation of the corresponding hydroxylamines
4aa, 4ab, 4ba, and 6b.[21] In the case of 7aa, crystals suitable
Scheme 2. Preparation of bis-methylated hydroxylamines 6.
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FULL PAPER
tention was paid to the oxidative capacity of these co-cata-
lysts in the absence of nitroxide, as it could be detrimental
to enantioselective oxidation. Representative results are pre-
sented in Table 2.
Figure 2. ORTEP drawing of hydroxylamine 4ab. Ellipsoids are
drawn at the 50% probability level. Hydrogen atoms have been
omitted for clarity.
for X-ray diffraction analysis were obtained (Figure 3).[22]
The nitroxide N–O bond length is consistent with litera-
ture[23,13d] values (1.271 Å), but it is worth noting that the
out-of-plane angle (between the N–O bond and the C–N–
C plane) is 14.4°.[24] In previously reported crystal struc-
tures of five-membered cyclic nitroxides,[23,25] this angle
ranges from 0 to 8°, with one exception, the geometrically
strained bicyclic 1,5-dimethyl-8-azabicyclo[3,2,1]octan-3-
one-8-oxyl (24.8°).[26] This suggests that nitroxide 7aa could
be geometrically strained as well because of the steric repul-
sion between the bulky isopropyl group and the aryl group.
Figure 4. Hydroxylamines and nitroxides evaluated in the aerobic
oxidation of benzyl alcohol.
Co-catalytic System CuBr2/tBuOK/bipy (Method E)
We started our study by using the conditions developed
by Sheldon and co-workers (Method E),[9] namely a CuII
salt with 2,2Ј-bipyridine as a ligand and KOtBu as base. At
20–30 °C and under 1–4 bar O2, the oxidation of benzyl
alcohol was much slower in the presence of imidazolidi-
none-based hydroxylamines 6a and 6b than with TEMPO
(Table 2, compare entries 7 and 9 vs. 1 and 2). When the
reaction was performed at 80 °C under 4 bar O2, with
MiPNO-derived hydroxylamine 6a, the reaction started
sluggishly and stalled after a few hours (entry 8). On the
other hand, 6b and the corresponding nitroxide 8b were
found to catalyze cleanly the oxidation of benzyl alcohol to
benzaldehyde: complete conversion was reached in less than
4 h (compare entries 11 and 12 vs. 6).
The same trends were observed with aryl-substituted hy-
droxylamines 4. At ambient temperature, the oxidation of
benzyl alcohol was slow (entries 16 and 23). At 80 °C, the
catalysis was inefficient with isopropyl-bearing compounds
4aa and 4ab (entries 14 and 21), but led to complete conver-
sion within a few hours with permethylated analogues 4ba
and 4bb (entries 18 and 25). The case of hydroxylamine 4ca
with a spiro-cyclohexane moiety is intermediate: the reac-
tion does not stall but is slower than with 4ba (compare
entries 19 vs. 18).
Figure 3. ORTEP drawing of nitroxide 7aa. Ellipsoids are drawn at
the 50% probability level. Hydrogen atoms have been omitted for
clarity.
Interestingly, with 2-pyridyl-substituted 4bb, and con-
trary to what is known with TEMPO,[9,27] the oxidation oc-
curs even in the absence of the 2,2Ј-bipyridine ligand (en-
Aerobic Oxidation of Benzyl Alcohol
The prepared hydroxylamines and nitroxides (Figure 4) try 26), albeit slowly. A similar result was observed by Gart-
were evaluated as catalysts in the oxidation of benzyl shore and Lupton with oxazolidine nitroxyl radicals.[8] It is
alcohol by molecular oxygen. We selected several co-cata- believed that the pyridinyl nitrogen atom coordinates to the
lysts that had been developed with TEMPO. Particular at- copper to help stabilize the active species.[28]
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Imidazolidinone Nitroxide Catalysts in Alcohol Oxidation
Table 2. Aerobic oxidation of benzyl alcohol using imidazolidinone-based hydroxylamine or nitroxide catalysts and different co-catalysts.
Entry
Cat.[a]
Method E[b]
CuBr2/tBuOK/bipy
Method F[c]
CuBr2/NaNO2
Method G[d]
HBr/TBN
T [°C] P [bar] t [h]
Conv.[e]
[%]
T [°C] P [bar]
t [h]
Conv.[e]
[%]
T [°C] P [bar]
t [h]
Conv.[e]
[%]
1
TEMPO
None
20
Patm
0.3
97
20
Patm
3
5
89
100
20
Patm
3
5
78
100
2
3
4
30
80
20
4
4
Patm
0.3
Ͻ1
23
100
100
4
80
20
4
Patm
1
24
100
3
80
20
4
Patm
1
5
100
9
21
14
14
14
11
6
73
1
5
6
7
8
9
30
80
30
80
20
4
4
4
4
Patm
14
14
14
14
5
3
30
80
30
4
4
4
Ͻ1
10[f]
12[f]
8
80
4
14
4
6a
6b
80
20
4
Patm
14
5
23
48
6[f]
2
4
20
30
30
20
30
30
20
30
Patm
3
5
21
14
88
97
100
100
23
13
7
10
11
12
13
14
15
16
4
4
80
80
4
4
3.5
3.5
100
100
80
4
14
49
8b
4aa
14
2
80
20
4
14
12[f]
80
80
20
4
4
Patm
14
14
5
23
48
6[f]
8[f]
2
4
6
7aa
4ba
Patm
5
23
8
13
Patm
3
5
21
14
62
82
98
96
17
18
19
20
21
22
23
4
80
80
4
4
6
14
98
70
80
80
4
4
14
14
44
32
4ca
4ab
4
14
1
80
20
4
14
0
80
80
20
4
4
Patm
14
14
5
23
48
25[f]
24[f]
19
25
37
7ab
4bb
Patm
5
23
9
14
Patm
3
5
21
14
3
4
9
5
24
25
26
4
80
80
4
4
6
14
91
80
4
4
100
56[g]
[a] Hydroxylamine or nitroxide used. [b] Method E: benzyl alcohol (1 mmol), catalyst (5 mol-%), CuBr2 (5 mol-%), tBuOK (5 mol-%),
2,2Ј-bipyridine (5 mol-%) in MeCN/H2O (2:1, 1 m). [c] Method F: benzyl alcohol (1 mmol), catalyst (5 mol-%), CuBr2 (5 mol-%), NaNO2
(5 mol-%) in PhCF3 (1 m). [d] Method G: benzyl alcohol (1 mmol), catalyst (5 mol-%), HBr (5 mol-%), TBN (5 mol-%) in MeCN (1 m).
[e] Conversion of benzyl alcohol, determined by GC analysis. [f] According to the monitoring of O2 uptake, the reaction stalls within 1–
3 h. [g] Reaction performed without 2,2Ј-bipyridine.
Co-catalytic System CuBr2/NaNO2 (Method F)
Me; entries 11, 18, and 25) with a striking beneficial effect
of the 2-pyridyl group: Oxidation to benzaldehyde was
complete in 4 h.[31]
Oxidation at room temperature under an atmospheric O2
pressure was investigated with hydroxylamines 4/6b (en-
tries 9, 16, and 23) and proved much slower: A maximum
37% conversion was attained in 48 h with 2-pyridyl-substi-
tuted 4bb.
To further study the impact of a coordinating atom on
the nitroxide activity, we investigated a copper-based co-
catalytic system deriving from literature results:[29] CuBr2/
NaNO2 (Method F). The TEMPO-catalyzed oxidation of
benzyl alcohol proved efficient at room temperature as well
as at 80 °C (Table 2, compare entries 1 vs. 4 and 3 vs. 6).[30]
The oxidation was less rapid in the presence of imid-
azolidinone-based hydroxylamines. After 14 h at 80 °C,
only a modest 32% conversion was reached with 4ca (en-
try 19). The reaction proved again to stall rapidly with iso-
propyl-bearing compounds 4/6/7a (entries 8, 14, 15, 21, and
Co-catalytic System HBr/TBN (Method G)
We sought a co-catalyst that would allow a faster oxi-
22), a maximum 25% conversion being obtained with 4/7ab. dation of benzyl alcohol under mild conditions (20 °C,
Finally, the best results were found with 4/6b (R1 = R2 = Patm), and found that a combination of HBr and tert-butyl
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nitrite (TBN; Method G)[32] was effective. When the oxi-
dation of benzyl alcohol was carried out at 80 °C as origi-
nally described,[32] we observed a high level of background
oxidation over time (entries 3 and 6). On the other hand,
oxidation was limited at ambient temperature, whereas the
conversion was complete in 5 h in the presence of TEMPO
(entries 1, 4, and 5). Hardly any reaction occurred with iso-
propyl-substituted hydroxylamines 4/6a (entries 7, 13, and
20), whereas complete conversion of benzyl alcohol was
achieved within a day with hydroxylamines 6b and 4ba
(entries 9, 16, and 17).
Imidazolidinone Nitroxides as Oxidation Catalyts Ϫ
Conclusions
Several conclusions can be drawn from the above results.
i. Imidazolidinone nitroxides or their hydroxylamine pre-
cursors are indeed able to catalyze the aerobic oxidation of
benzyl alcohol. ii. The effect of nitroxide structure (piperi-
dine vs. imidazolidin-4-one) and α,αЈ-substitution strongly
depends on the co-catalytic system used. iii. The nature of
the alkyl substituents at the α position is important for cata-
lytic capability; the isopropyl group proved detrimental.
iv. Compounds with an aryl group at the αЈ position can be
as efficient as their permethylated analogues, and even more
efficient in the case of a 2-pyridyl group.
Moreover, the best results for the oxidation of benzyl
alcohol at room temperature under an atmospheric O2 pres-
sure were obtained with the HBr/TBN co-catalytic system
(Method G). These conditions were therefore selected for
the first study of asymmetric oxidation.
Scheme 3. Preparation of enantiopure nitroxide (+)-7ba.
The increasing interest in atropisomerism in drug discov-
ery[34] led us to investigate the atroposelective oxidative de-
symmetrization of a diol[35,36] to evaluate the enantiodiffer-
entiating ability of imidazolidinone-based nitroxide (+)-
7ba. Diol 12 was selected as a model and its synthesis is
depicted in Scheme 4. Suzuki–Miyaura coupling[37] of read-
ily prepared boronic ester 13[38] and 2-bromo-m-xylene led
to biaryl 14 in 61% unoptimized yield. Bromination of both
benzylic positions followed by hydrolysis[39] gave diol 12 in
45% yield over three steps.
