Inexpensive, multigram-scale preparation of an enantiopure cyclic nitrone via resolution at the hydroxylamine stage

Article abstract of DOI:10.1016/j.tetasy.2011.07.002

The reduction of the chiral, racemic nitrone MiPNO provides a secondary hydroxylamine. Its O-acylation with O,O'-dibenzoyl-l-tartaric acid anhydride gives two diastereomers, that can be easily separated by selective dissolution in orthogonal solvents. The recovery of the enantiopure nitrone is then carried out in a single step. The process allows the straightforward isolation of (R) and (S)-MiPNO in 57% and 38% yield, respectively, from rac-MiPNO.

Full text of DOI:10.1016/j.tetasy.2011.07.002

Tetrahedron: Asymmetry 22 (2011) 1266–1273
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Tetrahedron: Asymmetry
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Inexpensive, multigram-scale preparation of an enantiopure cyclic nitrone
via resolution at the hydroxylamine stage
⇑
Maryse Thiverny, Emilien Demory, Benoit Baptiste, Christian Philouze, Pierre Y. Chavant ,
Véronique Blandin
⇑
Département de Chimie Moléculaire, UMR-5250, ICMG FR-2607, CNRS, Université Joseph Fourier, BP-53, 38041 Grenoble Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The reduction of the chiral, racemic nitrone MiPNO provides a secondary hydroxylamine. Its O-acylation
with O,O’-dibenzoyl-L-tartaric acid anhydride gives two diastereomers, that can be easily separated by
selective dissolution in orthogonal solvents. The recovery of the enantiopure nitrone is then carried
out in a single step. The process allows the straightforward isolation of (R) and (S)-MiPNO in 57% and
38% yield, respectively, from rac-MiPNO.
Received 5 May 2011
Accepted 5 July 2011
Available online 17 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
the resolution of amine 2 through classical diastereomeric salt
formation. As we could not obtain satisfactory results, we rapidly
Enantiopure cyclic aldonitrones are generally derived from the
chiral pool, especially sugars.1 Their preparation, with varying
degrees of success, via resolution of the corresponding cyclic sec-
ondary amine,2 or via a kinetic resolution step at the hydroxyl-
amine3 or the nitrone4 stage has also been reported in the
literature.5 We are currently developing the applications of the chi-
ral cyclic aldonitrone 1 (2-isopropyl-2,3-dimethyl-1-oxy-2,3-dihy-
dro-imidazol-4-one, aka MiPNO,6 Scheme 1), which exhibits a high
degree of facial differentiation in cycloaddition6 and nucleophilic
addition7 reactions. We therefore needed an efficient, multigram-
scale preparation of enantiopure MiPNO. The following
requirements were set: efficient recovery of both enantiomers,
inexpensive reagents, no chromatographic separation, and easy
handling of solid compounds. Herein, we report our investigation,
which led to resolution at the hydroxylamine stage via the forma-
tion of covalent diastereomers. This case turned out to be a rare
example of diastereomer separation by selective dissolution.
favored the optical resolution of the corresponding hydroxylamine
3 (Scheme 1) via O-acylation with a chiral carboxylic acid. We have
previously shown10 that we were able to take advantage of the
high nucleophilicity of the hydroxylamine oxygen atom11 in such
a derivatization. The enantiopure hydroxylamine is then oxidized
into enantiopure MiPNO. Compound 3 can a priori be obtained
either by oxidation of 2 (path a) or reduction of 1 (path b); the che-
moselectivity of the reaction was crucial for preparative purposes.
[ox]
ref. 6
O
*
*
N
HCl•H2N
OEt
O
HN
N
N
O
O
2
[ox]
MiPNO 1
[ox]
[red]
2. Results and discussion
HO
*
N
N
2.1. Preparation of hydroxylamine 3
path a
path b
O
3
The preparation of racemic MiPNO 1 (Scheme 1) started from
glycine ethyl ester hydrochloride. The previously described6 path-
way to the intermediate imidazolidinone 2 was slightly improved8
upon allowing an inexpensive molar scale preparation. The
secondary amine 2 was then oxidized into 1. Considering the
literature precedent on a related structure,9 we first envisaged
Scheme 1. General scheme for the preparation of MiPNO 1 and hydroxylamine 3.
The direct oxidation of secondary amines into hydroxylamines
is generally difficult because the hydroxylamine is usually overox-
idized to the nitrone. Selective oxidation into a hydroxylamine has
been reported using dilute solutions of dimethyldioxirane.12
A
surface-mediated reaction with oxone over silica gel13 and a so-
dium tungstate-catalysed oxidation involving urea–hydrogen per-
oxide complex (UHP)14 in diethyl ether15 have also been described.
⇑
Corresponding authors. Tel.: +33 476514803; fax: +33 476635983.
E-mail
addresses:
Pierre-Yves.Chavant@ujf-grenoble.fr
(P.Y.
Chavant),
Veronique.Blandin@ujf-grenoble.fr (V. Blandin).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.002

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
1267
Previous work on the oxidation of related imidazolidinones in our
group16 showed that: (i) selective oxidation with 1 equiv m-chloro
perbenzoic acid17 was possible, but separation of the benzoic by-
product was troublesome; and (ii) the use of UHP with methyltri-
oxorhenium (MTO) as a catalyst, in dichloromethane,18 led to the
hydroxylamines in good yields. We thus investigated the UHP/
MTO system for the oxidation of amine 2 into hydroxylamine 3.
The reaction with 2 was much slower than in the case of the iso-
meric imidazolidinone studied previously,16b therefore the oxida-
tion was performed at 30–35 °C (Scheme 2). Unfortunately, even
at 43% conversion of the amine, nitrone 1 was present. Longer reac-
tion times allowed complete conversion of the amine into a mix-
ture of 3 and 1 but the hydroxylamine and the nitrone could not
be efficiently separated on a large scale.
The reduction of nitrone 1 was next investigated using various
conditions (Scheme 4 and Table 1). The reduction of nitrones into
hydroxylamines is generally performed using sodium cyanoboro-
hydride in acidic media22 or sodium borohydride,23 both in alco-
holic solvents. In the case of nitrone 1, reduction with sodium
borohydride in methanol (MeOH) was accompanied by dehydra-
tion into imine 4 (entry 1). No reaction occurred using borane–pyr-
idine or borane–triethylamine complexes in tetrahydrofuran (THF)
at 40–50 °C (entries 2 and 3). On the other hand, the more reactive
borane–dimethylsulfide complex was efficient at room tempera-
ture and hydroxylamine 3 was obtained selectively (entry 4).
Although the crude product was very clean, we verified that the
hydroxylamine was chromatography-stable and 3 could be recov-
ered in 84% yield. Diethylanilineborane (BH3ꢀDEAN), a more conve-
nient source of borane for large scale synthesis,24 was also efficient
(entry 5) however the elimination of N,N-diethylaniline required
an elevated temperature, causing degradation of hydroxylamine
3. Finally, the reduction of 1 with sodium borohydride or lithium
borohydride in THF at 20 °C cleanly afforded hydroxylamine 3 as
the sole product (entries 6 and 7). We chose to continue with
inexpensive sodium borohydride in THF; the reaction was per-
formed up to a 0.3 mol scale, leading in quantitative yield to the
crude hydroxylamine 3 which could be used in the following step
without further purification.
0.9 equiv. UHP
0.5 % MTO
HO
O
+
HN
N
N
N
N
N
CH2Cl2
30-35 °C, 2.5h
O
O
O
2
3
1
43% conv.
88:12
Scheme 2. Selectivity in the oxidation of imidazolidinone 2.
We then explored a two-step procedure: the preparation of
racemic MiPNO 1 and its selective reduction into hydroxylamine
3 (Scheme 1). We previously performed6 the oxidation of imidazo-
lidinone 2 into the nitrone on a 200 mmol scale with solid UHP,
using the inexpensive precatalyst Na2WO4ꢀ2H2O19 in methanol.