Is Enantioselective Oxidation Possible with Imidazolidinone
Nitroxides?
The above conclusions show that one of the original
goals of this study, the application of enantiopure com-
pounds 4a, readily available from enantiopure MiPNO (1a),
to enantioselective aerobic oxidation, could not be achieved
directly. Nevertheless, hydroxylamines 4b are also chiral,
very easily accessed in racemic form, and resolution can be
considered. We previously proposed a successful strategy
for the resolution of such chiral hydroxylamines by O-acyl-
ation.[33] We therefore sought to obtain 4ba in enantiopure
form. However, our attempts towards resolution so far have
failed. We therefore turned to a less elegant but straightfor-
ward synthesis of the corresponding nitroxide 7ba
(Scheme 3).
Enantiopure (+)-3aa and (–)-4aa were prepared from
(+)-MiPNO (1a) according to Scheme 1. The N–O bond
was reduced by using zinc in acetic acid under sonication
and hydrolytic cleavage of the resulting aminal was per-
formed over 40 min under microwave irradiation to cleanly
give amino amide 10. Subsequent reaction with acetone re-
installed the imidazolidinone ring. Finally, amine oxidation
with mCPBA gave enantiopure nitroxide (+)-7ba. The
global yield starting from (+)-1a was 20–25%.
Scheme 4. Preparation of symmetrical diol 12.
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Imidazolidinone Nitroxide Catalysts in Alcohol Oxidation
We then submitted diol 12 to oxidation in the presence
The CV curve of the nitroxyl radical 8b (Figure 5, a) dis-
of 5 mol-% 7ba, HBr, and TBN under atmospheric O2 pres- plays one reversible oxidation and one irreversible re-
sure at room temperature (Table 3).
duction at E1/2 = +0.8 V and Epc = –1.6 V, respectively. By
analogy with reported studies of other nitroxyl radicals,[43]
the oxidation wave has been assigned to the formation of
the corresponding oxoammonium cation following a one-
electron transfer (Scheme 5, a). Compared with TEMPO,
the reversible N=O+/N–O· couple of 8b appears at a signifi-
cantly higher potential (Table 4, compare entries 2 vs. 1).
This result is consistent with the presence of an electron-
withdrawing group[43c,44] and also corroborates previous
studies in which five-membered cyclic nitroxides were found
to be more difficult to oxidize than six-membered-ring ni-
troxides.[43c] The reduction of 8b at low potential has been
attributed to the formation of the deprotonated hydroxyl-
amine (Scheme 5, a).[45] It is known that this process
strongly depends on the experimental conditions (pH, elec-
trode material, solvent) because it can involve proton trans-
fer coupled to electron exchange.[46,47]
Table 3. Aerobic oxidation of diol 12 catalyzed by nitroxide (R)-
7ba.[a]
Entry Amount of (R)-7ba Time Conv. of 12[b] ee of 16[c]
[mol-%]
[h]
[%]
[%]
1
0
24
48[d]
96[d]
24
2
4
8
12
39
22
–
–
–
36
24
44
2
3
5
96[d]
24
20
[a] Reagents and conditions: Diol 12 (0.2 mmol), (R)-7ba (5 mol-
%), HBr (5 mol-%), TBN (5 mol-%) in MeCN (0.2 m). [b] Conver-
sion determined by 19F NMR spectroscopy. [c] Enantiomeric excess
determined by HPLC analysis. [d] Additional HBr (5 mol-%) and
TBN (5 mol-%) were introduced into the reaction mixture every
24 h.
The reaction proved much slower than benzyl alcohol
oxidation, and stalled after 1 day with 12% conversion and
36% ee (entry 2). Notably, daily additions of the same
amounts of HBr and TBN caused the conversion to rise
slowly to 39%.[40] The slight decrease in ee after 4 d is con-
sistent with the occurrence of limited oxidation in the ab-
sence of 7ba (entry 1). Another experiment with 20 mol-%
of nitroxide 7ba confirmed the trend (entry 3): The reaction
stalled within a day, but having achieved a higher conver-
sion (22 vs. 12%) and with a slight increase in the ee.[41]
Thus, it is likely that the prime limitation of this catalytic
system is the loss of the nitrogen oxide species that allows
the reoxidation of the hydroxylamine by O2 and thus the
catalytic cycle to start again.[42] We are currently investiga-
ting other co-catalysts. A major conclusion, however, is that
chiral imidazolidinone-based nitroxides can induce enantio-
selectivity in aerobic oxidation reactions.
Figure 5. Cyclic voltammograms of a) 8b, b) 6b, and c) 6a in 0.2 m
NaClO4 in acetonitrile/water (95:5, v/v) in the presence of 2,6-luti-
dine (8 equiv.). Working electrode: vitreous carbon; scan rate:
100 mVs–1.
The cyclic voltammograms of the hydroxylamines 4 and
6 each exhibit only one oxidation process in the –2 to +1 V
range, which has been attributed to the formation of the
Cyclic Voltammetry Study
The electrochemical behavior of nitroxide 8b and hydrox- oxoammonium cation. The potentials of these oxidation
ylamines 4 and 6 (and TEMPO for comparison) was inves- signals logically vary with the nature and substitution of
tigated by cyclic voltammetry (CV). Experiments were con- the rings, but remain close to +0.8 V (see Table 4 for data).
ducted under an inert atmosphere in a classical three-elec- However, as illustrated in Figure 5b,c, two different types
trode cell with a glassy carbon disk as working electrode. of electrochemical behavior can be clearly identified, de-
Measurements were performed in acetonitrile/water (95:5, pending on the nature of the substituents.
v/v) containing sodium perchlorate (0.2 m) as supporting
In the case of the dimethyl- (6b, 4ba, and 4bb) and cyclo-
electrolyte. 2,6-Lutidine was also added (8 equiv.) to be con- hexyl-substituted (4ca) compounds, the oxidation process
sistent with catalytic experiments (see below). The cyclovol- appears reversible with a well-defined reduction wave dur-
tammetric data are listed in Table 4.
ing the reverse scan and a peak separation (Epa – Epc) close
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groups on the ring; elimination of propene would therefore
be favored by steric decompression. The same elimination
from the less encumbered spiro derivative 4ca would be less
favorable enthalpically and entropically. This instability of
the oxoammonium unit is in total agreement with the poor
catalytic properties of the isopropyl-containing systems.
Scheme 6. Hypothetical mechanism for the decomposition of the
oxoammonium cation in the 4/6a series.
Scheme 5. a) One-electron oxidation and reduction of nitroxide 8b
and b) comproportionation reaction to give the nitroxyl radical.
To support our catalytic results, the influence of benzyl
alcohol on the electrochemical behavior of the dimethyl-
(6b, 4ba, 4bb) and cyclohexyl-substituted (4ca) hydroxyl-
amines was examined. An example of the response is given
in Figure 6. As expected, in all cases, upon addition of
benzyl alcohol, the oxidation wave corresponding to the
formation of the oxoammonium unit became fully irrevers-
ible and a gradual increase in the current was observed.[51]
This behavior is typical of electrocatalytic processes,[52] that
is, the electrogenerated oxoammonium rapidly reacts chemi-
cally with benzyl alcohol (this reaction being faster than the
CV timescale) to regenerate the nitroxide moiety, which
then re-enters the electrocatalytic cycle. Further investi-
gations beyond the scope of this paper are underway to de-
termine the kinetic parameters.
Table 4. Oxidation potentials for nitroxides, hydroxylamines, and
TEMPO.
Entry
Compound
E1/2 (ΔEP)[a,b]
1
2
3
4
5
6
7
8
9
TEMPO
8b
0.317 (0.085)
0.800 (0.095)
0.790 (0.085)
0.840 (0.075)
0.835 (0.080)
0.770 (0.075)
0.843[c]
6b
4ba
4bb
4ca
6a
4aa
4ab
0.840[c]
0.846[c]
[a] E1/2 [V] vs. Ag/AgNO3, 10–2 m in CH3CN. [b] E1/2 = (Epa + Epc)/
2 at 0.1 Vs–1; ΔEp = Epa – Epc. [c] Oxidation peak potential (Epa
,
irreversible process).
to 80 mV (see, for example, Figure 5, b). It is also important
to note that the oxidation wave for 6b appears at the same
potential as the oxidation signal of the corresponding ni-
troxide 8b. This behavior corroborates previous re-
sults,[43d,46,48] and can be explained by comproportionation
reactions between the electrogenerated oxoammonium cat-
ions and the hydroxylamine moieties leading to the corre-
sponding nitroxyl radical (Scheme 5, b). These results are
in accordance with our catalytic experiments (Table 2) re-
vealing that hydroxylamines 4 and 6 or their corresponding
nitroxyl radicals 7 and 8 could be used indifferently as oxi-
dation catalysts.
In contrast, the CV curves of the isopropyl-substituted
compounds 6a, 4aa, and 4ab exhibit one fully irreversible
oxidation wave (see, for example, Figure 5, c) irrespective of
the scan rate (voltammograms up to 10 Vs–1 have
been recorded). Such irreversibility indicates that the elec-
trogenerated isopropyl-containing oxoammonium cations
are chemically unstable under the experimental conditions
on the CV timescale because of the presence of chemical
reactions coupled with electron transfer.[43b,43c,49] An analo-
gous decrease in the stability of an oxoammonium cation
Figure 6. Cyclic voltammograms of 4ca in the presence of
a) 0 equiv., b) 0.5 equiv., c) 2 equiv., d) 5 equiv., and e) 8 equiv. of
benzyl alcohol. Data were recorded in 0.2 m NaClO4 in acetonitrile/
water (95:5, v:v) in the presence of 2,6-lutidine (8 equiv.). Working
electrode: vitreous carbon; scan rate: 100 mVs–1.
Conclusions
Various hydroxylamines and nitroxides with an imid-
when the α substituent is changed from methyl to ethyl or azolidin-4-one skeleton have been prepared from cyclic
higher alkyl groups was recently pointed out by Coote and nitrones in a straightforward reaction sequence. Both types
co-workers.[49] The proposed explanation[49] could be ap- of species catalyze the aerobic oxidation of benzyl alcohol.
plied to our study; it would involve the evolution of propene In some cases, rapid oxidation to benzaldehyde could even
and a new nitrone[50] (Scheme 6). We mentioned above that be achieved at room temperature under atmospheric O2
the isopropyl unit interacts sterically with the neighboring pressure. Regarding the substitution of the imidazolidinone
4890
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4884–4896

Imidazolidinone Nitroxide Catalysts in Alcohol Oxidation
a
brown oil (43.8 g). EtOH (100 mL) and a solution of
ring, and by comparison with the permethylated analogue,
an aryl group is viable. The catalyst can be readily modified
by the direct C–H arylation of nitrones 1.[17] On the other
hand, an isopropyl substituent seems detrimental to the re-
action. A cyclic voltammetry study indicated poor stability
of the corresponding oxoammonium cation, which could
explain its poor catalytic properties. It should be under-
lined, however, that the extent of the substituent effect was
dependent on the co-catalytic system used. In particular, an
Na2WO4·2H2O (4.4 g) in water (6 mL) was added. The flask was
plunged into a water bath at 15 °C and a 35% solution of H2O2 in
water (75 mL) was added dropwise over 3 h, keeping the reaction
temperature below 50 °C. Stirring was continued for 1 h and then
small portions of MnO2 were added to destroy the excess peroxides
until the end of O2 evolution. EtOH was evaporated, the mixture
was dissolved in EtOAc (400 mL), decanted, and washed with
brine. After drying over Na2SO4 and concentration, nitrone 1b was
recovered as a yellow solid (35.1 g, 85%). Recrystallization in acet-
interesting synergy between a 2-pyridyl substituent and a one yielded analytically pure 1b (m.p. 103–104 °C). 1H NMR
(400 MHz, CDCl3): δ = 7.04 (s, 1 H, HC=N), 3.02 (s, 3 H, CH3N),
1.64 (s, 6 H, CH3C) ppm. 13C NMR (101 MHz, CDCl3): δ = 161.6
(CO), 123.9 (CH=N), 89.7 [C(CH3)2], 25.3 (CH3N), 23.8
Cu-based co-catalyst was observed. Work is underway to
take advantage of this cooperative effect. Finally, in the case
of an enantiopure imidazolidinone nitroxide, very promis-
ing results were obtained in the atroposelective oxidative
desymmetrization of a diol.
[(CH ) C] ppm. IR: ν = 3120, 3092, 2990, 1690, 1561 cm–1. LRMS
˜
3 2
(ESI+): m/z = 143 [M + H]+, 165.0 [M + Na]+. C6H10N2O2
(142.16): calcd. C 50.68, H 7.10, N 19.71; found C 50.25, H 7.02,
N 19.87.
Preparation of Arylnitrones 3: Arylnitrones 3 were prepared by di-
rect C–H arylation of nitrones 1 using Method A or B. The prepa-
rations of 3aa and 3ab have been described elsewhere.[17]
Experimental Section
Method A Ϫ Coupling Reactions Between Nitrones 1a–c and 4-
Bromotoluene (2a): A Schlenk flask under N2 was charged with
nitrone 1, 4-bromotoluene (2a; 1.1 equiv.), [Pd2(dba)3] (1 mol-%;
i.e., 2 mol-% Pd), triphenylphosphine (2 mol-%), pivalic acid
(0.2 equiv.), and K2CO3 (1.5 equiv.). The flask was evacuated and
purged with N2, and anisole was added to give a 1.0 m solution.
The Schlenk flask was plunged into a 150 °C preheated oil bath,
and the reaction was monitored by H NMR analysis of small ali-
quots. After completion of the reaction (Ͻ2 h), the crude solution
was purified over silica gel to give the arylnitrone.
General: All experiments were carried out under nitrogen in oven-
dried glassware equipped with a magnetic stirring bar. Standard
inert-atmosphere techniques were used to handle all air- and moist-
ure-sensitive reagents. THF and Et2O were freshly distilled from
sodium benzophenone ketyl, and CH2Cl2 and DMF from CaH2.
Anisole was washed with 10% aqueous NaOH and water, dried
with magnesium sulfate, distilled, stored, and handled under N2.
Palladium sources were stored in a desiccator and weighed out in
air. All other reagents and solvents were purchased from commer-
cial sources and used as received.
1
Method B Ϫ Coupling Reactions Between Nitrones 1a–c and 2-
Bromopyridine (2b): A Schlenk flask under N2 was charged with
nitrone 1, 2-bromopyridine (2b; 1.1 equiv.), [Pd2(dba)3] (1 mol-%;
i.e., 2 mol-% Pd), triphenylphosphine (2 mol-%), CuBr·DMS
(5 mol-%), 1,10-phenanthroline (5 mol-%), and K2CO3 (1.5 equiv.).
The flask was evacuated and purged with N2, and anisole was
added to give a 1.0 m solution. The Schlenk flask was plunged into
a 150 °C preheated oil bath, and the reaction was monitored by 1H
NMR analysis of small aliquots. After completion of the reaction
(Ͻ2 h), the crude solution was purified over silica gel to give the
arylnitrone.
Product purifications by dry-column vacuum chromatography[53]
were performed using Macherey–Nagel silica gel 60 (0.015–
0.04 mm) and gradient elution: cyclohexane/ethyl acetate (10:0 to
0:10), then ethyl acetate/ethanol (10:0 to 9:1).
For optical rotations [α], the corresponding concentration is given
in g per 100 cm–3. IR spectra were recorded by using ATR (attenu-
1
ated total reflection). H and 13C NMR spectra were recorded in
1
CDCl3 (standard for H spectra: tetramethylsilane, δH = 0.0 ppm;
standard for 13C spectra: CDCl3, δC = 77.16 ppm) or [D4]MeOH
(standard for 1H NMR spectra: CHD2OD δH = 3.31 ppm). Multi-
plicities are given as follows: s (singlet), d (doublet), t (triplet), q
(quadruplet), sept (septet), m (multiplet), br. (broad). Coupling
constants (J) are given in Hertz.
1,2,2-Trimethyl-5-oxo-4-(p-tolyl)-2,5-dihydro-1H-imidazole 3-Oxide
(3ba): The title compound was prepared according to Method A
from 1b (1.42 g, 10 mmol) and 4-bromotoluene (2a; 1.88 g,
11 mmol) to give a yellow solid (2.30 g, 99%), m.p. 117–118 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.72 (d, J = 8.4 Hz, 2 H, CHar ortho),
7.27 (d, J = 8.4 Hz, 2 H, CHar-m), 3.10 (s, 3 H, CH3N), 2.40 (s, 3
H, CH3-Ar), 1.69 (s, 6 H, CH3C) ppm. 13C NMR (101 MHz,
CDCl3): δ = 162.1 (CO), 141.5 (Cipso-Me), 129.9 (C=N), 129.1
(CHar-o), 127.6 (CHar-m), 123.6 (Cipso), 86.7 [C(CH3)2], 25.5
Preparation of Nitrones 1: Nitrones 1 were prepared by using a
previously described sequence,[18] starting from a glycine derivative
and a ketone. The synthesis of 1b is reported below, the prepara-
tions of 1a[18b] and 1c[16d] have been described elsewhere.
1,2,2-Trimethyl-5-oxo-2,5-dihydro-1H-imidazole 3-Oxide (1b): In a
250-mL round-bottomed flask, glycine ethyl ester hydrochloride
(40.7 g, 0.292 mol) was added in one portion to a 40% aqueous
solution of methylamine (102 mL) and the solution was stirred
overnight. Excess methylamine and water were eliminated by re-
peated co-evaporations with EtOH to yield a white sticky solid
(51 g). Acetone (100 mL) and triethylamine (60 mL) were added,
and the flask was fitted with a Soxhlet extractor filled with acti-
vated molecular sieves (4 Å, 110 g). After heating at reflux for 3 h,
the reaction mixture was concentrated, and then EtOAc (200 mL)
and triethylamine (3 mL) were added. The precipitate (triethyl-
amine hydrochloride) was filtered and rinsed with EtOAc. Concen-
tration of the filtrate yielded 2,2,3-trimethylimidazolidin-4-one as
(CH N), 24.3 [(CH ) C], 21.9 (CH -Ar) ppm. IR: ν = 3075, 2995,
˜
3
3 2
3
2932, 2910, 1701, 1550, 1501, 1435, 1355 cm–1. HRMS (ESI): calcd.
for C13H17N2O2 [M + H]+ 233.1285; found 233.1289.
1,2,2-Trimethyl-5-oxo-4-(pyridin-2-yl)-2,5-dihydro-1H-imidazole 3-
Oxide (3bb): The title compound was prepared according to
Method B from 1b (156 mg, 1.1 mmol) and 2-bromopyridine (2b;
158 mg, 1.0 mmol) as a yellow solid (166 mg, 81%), m.p. 125–
126 °C. 1H NMR (400 MHz, CDCl3): δ = 8.89–8.82 (m, 1 H, CHar-
N), 8.44 (dt, J = 7.9, 0.9 Hz, 1 H, CHar-o), 7.82 (td, J = 7.9, 1.8 Hz,
1 H, CHar-m), 7.34 (ddd, J = 7.9, 4.8, 1.1 Hz, 1 H, CHar-p), 3.12 (s,
3 H, CH3N), 1.72 (s, 6 H, CH3C) ppm. 13C NMR (101 MHz,
Eur. J. Org. Chem. 2014, 4884–4896
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4891

M. Carbó López, G. Royal, C. Philouze, P. Y. Chavant, V. Blandin
FULL PAPER
CDCl3): δ = 160.9 (CO), 150.2 (CHar-o), 145.7 (Cipso), 136.4 (rac)-(2S*,5R*)-1-Hydroxy-2-isopropyl-2,3,5-trimethyl-5-(pydridin-
(CHar-p), 130.2 (C=N), 124.60 (CHar), 124.57 (CHar), 88.0 [C- 2-yl)imidazolidin-4-one (4ab): The title compound was prepared ac-
(CH ) ], 25.6 (CH N), 24.3 [(CH ) C] ppm. IR: ν = 3110, 3060, cording to Method C from 3ab (2.29 g, 9.3 mmol) and methylmag-
˜
3 2
3
3 2
2993, 2933, 2790, 1698, 1574, 1548, 1428, 1385, 1358 cm–1. HRMS
nesium chloride (2.6 m, 5.3 mL, 13.9 mmol) as a brown solid
(ESI): calcd. for C11H14N3O2 [M + H]+ 220.1081; found 220.1085.