On a larger scale, the poor solubility of Na2WO4 in methanol made
control of the exothermic reaction difficult, and whenever the reac-
tion temperature went above 50 °C, a large amount of by-product
was formed.20 This was solved by performing the H2O2/Na2WO4
oxidation in water, as adapted from Murahashi’s procedure.21
The reaction was best run between 20 and 30 °C using 5 mol % cat-
alyst; heat evolution was thus slow and easily controlled. The con-
version of imidazolidinone 2 into the nitrone was complete within
4 h and MiPNO 1 was conveniently purified by recrystallization
from ethyl acetate/cyclohexane (Scheme 3). The overall yield in
recrystallized MiPNO, from glycine ethyl ester hydrochloride
(three steps) is typically 53%.
[H]
HO
O
+
N
N
N
N
N
N
O
O
O
1
3
4
Scheme 4. Reduction of MiPNO 1 into hydroxylamine 3.
2.2. Resolution of ( )-3 via the Moc-L-Phe-OH ester
In order to rapidly obtain milligrams of MiPNO in enantiopure
form, we first selected the N-protected -amino acid Moc-Phe-OH
(N-methoxycarbonyl- -phenylalanine) as chiral derivatizing
L
L
a
agent providing the chromatographically separable diasteromers
5.6 One diastereomer 5a led to crystals appropriate for X-ray dif-
fraction analysis, giving access to the relative (S,R) configuration
of the two stereogenic centres and, accordingly, to the (R) stereo-
chemistry of the imidazolidinone moiety.6
For the release of the hydroxylamine (Scheme 5 and Table 2),
the conditions previously used in our group,10a using LiOH as the
nucleophile, were unsuccessful due to the acidity of the imidazo-
lidinone ring proton (entry 1): imine 4 was formed in a large
amount. We anticipated that a more suitable nucleophilicity versus
basicity ratio could be met with aqueous hydrogen peroxide in the
presence of sodium hydrogen carbonate.25 Furthermore, we
expected that the bicarbonate-activated peroxide26 would oxidize
the evolved hydroxylamine to the expected nitrone 1. The conver-
1) H2O2 (aq)
1) MeNH2 (aq)
rt, 3 h
Na2WO4•2H2O cat.
H2O, 20-30 °C, 4 h
HCl
H2N
O
2
OEt
O
N
N
2)
2) recrystallization
NEt3
O
O
EtOH
1 mole
1
MS 4Å
53% (3 steps)
70 °C, 32 h
Scheme 3. Improved preparation of racemic MiPNO 1.
Table 1
Conditions for the reduction of MiPNO 1 into hydroxylamine 3
Entry
[H]
Equiv
Solvent
T (°C)
t (h)
Conv. (%)
3:4 Ratioa
Isolated yield in 3b (%)
1
2
3
4
5
6
7
NaBH4
BH3ꢀPy
3.0
1.5
1.5
1.3
1.5
2.0
2.0
MeOH
THF
THF
THF
THF
THF
THF
0–20
50d
40d
20
20
20
1.5
16
5
0.3
4
100
0
0
100
100
100
100
70:30
—
—
100:0
100:0
100:0
100:0
ndc
—
—
BH3ꢀTEA
BH3ꢀDMS
BH3ꢀDEAN
NaBH4
Quant.
ndc
1.5
4.5
Quant.
83
LiBH4
20
a
b
c
Determined on the basis of the 1H NMR spectrum of the crude material.
Crude product.
Not determined.
No reaction occurred at 20 °C.
d

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M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
Table 2
Conditions for the removal of Moc-L-Phe-OH
Entry
Reactant
Equiv
Solvent
T (°C)
t (h)
Conv. (%)
(R)-3:(R)-1 ratioa
1
2
3
4
5
LiOH
2
10
10
10
10
MeOH/THF
THF/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
0
20
20
20
20
1
6.5
4
7
24
100
34
100
100
100
100:0b
100:0
ndc
14:86
0:100
H2O2 (aq)/NaHCO3
H2O2 (aq)/NaHCO3
H2O2 (aq)/NaHCO3
H2O2 (aq)/NaHCO3
a
b
c
Determined on the basis of the 1H NMR spectrum of the crude material.
A 56:44 mixture of 3 and 4, respectively, was obtained.
Not determined.
sion of 5a was slow in THF (entry 2). In methanol no starting mate-
rial remained after 4 h. The hydroxylamine obtained was slowly
oxidized in situ into (ꢁ)-(R)-MiPNO (entries 3–5), but this reaction
was too sluggish to be practically useful.
Attempts to perform fractional crystallization from different
solvents came up against the relative insolubility of either diaste-
reomer. Starting from a 1:1 mixture, a solid enriched in one diaste-
reomer (7a/7b–ca. 9:1)29 remained in boiling toluene or in a
boiling 2:1 mixture of cyclohexane and ethyl acetate. This led us
to attempt selective dissolution: we investigated the trituration
of the 1:1 mixture of 7a and 7b in various solvents, and found an
outstanding couple of orthogonal solvents. Indeed, after trituration
at room temperature, solid 7a was preferentially recovered in the
case of ethyl acetate (7a/7b–ca. 9:1) and solid 7b in the case of
dichloromethane (7a/7b–ca. 1:9). Solubility measurements on iso-
lated compounds proved that 7a was six times more soluble than
7b in dichloromethane, whereas 7b was five times more soluble
than 7a in ethyl acetate.30
O
O
HO
O
and/or
N
N
N
N
N
N
N
H
MeO
O
O
O
O
5a: (S,R)
(R)-3
(R)-1
Scheme 5. Resolution via the Moc-L-Phe-OH ester: desired products from removal
of the resolving agent.
Thus, with these orthogonal solvents in hand, we developed a
diastereomer separation by selective dissolution. The optimized
process is illustrated in Chart 1 on a 0.3 mol scale. The amounts
of solvents were adjusted to the theoretical minimum required
to dissolve the more soluble diastereomer. The 1:1 mixture of dia-
stereomers 7a/7b was first triturated in dichloromethane at room
temperature for 30 min, then filtered. The resulting solid I already
presented an excellent enrichment in 7b. After a second treatment
with dichloromethane, diastereopure 7b was isolated (solid I0, 30%
of the initial mass). Filtrate I was concentrated to yield a solid that
was enriched in 7a. This solid was triturated in ethyl acetate to
selectively dissolve the minor diastereomer 7b. The remaining so-
lid II (33% of the initial mass) was diastereopure 7a. Filtrate II was
concentrated to a solid, and another trituration in dichloromethane
Finally, we chose to combine the rapid liberation of hydroxyl-
amine (R)-3 with basic aqueous hydrogen peroxide and the
efficiency of manganese dioxide-mediated oxidation of hydroxyl-
amines into nitrones27 by simply adding excess MnO2 in the reac-
tion mixture as soon as the first step was complete (Scheme 6). The
enantiomeric excess of (ꢁ)-(R)-MiPNO was above 99% as deter-
mined by chiral HPLC analysis.6
H2O2 (aq), NaHCO3, MeOH, 4h
then MnO2,15 min
O
5a
N
N
70%
O
(-)-(R)-1
7a/7b – 50:50
141.8 g
ee > 99%
Scheme 6. Resolution via the Moc-
L-Phe-OH ester: one-pot removal of the
ProcedureA
resolving agent and oxidation.
solid I
2.3. Resolution of ( )-3 via the O,O0-dibenzoyl-
L-tartaric acid
monoester
filtrate I
7a/7b – 5:95
7a/7b – 63:37
45.9 g
1) Evaporation to dryness
ProcedureA
2) Procedure B
In order to perform the resolution on a larger scale, a resolving
agent that would give solid diastereomers with different solubilities
was sought. A screen of candidates led to the selection of O,O0-diben-
solid I’
7a/7b > 1:99
43.2 g
zoyl-L
-tartaric acid anhydride 6.28 The reaction of 6 with the racemic
solid II
filtrate II
hydroxylamine 3 in dichloromethane (DCM) in the presence of a
catalytic amount of 4-dimethylaminopyridine (DMAP) gave a 1:1
mixture of diasteromers 7 in quantitative yield (Scheme 7).