(1.79 g, 73%), m.p. 158–160 °C. H NMR (400 MHz, CDCl3): δ =
1
8.54 (d, J = 4.3 Hz, 1 H, CHar-N), 7.70 (d, J = 8.0 Hz, 1 H, CHar-
o), 7.66–7.59 (m, 1 H, CHar-m), 7.19–7.09 (m, 1 H, CHar-p), 5.32 (s,
1 H, OH), 2.85 (s, 3 H, CH3N), 1.98–1.84 (m, 1 H, CH iPr), 1.77
(s, 3 H, CH3-C-Ar), 1.57 (s, 3 H, CH3-C-iPr), 1.07 (d, J = 6.9 Hz,
3 H, CH3 iPr), 0.77 (d, J = 6.6 Hz, 3 H, CH3 iPr) ppm. 13C NMR
(101 MHz, CDCl3): δ = 171.6 (CO), 162.0 (Cipso), 149.0 (CHar-N),
136.4 (CHar-m), 122.2 (CHar-o), 120.7 (CHar-p), 83.9 [C(Me)-iPr],
70.6 [C(Me)-Ar], 36.0 (CH iPr), 25.7 (CH3N), 19.7 (CH3-C-Ar),
4-Methyl-3-oxo-2-(p-tolyl)-1,4-diazaspiro[4.5]dec-1-ene
(3ca): The title compound was prepared according to Method A
from 1c (1.00 g, 5.5 mmol) and 4-bromotoluene (2a; 0.85 g,
1-Oxide
1
5 mmol) as a beige solid (1.20 g, 88%), m.p. 140–141 °C. H NMR
(400 MHz, CDCl3): δ = 8.69 (d, J = 8.4 Hz, 2 H, CHar-o), 7.27 (d,
J = 8.4 Hz, 2 H, CHar-m), 3.17 (s, 3 H, CH3N), 2.39 (s, 3 H, CH3-
Ar), 2.33–2.20 (m, 2 H, CH cy), 2.19–2.07 (m, 2 H, CH cy), 1.94–
1.83 (m, 2 H, CH cy), 1.83–1.66 (m, 3 H, CH cy), 1.59–1.46 (m, 1
H, CH cy) ppm. 13C NMR (101 MHz, CDCl3): δ = 162.6 (CO),
141.2 (Cipso-Me), 129.7 (C=N), 129.0 (CHar-o), 127.6 (CHar-m),
123.6 (Cipso), 86.8 (Cspiro), 34.0 (CH2 cy), 26.6 (CH3N), 23.9 (CH2
18.1 (CH3-C-iPr), 17.7 (CH3 iPr), 16.8 (CH3 iPr) ppm. IR: ν =
˜
3271, 2986, 2936, 2885, 1675, 1470, 1425, 1372 cm–1. LRMS
(ESI+): m/z = 564.1 [M + H]+. C14H21N3O2 (263.34): calcd. C
63.84, H 8.05, N 15.96; found C 63.82, H 8.03, N 15.81. On storage,
spontaneous recrystallization by sublimation provided white crys-
tals suitable for X-ray analysis.[19]
cy), 21.84 (CH -Ar), 21.76 (CH cy) ppm. IR: ν = 3034, 2947, 2925,
˜
3
2
2865, 1685, 1559 cm–1. LRMS (DCI): m/z = 273.3 [M + H]+.
C16H20N2O2 (272.35): calcd. C 70.55, H 7.42, N 10.29; found C
70.80, H 7.58, N 10.44.
1-Hydroxy-2,2,3,5-tetramethyl-5-(p-tolyl)imidazolidin-4-one (4ba):
The title compound was prepared according to Method D from 3ba
(117 mg, 0.5 mmol) and methylmagnesium iodide (1.0 m, 1.00 mL,
1.0 mmol) as a yellow solid (50 mg, 40%), m.p. 146–149 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 8.1 Hz, 2 H, CHar-o),
7.14 (d, J = 8.1 Hz, 2 H, CHar-m), 5.22 (br. s, 1 H, OH), 2.87 (s, 3
H, CH3N), 2.32 (s, 3 H, CH3-Ar), 1.71 (s, 3 H, CH3-C-Ar), 1.49
(s, 3 H, CH3C), 1.31 (s, 3 H, CH3C) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.6 (CO), 139.3 (Cipso), 137.2 (Cipso-Me), 129.0
(CHar-m), 126.9 (CHar-o), 81.1 [C(CH3)2], 69.8 [C(Me)-Ar], 26.0
(CH3-C-CH3), 25.3 (CH3N), 22.0 (CH3-C-Ar), 21.1 (CH3-Ar), 20.6
Preparation of Hydroxylamines 4: Hydroxylamines 4 were prepared
by methylation of arylnitrones 3 using Method C or D.
Method C Ϫ Nitrone Methylation with MeMgCl in THF: MeMgCl
(1.5–2.0 equiv.) in THF was rapidly added to a stirred solution of
nitrone 3 in anhydrous THF (0.5–1.0 m) at room temperature
(water bath) under N2. The mixture was stirred for 15 min and
quenched by the addition of a saturated ammonium chloride solu-
tion. The aqueous layer was extracted three times with ethyl acet-
ate. The combined organic layers were washed with brine, dried
with MgSO4, filtered, and concentrated under reduced pressure.
The crude material was purified over silica gel to give the desired
hydroxylamine.
(CH -C-CH ) ppm. IR: ν = 3285, 2987, 2936, 2860, 1666, 1434,
˜
3
3
1402, 1379, 1362 cm–1. HRMS (ESI): calcd. for C14H21N2O2 [M +
H]+ 249.1598; found 249.1601.
Method D Ϫ Nitrone Methylation with MeMgI in Diethyl Ether:
MeMgI (2.0–3.5 equiv.) in Et2O was added dropwise to a stirred
solution of nitrone 3 in anhydrous Et2O (0.1 m) at 0 °C under N2
and immediate precipitation took place. The mixture was stirred
for 30 min at room temperature and quenched by the addition of
a saturated ammonium chloride solution. The aqueous layer was
extracted three times with ethyl acetate. The combined organic lay-
ers were washed with brine, dried with MgSO4, filtered, and con-
centrated under reduced pressure. The crude material was purified
over silica gel to give the desired hydroxylamine.
1-Hydroxy-2,2,3,5-tetramethyl-5-(pyridin-2-yl)imidazolidin-4-one
(4bb): The title compound was prepared according to Method C
from 3bb (811 mg, 3.7 mmol) and methylmagnesium chloride
(2.5 m, 2.2 mL, 5.6 mmol) as an orange oil (777 mg, 89%) that crys-
tallized upon standing, m.p. 116–117 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.60 (br. s, 1 H, OH), 8.45 (d, J = 4.6 Hz, 1 H, CHar-
N), 7.77–7.58 (m, 2 H, CHar), 7.23–7.07 (m, 1 H, CHar-p), 2.86 (s,
3 H, CH3N), 1.77 (s, 3 H, CH3-C-Ar), 1.48 (s, 3 H, CH3C), 1.27
(s, 3 H, CH3C) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.1
(CO), 162.4 (Cipso), 147.3 (CHar), 136.9 (CHar), 122.2 (CHar), 121.8
(CHar), 80.1 [C(CH3)2], 67.9 [C(Me)-Ar], 25.0 (CH3N), 23.7 (CH3-
(rac)-(2S*,5R*)-1-Hydroxy-2-isopropyl-2,3,5-trimethyl-5-(p-tolyl)-
imidazolidin-4-one (4aa): The title compound was prepared accord-
ing to Method C from 3aa (2.42 g, 9.3 mmol) and methylmagne-
sium chloride (2.6 m, 7.2 mL, 18.6 mmol) as a pale-yellow solid
(2.28 g, 89% yield), m.p. 160–161 °C. 1H NMR (400 MHz, CDCl3):
δ = 7.51 (d, J = 8.3 Hz, 2 H, CHar-o), 7.16 (d, J = 8.3 Hz, 2 H,
CHar-m), 4.36 (s, 1 H, OH), 2.81 (s, 3 H, CH3N), 2.33 (s, 3 H, CH3-
Ar), 2.00–1.83 (m, 1 H, CH iPr), 1.71 (s, 3 H, CH3-C-Ar), 1.56 (s,
3 H, CH3-C-iPr), 1.10 (d, J = 6.9 Hz, 3 H, CH3 iPr), 0.84 (d, J =
6.6 Hz, 3 H, CH3 iPr) ppm. 13C NMR (101 MHz, CDCl3): δ =
171.9 (CO), 139.9 (Cipso), 136.4 (Cipso-Me), 128.5 (CHar-m), 126.2
(CHar-o), 83.7 [C(Me)-iPr], 68.8 [C(Me)-Ar], 36.9 (CH iPr), 25.4
(CH3N), 20.7 (CH3-Ar), 19.9 (CH3-C-Ar), 17.9 (CH3-C-iPr), 17.6
C-Ar), 23.2 (CH -C-CH ), 22.7 (CH -C-CH ) ppm. IR: ν = 3153,
˜
3
3
3
3
3003, 2865, 1682, 1594, 1425, 1400, 1366 cm–1. LRMS (ESI+): m/z
= 236.2 [M + H]+, 258.1 [M + Na]+. C12H17N3O2 (235.29): calcd.
C 61.24, H 7.30, N 17.86; found C 60.76, H 7.38, N 17.79.
4-Hydroxy-1,3-dimethyl-3-(p-tolyl)-1,4-diazaspiro[4.5]decan-2-one
(4ca): The title compound was prepared according to Method D
from 3ca (136 mg, 0.5 mmol) and methylmagnesium iodide (1.7 m,
1.03 mL, 1.75 mmol) as a yellow solid (80 mg, 55%), m.p. 180–
182 °C. 1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.1 Hz, 2
H, CHar-o), 7.08 (d, J = 8.1 Hz, 2 H, CHar-m), 5.03 (s, 1 H, OH),
2.82 (s, 3 H, CH3N), 2.44–2.24 (m, 1 H, CH cy), 2.30 (s, 3 H, CH3-
Ar), 1.84–1.46 (m, 6 H, CH cy), 1.62 (s, 3 H, CH3-C-Ar), 1.41–
1.06 (m, 2 H, CH cy), 0.98–0.88 (m, 1 H, CH cy) ppm. 13C NMR
(101 MHz, CDCl3): δ = 173.6 (CO), 141.9 (Cipso), 136.7 (Cipso-Me),
129.0 (CHar-o), 125.6 (CHar-m), 84.5 (Cspiro), 73.1 [C(Me)-Ar], 33.5
(CH2 cy), 31.7 (CH2 cy), 25.8 (CH3N), 25.08 (CH2 cy), 25.04 (CH3-
(CH3 iPr), 16.7 (CH3 iPr) ppm. IR: ν = 3319, 2971, 2938, 1666,
˜
1429, 1368 cm–1. HRMS (ESI): calcd. for C16H25N2O2 [M + H]+
277.1911; found 277.1914.
Compound (2S,5R)-4aa was prepared according to Methods A and
D from (S)-1a (1.4 g, 9.9 mmol) and 4-bromotoluene (2a; 1.88 g,
11 mmol) as a yellow-white solid (1.95 g, 76%), m.p. 168–169 °C.
[α]2D0 = –111.7 (c = 0.46, CHCl3).
C-Ar), 23.2 (CH cy), 22.7 (CH cy), 21.1 (CH -Ar) ppm. IR: ν =
˜
2
2
3
4892
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4884–4896

Imidazolidinone Nitroxide Catalysts in Alcohol Oxidation
3368, 2977, 2922, 2857, 1672, 1474, 1403, 1360 cm–1. HRMS (ESI):
calcd. for C17H25N2O2 [M + H]+ 289.1911; found 289.1910.
Preparation of Nitroxides 7 and 8
Oxidation of Hydroxylamines to Nitroxides
Preparation of Methylnitrones 5
Method 1: The hydroxylamine (0.5 mmol) and mCPBA (0.5 mmol)
were dissolved in CH2Cl2 (5 mL) and stirred at 20 °C for 1 h. MnO2
(50 mg) was added and stirring was continued for 15 min to destroy
the excess peroxides and the solvent was evaporated. The residue
was taken up in EtOAc (20 mL) and washed with a saturated aque-
ous solution of K2CO3. The organic phase was dried with MgSO4,
filtered, and concentrated under reduced pressure to yield the ni-
troxide.
2-Isopropyl-1,2,4-trimethyl-5-oxo-2,5-dihydro-1H-imidazole 3-Ox-
ide (5a): MiPNO (1a; 2.55 g, 15 mmol) was methylated with meth-
ylmagnesium chloride (2.6 m, 6.35 mL, 16.5 mmol) according to
Method C. The crude hydroxylamine was dissolved in CH2Cl2
(13 mL) and MnO2 (2.73 g, 31.5 mmol) was added. The reaction
mixture was stirred for 1.5 h and then the solvent was removed
under reduced pressure. The crude material was purified over silica
gel to give the desired nitrone as a yellow oil (1.52 g, 65%). 1H
NMR (400 MHz, CDCl3): δ = 3.03 (s, 3 H, CH3N), 2.41–2.28 (m,
1 H, CH iPr), 2.12 (s, 3 H, CH3-C=N), 1.65 (s, 3 H, CH3-C-iPr),
0.98 (d, J = 6.7 Hz, 3 H, CH3 iPr), 0.94 (d, J = 6.8 Hz, 3 H, CH3
iPr) ppm. 13C NMR (101 MHz, CDCl3): δ = 163.5 (CO), 134.6
(C=N), 92.0 [C(Me)-iPr], 34.4 (CH iPr), 26.5 (CH3N), 21.3 (CH3-
Method 2: MnO2 (1 mmol) was added to a solution of hydroxyl-
amine (0.5 mmol) in CH2Cl2 (5 mL). The suspension was stirred
at room temperature for 16 h, diluted in CH2Cl2 (15 mL), filtered
through Celite, and concentrated under reduced pressure to yield
the nitroxide.
(rac)-(2S*,5R*)-2-Isopropyl-2,3,5-trimethyl-5-(p-tolyl)imidazolidin-
4-one-1-oxyl (7aa): The title compound was prepared according to
Method 1 from 4aa (138 mg, 0.5 mmol) as a yellow oil (120 mg).[54]
The product was used directly in the oxidation reactions. Slow
evaporation of a solution 7aa in ethanol yielded crystals suitable
for X-ray analysis.[22] HRMS (ESI): calcd. for C16H24N2O2 [M +
H]·+ 276.1832; found 276.1835.
C-iPr), 16.2 (CH iPr), 15.6 (CH iPr), 7.6 (CH -C=N) ppm. IR: ν
˜
3
3
3
= 3556, 2968, 2875, 1701, 1590, 1252 cm–1. HRMS (ESI): calcd.
for C9H17N2O2 [M + H]+ 185.1285; found 185.1290.
1,2,2,4-Tetramethyl-5-oxo-2,5-dihydro-1H-imidazole 3-Oxide (5b):
Compound 1b (2 mmol) was methylated with methylmagnesium
chloride (1.33 m, 2.3 mL, 3 mmol) according to Method C. The
crude hydroxylamine was dissolved in CH2Cl2 (15 mL) and MnO2
(0.435 g, 5 mmol) was added. The reaction mixture was stirred
overnight, filtered through Celite, and the filtrate concentrated. The
crude material was purified over silica gel to give the desired
nitrone as a yellow oil (0.179 g, 57%) that crystallized upon stand-
(rac)-(2S*,5R*)-2-Isopropyl-2,3,5-trimethyl-5-(pyridin-2-yl)imid
azolidin-4-one-1-oxyl (7ab): The title compound was prepared ac-
cording to Method 2 from 4ab (526 mg, 2 mmol) as a red oil
(522 mg).[54] The product was used directly in the oxidation reac-
+
˙
tions. HRMS (ESI): calcd. for C14H21N3O2 [M + H] 263.1628;
1
ing, m.p. 123–125 °C. H NMR (300 MHz, CDCl3): δ = 3.04 (s, 3
found 263.1636.
H, CH3N), 2.13 (s, 3 H, CH3-C=N), 1.62 [s, 6 H, (CH3)2C] ppm.
13C NMR (75 MHz, CDCl3): δ = 162.4 (CO), 133.8 (C=N), 87.7
[C(CH3)2], 25.4 (CH3N), 23.9 [(CH3)2C], 8.0 (CH3-C=N) ppm. IR:
2,2,3,5,5-Pentamethylimidazolidin-4-one-1-oxyl (8b): The title com-
pound was prepared according to Method 2 from 6b (142 mg,
1 mmol) as an orange solid (140 mg), m.p. 65–66 °C.[54] The prod-
ν = 2990, 1693, 1597 cm–1. HRMS (ESI): calcd. for C H N O [M
˜
7
13
2
2
uct was used directly in the oxidation reactions. HRMS (ESI):
+ H]+ 157.0972; found 157.0975.
+
˙
calcd. for C8H16N2O2 [M + H] 172.1206; found 172.1211.
Preparation of Hydroxylamines 6
(R)-2,2,3,5-Tetramethyl-5-(p-tolyl)imidazolidin-4-one-1-oxyl [(R)-
7ba]: Four consecutive steps were telescoped to synthesize the de-
sired product from hydroxylamine (2S,5R)-4aa.
1-Hydroxy-2-isopropyl-2,3,5,5-tetramethylimidazolidin-4-one (6a):
The title compound was prepared according to Method C from 5a
(523 mg, 2.8 mmol) in THF (10 mL) and methylmagnesium chlor-
ide (2.6 m, 3.6 mL, 9.3 mmol) as a beige solid (936 mg, 60%), m.p.
97–98 °C. 1H NMR (400 MHz, CDCl3): δ = 4.53 (s, 1 H, OH), 2.75
(s, 3 H, CH3N), 1.89–1.77 (m, 1 H, CH iPr), 1.45 (s, 3 H, CH3-C-
iPr), 1.30 [s, 3 H, (CH3)2C], 1.29 [s, 3 H, (CH3)2C], 1.03 (d, J =
Zinc dust (8.10 g, 124 mmol) was added to a solution of (2S,5R)-
4aa (1.71 g, 6.2 mmol) in glacial AcOH (10 mL). The suspension
was sonicated at 80 °C for 3 h, filtered through Celite, and the fil-
trate was evaporated under reduced pressure to obtain (2R,5R)-2-
isopropyl-2,3,5-trimethyl-5-(p-tolyl)imidazolidin-4-one acetate (9)
1
6.9 Hz, 3 H, CH3 iPr), 0.77 (d, J = 6.6 Hz, 3 H, CH3 iPr) ppm. 13
C
as a yellow oil (1.20 g). H NMR (400 MHz, [D4]MeOH): δ = 7.62
(d, J = 8.1 Hz, 2 H, CHar-o), 7.10 (d, J = 8.1 Hz, 2 H, CHar-m),
2.79 (s, 3 H, CH3N), 2.30 (s, 3 H, CH3-Ar), 1.99 (s, 6 H, AcOH),
1.87 (sept, J = 6.8 Hz, 1 H, CH iPr), 1.59 (s, 3 H, CH3-C), 1.51 (s,
3 H, CH3-C), 0.98 (d, J = 6.8 Hz, 3 H, CH3 iPr), 0.51 (d, J =
6.8 Hz, 3 H, CH3 iPr) ppm.
NMR (101 MHz, CDCl3): δ = 173.9 (CO), 83.8 [C(Me)-iPr], 64.4
[C(CH3)2], 35.5 (CH iPr), 25.6 (CH3-C-CH3), 25.4 (CH3N), 20.4
(CH3-C-CH3), 17.9 (CH3-C-iPr), 17.7 (CH3 iPr), 16.3 (CH3
iPr) ppm. IR: ν = 3354, 2970, 2932, 2879, 1663, 1479, 1400 cm–1.
˜
HRMS (ESI): calcd. for C10H21N2O2 [M + H]+ 201.1598; found
201.1600.
A solution of crude 9 in aqueous HCl (6 n, 10 mL) was exposed to
microwave irradiation at 120 °C for 40 min to afford (R)-2-amino-
N-methyl-2-(p-tolyl)propanamide hydrochloride (10) as a colorless
oil (1.21 g). 1H NMR (400 MHz, [D4]MeOH): δ = 7.40 (d, J =
8.3 Hz, 2 H, CHar-o), 7.31 (d, J = 8.3 Hz, 2 H, CHar-m), 2.73 (s, 3
H, CH3N), 2.37 (s, 3 H, CH3-Ar), 1.97 (s, 3 H, CH3-C-Ar) ppm.
1-Hydroxy-2,2,3,5,5-pentamethylimidazoldin-4-one (6b): The title
compound was prepared according to Method C from 5b (2.34 g,
15 mmol) and methylmagnesium chloride (3.0 m, 6.0 mL, 18 mmol)
1
as a yellow-brown solid (1.45 g, 68%), m.p. 173–174 °C. H NMR
(400 MHz, CDCl3): δ = 4.86 (br. s, 1 H, OH), 2.82 (s, 3 H, CH3N),
1.38 [s, 6 H, (CH3)2-C-N], 1.31 [s, 6 H, (CH3)2-C-CO] ppm. 13C
The crude 10, acetone (20 mL), 2,2-dimethoxypropane (20 mL),
NMR (101 MHz, CDCl3): δ = 172.9 (CO), 79.7 (N-C-N), 63.4 (C- and triethylamine (0.63 g, 6.2 mmol) were introduced into a
CO), 24.4 (CH3N), 23.4 [(CH3)2-C-N], 22.5 [(CH3)2-C-CO] ppm. 100 mL flask fitted with a Soxhlet extractor filled with activated
IR: ν = 3178, 2983, 2932, 2856, 1666, 1501, 1438, 1405, 1365 cm–1.
3 Å molecular sieves (50 g). The reaction mixture was heated at
reflux for 60 h and then the solvent was evaporated under reduced
pressure. The crude product was taken up in ethyl acetate (60 mL),
washed with concentrated NaOH (10 mL), and the aqueous phase
˜
LRMS (ESI+): m/z = 173.1 [M + H]+ , 195.0 [M + Na]+.
C12H17N3O2 (235.29): calcd. C 55.80, H 9.37, N 16.27; found C
55.73, H 9.33, N 16.70.
Eur. J. Org. Chem. 2014, 4884–4896
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4893

M. Carbó López, G. Royal, C. Philouze, P. Y. Chavant, V. Blandin
FULL PAPER
extracted with ethyl acetate (4ϫ 25 mL). The combined organic
layers were dried with MgSO4, filtered, and the solvent removed
under reduced pressure to afford (R)-2,2,3,5-tetramethyl-5-(p-tolyl)
imidazolidin-4-one (11; 672 mg). 1H NMR (300 MHz, CDCl3):
δ = 7.64 (d, J = 8.2 Hz, 2 H, CHar-o), 7.12 (d, J = 8.2 Hz, 2 H,
CHar-m), 2.80 (s, 3 H, CH3N), 2.31 (s, 3 H, CH3-Ar), 2.00 (br. s,
NH), 1.61 (s, 3 H, CH3-C), 1.45 (s, 3 H, CH3-C), 1.16 (s, 3 H, CH3-
C) ppm.
(376 MHz, CDCl ): δ = –60.3 ppm. IR: ν = 3149, 3066, 1311, 1172,
˜
3
1160 cm–1.
[2Ј-(Trifluoromethyl)-1,1Ј-biphenyl-2,6-diyl]dimethanol (12): K2CO3
(2.41 g, 17.1 mmol) was added to a solution of crude 15 (1.74 g)
and glacial AcOH (0.98 mL, 17.1 mmol) in DMF (10 mL). The
reaction mixture was stirred at 125 °C for 2.5 h and then treated
with H2O (5 mL). The aqueous phase was extracted with Et2O (2ϫ
20 mL). The combined organic layers were washed with a saturated
aqueous solution of NaCl (10 mL), dried with Na2SO4, and evapo-
rated under reduced pressure. The crude diacetate was dissolved in
EtOH (20 mL) and KOH (1.19 g, 21.3 mmol) was added. The reac-
tion mixture was stirred at room temperature for 21 h, treated with
H2O (15 mL), and the aqueous phase extracted with CH2Cl2 (2ϫ
20 mL). The combined organic layers were washed with brine
(10 mL), dried with MgSO4, filtered, and evaporated under reduced
pressure. Purification over silica gel gave 12 (540 mg, 45% from 14)
as a yellow solid, m.p. 84–87 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.79 (d, J = 7.9 Hz, 1 H, CHar 3Ј), 7.61 (t, J = 7.2 Hz, 1 H,
CHar), 7.57–7.45 (m, 4 H, CHar), 7.25 (d, J = 6.8 Hz, 1 H, CHar
6Ј), 4.32 (d, J = 13.1 Hz, 2 H, 2 CHH-OH), 4.23 (d, J = 13.1 Hz,
2 H, 2 CHH-OH), 1.51 (br. s, 2 H, OH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 139.3 (Car 2,6), 136.7 (Car 1Ј), 135.6 (Car 1), 132.1
mCPBA (1.07 g, 4.3 mmol) was added portionwise to a solution of
crude 11 in CH2Cl2 (5 mL). The mixture was stirred for 1.5 h at
room temperature and then quenched with dilute aqueous NaOH
(30 mL). The aqueous layer was extracted with CH2Cl2 (2ϫ
50 mL) and the combined organic layers dried with MgSO4, fil-
tered, and concentrated under reduced pressure to give a red oil.
Purification over silica gel gave (R)-7ba as an orange oil that crys-
tallized upon standing [407 mg, 30% from (2S,5R)-4aa], m.p. 70–
71 °C. [α]2D0 = +86.3 (c = 0.24, CHCl3). HRMS (ESI): calcd. for
+
˙
C14H20N2O2 [M + H] 248.1519; found 248.1522.
A sample of (rac)-7ba was prepared according to Method 1 from
4ba (38 mg, 0.15 mmol) as a low-melting beige solid (35 mg).
The enantiomeric purity of (R)-7ba (Ն96% ee) was determined by
SFC on a Daicel Chiralpak IA-3 column, 4.6 ϫ100 mm, eluent
2
(CHar 4Ј), 131.9 (CHar 6Ј), 129.0 (CHar 4), 128.8 (q, J = 29.5 Hz,
scCO2/MeOH, 80:20, 1.7 mL/min, 37 °C, UV detection (220 nm), Car 2Ј), 128.3 (CHar 5Ј), 126.7 (CHar 3,5), 126.6 (q, 3J = 5.2 Hz,
1
retention time 2.9 min for (R)-7ba and 3.5 min for (S)-7ba.
CHar 3Ј), 124.0 (q, J = 273.9 Hz, CF3), 63.0 (CH2-OH) ppm. 19F
NMR (376 MHz, CDCl ): δ = –60.3 ppm. IR: ν = 3301, 2929,
˜
3
Preparation of Diol 12
2876, 1310, 1122, 1109 cm–1. HRMS (ESI): calcd. for
C15H13F3O2Na [M + Na]+ 305.0760; found 305.0761.
2,6-Dimethyl-2Ј-(trifluoromethyl)-1,1Ј-biphenyl (14):
A
10 mL
Schlenk flask under nitrogen was charged with 1-bromo-m-xylene
(1.85 g, 10.0 mmol), 4,4,6-trimethyl-2-[2-(trifluoromethyl)phenyl]-
1,3,2-dioxaborinane (13;[38] 4.08 g, 15 mmol), Pd(OAc)2 (22.0 mg,
0.1 mmol), S-Phos (82 mg, 0.2 mmol), and K3PO4 (6.37 g,
30 mmol). The flask was evacuated, purged with nitrogen, and a
toluene/water mixture (1:0.18; 12 mL) was added. The Schlenk was
then plunged into a 100 °C preheated oil bath and the reaction was
stirred for 22 h. Purification over silica gel gave 14 (1.52 g, 61%)
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J =
7.7 Hz, 1 H, CHar 3Ј), 7.60 (t, J = 7.7 Hz, 1 H, CHar 4Ј), 7.47 (t,
J = 7.7 Hz, 1 H, CHar 5Ј), 7.22–7.14 (m, 2 H, CHar 4,6Ј), 7.08 (d,
J = 7.7 Hz, 2 H, CHar 3,5), 1.94 (s, 6 H, CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 140.2 (Car 1Ј), 138.8 (Car 1), 136.4 (Car 2),
132.2 (CHar 3Ј), 131.3 (CHar 5Ј), 128.8 (q, 2J = 29.8 Hz, Car 2Ј),
Oxidation of Alcohols
General: Oxidation reactions under high pressures of O2 were per-
formed in a High Pressure ChemSCAN II – HEL apparatus
equipped with eight 16 mL stainless-steel reactors. Reactions were
performed at 4 bar O2 and stirred magnetically at 1000 rpm.
Reactions under atmospheric O2 pressure were performed in a
10 mL flask equipped with a balloon of O2 and stirred with an
orbital shaker (1000 rpm) to provide a large vortex.
Method E Ϫ CuBr2/tBuOK/bipy: The indicated amounts of rea-
gents were added as solids or as solutions in CH3CN/H2O (2:1):
benzyl alcohol (1 mmol, 1 m), catalyst (5 mol-%), CuBr2 (5 mol-%),
tBuOK (5 mol-%), and 2,2Ј-bipyridine (5 mol-%).
3
Method F Ϫ CuBr2/NaNO2: The indicated amounts of reagents
were added as solids or as solutions in PhCF3: benzyl alcohol
(1 mmol, 1 m) or diol 12 (0.2 mmol, 0.2 m), catalyst (5 mol-%),
CuBr2 (5 mol-%), and NaNO2 (5 mol-%).
127.8 and 127.4 (CHar 4,6Ј), 127.0 (CHar 3), 126.5 (q, J = 5.3 Hz,
CHar 3Ј), 124.1 (q, 1J = 273.9 Hz, CF3), 20.6 (CH3) ppm. 19F NMR
(376 MHz, CDCl ): δ = –61.3 ppm. IR: ν = 3065, 3022, 2926, 1311,
˜
3
1123, 1108 cm–1. LRMS (ESI+): m/z = 232.1 [M + H]+, 254.1 [M
+ Na]+.
Method G Ϫ HBr/TBN: The indicated amounts of reagents were
added as solids or as solutions in CH3CN: benzyl alcohol (1 mmol,
1 m) or diol 12 (0.2 mmol, 0.2 m), catalyst (5 mol-%), HBr (5 mol-
%), TBN (5 mol-%).
2,6-Bis(bromomethyl)-2Ј-(trifluoromethyl)-1,1Ј-biphenyl (15): Ben-
zoyl peroxide (15 mg, 0.05 mmol) was added to a solution of N-
bromosuccinimide (1.66 g, 9.4 mmol) and 14 (1.17 g, 4.7 mmol) in
CH2Cl2 (35 mL). The reaction mixture was heated at reflux for 6 h,
and then the solvent was evaporated under reduced pressure. Di-
ethyl ether was added, a precipitate of succinimide was filtered off,
and the filtrate evaporated to yield crude 15 (1.95 g) as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.7 Hz, 1 H,
CHar 3Ј), 7.70 (t, J = 7.7 Hz, CHar 4Ј), 7.60 (t, J = 7.7 Hz, 1 H,
CHar 5Ј), 7.54 (d, J = 7.7 Hz, 1 H, CHar 6Ј), 7.51–7.39 (m, 3 H,
CHar 3,4,5), 4.30 (d, J = 10.4 Hz, 2 H, 2 CHH-Br), 3.90 (d, J =
10.4 Hz, 2 H, CHH-Br) ppm. 13C NMR (126 MHz, CDCl3): δ =
Oxidation of Benzyl Alcohol: The oxidation reaction was performed
under the conditions of Method E, F, or G. The pressure, tempera-
ture, and reaction time are indicated in Table 2 for each particular
example. The reaction was monitored by GC analysis.
GC analyses were performed with a Shimadzu C17 apparatus
equipped with a flame ionization detector and a BPX5 column
(30 mϫ0.25 mm, SGE; 100 °C; carrier H2; velocity 29 ms–1). Re-
tention times: benzaldehyde, 1.52 min; benzyl alcohol, 2.01 min.
3
137.7 (Car 1), 137.1 (Car 2,6), 134.9 (q, J = 3.0 Hz, Car 1Ј), 132.6
Oxidation of Diol 12: The oxidation reaction was performed under
the conditions of Method G under an atmospheric O2 pressure at
room temperature. The reaction was monitored by 19F NMR spec-
(CHar), 132.0 (CHar), 130.5 (CHar 3,5), 129.5 (CHar), 128.9 (CHar),
127.5 (q, 2J = 29.5 Hz, Car 2Ј), 125.1 (q, 3J = 5.5 Hz, CHar 3Ј),
122.7 (q, 1J = 274.1 Hz, CF3), 31.5 (CH2-Br) ppm. 19F NMR troscopy.
4894
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4884–4896

Imidazolidinone Nitroxide Catalysts in Alcohol Oxidation
[5]
[6]
M. Shibuya, Y. Osada, Y. Sasano, M. Tomizawa, Y. Iwabuchi,
J. Am. Chem. Soc. 2011, 133, 6497–6500.
J. E. Steves, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 15742–
15745.
Characterization Data for 6-(Hydroxymethyl)-2Ј-(trifluoromethyl)-
1,1Ј-biphenyl-2-carbaldehyde (16): H NMR (400 MHz, CDCl3): δ
1
= 9.57 (s, 1 H, CHO), 7.95 (d, J = 7.8 Hz, 1 H, CHar), 7.87 (d, J
= 7.7 Hz, 1 H, CHar), 7.83 (d, J = 7.5 Hz, 1 H, CHar), 7.70–7.47
(m, 4 H, CHar), 7.31 (d, J = 7.4 Hz, 1 H, CHar), 4.37 (d, J =
13.6 Hz, 1 H, CHH-OH), 4.31 (d, J = 13.6 Hz, 1 H, CHH-
OH) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –59.7 ppm.
[7]
[8]
M. B. Lauber, S. S. Stahl, ACS Catal. 2013, 3, 2612–2616.
C. J. Gartshore, D. W. Lupton, Adv. Synth. Catal. 2010, 352,
3321–3328.
a) P. Gamez, I. W. C. E. Arends, J. Reedijk, R. A. Sheldon,
Chem. Commun. 2003, 2414–2415; b) P. Gamez, I. W. C. E. Ar-
ends, R. A. Sheldon, J. Reedijk, Adv. Synth. Catal. 2004, 346,
805–811.
For alcohol oxidation with phenyliodonium bis(trifluoroacet-
ate) (PIFA) catalyzed by PROXYL and its analogues, see: S.
Hamada, T. Furuta, Y. Wada, T. Kawabata, Angew. Chem. Int.
Ed. 2013, 52, 8093–8097.
a) Z. Ma, Q. Huang, J. M. Bobbitt, J. Org. Chem. 1993, 58,
4837–4843; b) S. D. Rychnovsky, T. L. McLernon, H. Raja-
pakse, J. Org. Chem. 1996, 61, 1194–1195; c) F. Formaggio, M.
Bonchio, M. Crisma, C. Peggion, S. Mezzato, A. Polese, A.
Barazza, S. Antonello, F. Maran, Q. B. Broxterman, B. Kapt-
ein, J. Kamphuis, R. M. Vitale, M. Saviano, E. Benedetti, C.
Toniolo, Chem. Eur. J. 2002, 8, 84–93; d) B. Graetz, S. Rych-
novsky, W.-H. Leu, P. Farmer, R. Lin, Tetrahedron: Asymmetry
2005, 16, 3584–3598.
[9]
Characterization Data for 2Ј-(Trifluoromethyl)-1,1Ј-biphenyl-2,6-di-
carbaldehyde (17): Compound 17 is issued from the double oxi-
dation of diol 12 in experiments not reported here; see ref.[40] 1
H
[10]
[11]
NMR (400 MHz, CDCl3): δ = 9.65 (s, 2 H, CHO), 8.26 (d, J =
7.7 Hz, 2 H, CHar-C-CHO), 7.94–7.87 (m, 1 H, CHar-C-CF3), 7.74
(t, J = 7.7 Hz, 1 H, CHar-CH-C-CHO), 7.70–7.63 (m, 2 H, CHar),
7.45–7.37 (m, 1 H, CHar-o) ppm. 19F NMR (376.5 MHz, CDCl3):
δ = –59.1 ppm.
The enantiomeric purity of 16 was determined by HPLC using a
Chiralcel OD-H column (25 mϫ0.46 cm, 10% EtOH/hexane,
0.5 mL/min, UV detection at 289 nm); retention times: major
enantiomer, 8.70 min; minor enantiomer, 9.46 min.
Electrochemical Measurements: Electrochemical measurements
were conducted at 293 K under argon in a standard one-compart-
ment, three-electrode electrochemical cell using a CH-Instrument
660B potentiostat. Investigations were carried out with 2 mm solu-
tions of compounds in acetonitrile/water (95:5, v:v) containing so-
dium perchlorate (0.2 m) as supporting electrolyte and 2,6-lutidine
(8 equiv.) as base. An automatic ohmic drop compensation pro-
cedure was systematically implemented prior to recording CV data.
CH-Instrument vitreous carbon (Ø = 3 mm) working electrodes
were polished with 1 µm diamond paste before each recording. The
reference electrode was Ag/AgNO3 (10 mm in CH3CN containing
0.1 m TBAP). The potential of the regular ferrocene/ferrocenium
(Fc/Fc+) redox couple in acetonitrile was 0.07 V under our experi-
mental conditions. A platinum wire was used as the counter elec-
trode.
[12]
[13]
a) K. Murayama, S. Morimura, T. Yoshioka, Bull. Chem. Soc.
Jpn. 1969, 42, 1640–1643; b) T. Toda, S. Morimura, E. Mori,
H. Horiuchi, K. Murayama, Bull. Chem. Soc. Jpn. 1971, 44,
3445–3450.
a) A. A. Gridnev, Macromolecules 1997, 30, 7651–7654; b)
Y. K. Chong, F. Ercole, G. Moad, E. Rizzardo, S. H. Thang,
A. G. Anderson, Macromolecules 1999, 32, 6895–6903; c) P.
Dervan, F. Aldabbagh, P. B. Zetterlund, B. Yamada, J. Polym.
Sci., Part A: Polym. Chem. 2003, 41, 327–334; d) F. Aldabbagh,
P. Dervan, M. Phelan, K. Gilligan, D. Cunningham, P.
McArdle, P. B. Zetterlund, B. Yamada, J. Polym. Sci., Part A:
Polym. Chem. 2003, 41, 3892–3900; e) E. Bagryanskaya, D.
Bertin, D. Gigmes, I. Kirilyuk, S. R. A. Marque, V. Reznikov,
G. Roshchupkina, I. Zhurko, D. Zubenko, Macromol. Chem.
Phys. 2008, 209, 1345–1357.
Supporting Information (see footnote on the first page of this arti-
cle): Determination of the optical purity of (R)-7ba, UHPLC/MS
[14]
[15]
[16]
a) P. Nesvadba, L. Bugnon, M. Frey, US Pat., US 2009/
0274947 A1, 2009; b) P. Nesvadba, L. Bugnon, P. Maire, P.
Novák, Chem. Mater. 2010, 22, 783–788.
See also: C. Ysacco, H. Karoui, G. Casano, F. Le Moigne, S.
Combes, A. Rockenbauer, M. Rosay, W. Maas, O. Ouari, P.
Tordo, Appl. Magn. Reson. 2012, 43, 251.
a) F. Cantagrel, S. Pinet, Y. Gimbert, P. Y. Chavant, Eur. J. Org.
Chem. 2005, 2694–2701; b) A. Pernet-Poil-Chevrier, F. Cantag-
rel, K. Le Jeune, C. Philouze, P. Y. Chavant, Tetrahedron:
Asymmetry 2006, 17, 1969–1974; c) M. Thiverny, Ph. D. Disser-
tation, Université de Grenoble, France, 2010; d) K. Ranieri,
M. Conradi, P. Y. Chavant, V. Blandin, C. Barner-Kowollik, T.
Junkers, Aust. J. Chem. 2012, 65, 1110–1116.
1
analyses of 4/7ba, H and 13C NMR spectra of 1b, 3ba, 3bb, 3ca,
4–6, 12, 14, and 15.
Acknowledgments
The authors wish to acknowledge the support of the ICMG FR-
2607 Chemistry Nanobio Platform, Grenoble, where low-resolu-
tion mass spectra and X-ray diffraction analyses were performed.
M. C. L. is grateful to the Université Joseph Fourier for a doctoral
fellowship.
[17]
[18]
E. Demory, D. Farran, B. Baptiste, P. Y. Chavant, V. Blandin,
J. Org. Chem. 2012, 77, 7901–7912.
MiPNO
=
2-isopropyl-1,2-dimethyl-5-oxo-2,5-dihydro-1H-
[1] For reviews, see: a) C. Brückner, in: Stable radicals: fundamen-
tals and applied aspects of odd-electron compounds (Ed.: R. G.
Hicks), Wiley, Chichester, UK, 2010, p. 433–460; b) L. Tebben,
A. Studer, Angew. Chem. Int. Ed. 2011, 50, 5034–5068; Angew.
Chem. 2011, 123, 5138.
[2] D. Lenoir, Angew. Chem. Int. Ed. 2006, 45, 3206–3210; Angew.
Chem. 2006, 118, 3280.
imidazole 3-oxide; a) M. Thiverny, E. Demory, B. Baptiste, C.
Philouze, P. Y. Chavant, V. Blandin, Tetrahedron: Asymmetry
2011, 22, 1266–1273; b) M. Thiverny, D. Farran, C. Philouze,
V. Blandin, P. Y. Chavant, Tetrahedron: Asymmetry 2011, 22,
1274–1281; c) M. Thiverny, C. Philouze, P. Y. Chavant, V.
Blandin, Org. Biomol. Chem. 2010, 8, 864–872.
[19]
[20]
CCDC-987363 (for 4ab) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
For the use of hydroxylamine catalysts in TCCA-mediated
alcohol oxidations, see: a) M. Tomizawa, M. Shibuya, Y. Iwab-
uchi, Org. Lett. 2009, 11, 1829–1831; b) H. Yamakoshi, M.
Shibuya, M. Tomizawa, Y. Osada, N. Kanoh, Y. Iwabuchi, Org.
Lett. 2010, 12, 980–983; c) for the use of N-hydroxyindoles as
[3] For reviews, see: a) C. Parmeggiani, F. Cardona, Green Chem.
2012, 14, 547–564; b) S. E. Allen, R. R. Walvoord, R. Padilla-
Salinas, M. C. Kozlowski, Chem. Rev. 2013, 113, 6234–6458;
for recent examples, see: c) S. Ma, J. Liu, Tetrahedron 2013, 69,
10161–10167; d) X. Liu, Q. Xia, Y. Zhang, C. Chen, W. Chen,
J. Org. Chem. 2013, 78, 8531–8536.
[4] a) For a review, see: S. Wertz, A. Studer, Green Chem. 2013,
15, 3116–3134; b) for a recent example, see: R. Prebil, G.
Stavber, S. Stavber, Eur. J. Org. Chem. 2014, 395–402.
Eur. J. Org. Chem. 2014, 4884–4896
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4895

M. Carbó López, G. Royal, C. Philouze, P. Y. Chavant, V. Blandin
FULL PAPER
aerobic alcohol oxidation catalysts, see: S.-S. Shen, V. Kartika,
Y. S. Tan, R. D. Webster, K. Narasaka, Tetrahedron Lett. 2012,
53, 986–990.
J. Garner, M. Breuning, Angew. Chem. Int. Ed. 2005, 44, 5384–
5427; Angew. Chem. 2005, 117, 5518; b) G. Bringmann, T.
Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev. 2011, 111,
563–639; c) P. G. Cozzi, E. Emer, A. Gualandi, Angew. Chem.
Int. Ed. 2011, 50, 3847–3849; Angew. Chem. 2011, 123, 3931.
[37] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
Am. Chem. Soc. 2005, 127, 4685–4696.
[38] E. Demory, V. Blandin, J. Einhorn, P. Y. Chavant, Org. Process
Res. Dev. 2011, 15, 710–716.
[39] Y. Nishii, K. Wakasugi, K. Koga, Y. Tanabe, J. Am. Chem.
Soc. 2004, 126, 5358–5359.
[21] See the Exp. Section.
[22] CCDC-987364 (for 7aa) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[23] H. Karoui, F. Le Moigne, O. Ouari, P. Tordo, in: Stable radi-
cals: fundamentals and applied aspects of odd-electron com-
pounds (Ed.: R. G. Hicks), Wiley, Chichester, UK, 2010, p.
175–177.
[24] For comparison, the N–O bond in the corresponding hydroxyl-
amine 4aa is 1.438 Å and the out-of-plane angle is 52.3°, and
in hydroxylamine 4ab, the N–O bond is 1.429 Å and the out-
of-plane angle is 55.2°.
[25] We examined 43 structures of five-membered cyclic nitroxides
from the Cambridge Structural Database.
[26] A. Capiomont, Acta Crystallogr., Sect. B 1973, 29, 1720–1722.
[27] For other studies illustrating the positive effect of a ligand on
the Cu/TEMPO co-catalysis, see, for example: a) S. Mannam,
S. K. Alamsetti, G. Sekar, Adv. Synth. Catal. 2007, 349, 2253–
2258; b) Z. Hu, F. M. Kerton, Appl. Catal. A 2012, 413–414,
332–339; c) I. Gamba, I. Mutikainen, E. Bouwman, J. Reedijk,
S. Bonnet, Eur. J. Inorg. Chem. 2013, 115–123.
[40] The dialdehyde 17 resulting from the oxidation of both alcohol
groups was not detected (1H NMR) in the reaction mixture for
these extents of conversion.
[41] We verified that i. no racemization of (R)-7ba occurred under
the oxidation conditions [(R)-7ba/HBr/TBN, 1:1:1, MeCN,
1 atm O2, room temp., 24 h] and ii. the ee of a scalemic sample
of 16 remained unaltered after 7 d at room temp. in hexane/
ethanol.
[42] See ref.[32] and references cited therein.
[43] a) J. R. Fish, S. G. Swarts, M. D. Sevilla, T. Malinski, J. Phys.
Chem. 1988, 92, 3745–3751; b) L. Marx, B. Schöllhorn, New
J. Chem. 2006, 30, 430–434; c) J. P. Blinco, J. L. Hodgson, B. J.
Morrow, J. R. Walker, G. D. Will, M. L. Coote, S. E. Bottle, J.
Org. Chem. 2008, 73, 6763–6771; d) R. A. Green, J. T. Hill-
Cousins, R. C. D. Brown, D. Pletcher, S. G. Leach, Electrochim.
Acta 2013, 113, 550–556.
[44] S. Manda, I. Nakanishi, K. Ohkubo, H. Yakumaru, K. Matsu-
moto, T. Ozawa, N. Ikota, S. Fukuzumi, K. Anzai, Org. Bio-
mol. Chem. 2007, 5, 3951–3955.
[28] For TEMPO derivatives including a ligand moiety, see: a) Z.
Lu, J. S. Costa, O. Roubeau, I. Mutikainen, U. Turpeinen, S. J.
Teat, P. Gamez, J. Reedijk, Dalton Trans. 2008, 3567–3573; b)
Z. Lu, T. Ladrak, O. Roubeau, J. van der Toorn, S. J. Teat, C.
Massera, P. Gamez, J. Reedijk, Dalton Trans. 2009, 3559–3570;
c) see ref.[3d]
.
[45] a) Y. Kato, Y. Shimizu, L. Yijing, K. Unoura, H. Utsumi, T.
Ogata, Electrochim. Acta 1995, 40, 2799–2802; b) E. Saint-
Aman, D. Serve, New J. Chem. 1989, 13, 121–130.
[46] M. F. Semmelhack, C. S. Chou, D. A. Cortes, J. Am. Chem.
Soc. 1983, 105, 4492–4494.
[29] N. Wang, R. Liu, J. Chen, X. Liang, Chem. Commun. 2005,
5322–5324.
[30] In our hands, a high level of background oxidation was ob-
served in the case of the originally reported FeCl3/NaNO2 sys-
tem. In the same vein, the ability of iron salts alone to catalyze
the aerobic oxidation of benzylamine has recently been re-
ported: E. Zhang, H. Tian, S. Xu, X. Yu, Q. Xu, Org. Lett.
2013, 15, 2704–2707.
[47] See also ref.[43b,43c,43d,45]
.
[48] See ref.[43d,46] and: A. Israeli, M. Patt, M. Oron, A. Samuni, R.
Kohen, S. Goldstein, Free Radical Biol. Med. 2005, 38, 317–
324.
[31] Notably, the addition of a catalytic amount of 2,2Ј-bipyridine
proved detrimental in the case of Method F.
[49] G. Gryn’ova, J. M. Barakat, J. P. Blinco, S. E. Bottle, M. L. Co-
ote, Chem. Eur. J. 2012, 18, 7582–7593.
[32] Y. Xie, W. Mo, D. Xu, Z. Shen, N. Sun, B. Hu, X. Hu, J. Org.
Chem. 2007, 72, 4288–4291.
[50] Efforts to detect this byproduct were unsuccessful.
[51] The same phenomena were observed upon addition of 1-phen-
ylethanol. Our attempts to oxidize 1-phenylethanol with O2 in
the presence of hydroxylamines 4/6b and Cu-based co-catalytic
systems (Method E or F) showed that the reaction was much
slower than with benzyl alcohol.
[33] a) See ref.[18a,18c]; b) O. N. Burchak, C. Philouze, P. Y. Chavant,
S. Py, Org. Lett. 2008, 10, 3021–3023.
[34] For discussions on the importance of atropoisomerism in drug
discovery, see: a) J. Clayden, W. J. Moran, P. J. Edwards, S. R.
LaPlante, Angew. Chem. Int. Ed. 2009, 48, 6398–6401; Angew. [52] See, for example, ref.[43d,45b] and: a) Y. Hahn, S. K. Song, Anal.
Chem. 2009, 121, 6516; b) S. R. LaPlante, L. D. Fader, K. R.
Fandrick, D. R. Fandrick, O. Hucke, R. Kemper, S. P. F. Miller,
P. J. E dwa rd s, J. Med. Chem. 2011, 54, 7005–7022.
Sci. 1997, 13 (suppl.), 329–332; b) D. Liaigre, T. Breton, E. M.
Belgsir, Electrochem. Commun. 2005, 7, 312–316; c) M. Barbier,
T. Breton, K. Servat, E. Grand, B. Kokoh, J. Kovensky, J. Car-
bohydr. Chem. 2006, 25, 253–266.
[35] For biocatalytic atroposelective desymmetrization of a diol by
aerobic oxidation, see: B. Yuan, A. Page, C. P. Worrall, F. Esca-
lettes, S. C. Willies, J. J. W. McDouall, N. J. Turner, J. Clayden,
Angew. Chem. Int. Ed. 2010, 49, 7010–7013; Angew. Chem.
2010, 122, 7164.
[36] For reviews and highlights of atroposelective syntheses, see: a)
G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser,
[53] D. S. Pedersen, C. Rosenbohm, Synthesis 2001, 2431–2434.
[54] The sample did not produce any NMR signal. After the ad-
dition of hydrazine hydrate to the NMR tube, signals of the
corresponding hydroxylamine protons were observed.
Received: April 28, 2014
Published Online: June 24, 2014
4896
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4884–4896