7a/7b>99:1
7a/7b – 32:68
47.7 g
1) Evaporation to dryness
2) ProcedureA
BzO
solid III
O
filtrate III
7a/7b> 1:99
7a/7b – 50:50
11.9 g
O
BzO
BzO
DMAP (cat.)
HO
+
O
N
N
O
*
N
N
OH
DCM, 20 °C,
30 min
BzO
O
ProcedureA: DCM, 21 ºC, 30 min;filtration;the cake is
rinsed with minimum DCM;filtration
Procedure B: EtOAc, 21 ºC, 30 min;filtration;the cake is
rinsed with minimum EtOAc;filtration
O
O
O
quant.
6
3
7a/7b - 1:1
Scheme 7. Resolution via the O,O0-dibenzoyl-
L
-tartaric acid monoester: diastereo-
Chart 1. Resolution via the O,O0-dibenzoyl-
L-tartaric acid monoester: flow diagram
mer formation.
of the separation process.

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
1269
led to a second batch of diastereopure 7b (solid III). Filtrate III was
concentrated, but the accumulation of protic impurities along the
process hindered the crystallization of the remaining mixture of
isomers, and only a small amount of 7b was recovered by classical
recrystallization from ethyl acetate.
(DHA) 162.1°). On the other hand, the crystal structure of rac-1 is
composed of heterochiral dimers, with two hydrogen bonds be-
tween the (R)- and (S)-enantiomers, both linking the aldonitrone
hydrogen of one enantiomer with the nitrone oxygen of its anti-
pode (Fig. 2,35 d(D–H) 0.95 Å, d(H. . .A) 2.37 Å, d(D. . .A) 3.27 Å; an-
gle (DHA) 158.2°).
These four triturations are sufficient to recover diastereopure 7a
in 67% yield and diastereopure 7b in 77% yield.
To the best of our knowledge, separation of diastereomers by
selective dissolution has rarely been reported.31 Remarkably, the
reversal of solubilities observed in the case of 7a/7b allows the iso-
lation of almost equal, large amounts of each diastereopure com-
pound from a single32 and inexpensive resolving agent.
Another advantage of esters 7a, b compared to the Moc-L-Phe-
OH derivative is their solubility in basic water caused by the free
carboxylic acid. Thus, when 7a, b was added to an equimolar mix-
ture of H2O2 and NaHCO3 in water (10-fold excess), dissolution was
followed by a fast and clean liberation of the hydroxylamine. More-
over, under these conditions the hydroxylamine is also rapidly oxi-
dized into nitrone MiPNO 1. After catalytic decomposition of the
excess peroxide by addition of the minimum amount of MnO2,
and repeated extractions in ethyl acetate, enantiopure MiPNO 1
was recovered in 57–74% yield (Scheme 8). The recycling of the
resolving agent 6 was also possible.30
Figure 1. Crystal structure of (R)-1. The dashed line represents the hydrogen bonds.
BzO
O
H2O2 (aq)
BzO
NaHCO3
O
O
*
*
N
N
N
N
OH
O
H2O
O
O
rt, 20 min
7a or 7b
(S)-(+)-1 or (R)-(-)-1
ee > 98%
Figure 2. Crystal structure of (rac)-MiPNO. The dashed lines represent the
hydrogen bonds.
Scheme 8. Resolution via the O,O0-dibenzoyl-
L
-tartaric acid monoester: removal of
the resolving agent.
We previously encountered such a double, head-to-tail H-bond-
ing arrangement, in the crystals of the closely related nitrone 4-
methyl-3-oxo-1,4-diazaspiro[4.5]dec-1-ene 1-oxide 8 (Fig. 3).36
The same pattern was also reported in a nitronyl-nitroxide.37 Inter-
rogation of the CSD database produced seven other occurrences.38
If the N+–Oꢁ motif is known to be a powerful hydrogen-bond
acceptor39 and the nitrones have been used as hydrogen-bonding
templates for supramolecular assembly,40 the hydrogen-bond do-
nor ability of the aldonitrone C–H motif has rarely been docu-
mented. An analogy with aromatic amine N-oxides can however
be proposed, as their self association in dimers or networks via
C–H. . .O interactions has been described.41,42
Diastereomer 7a led to (+)-MiPNO and 7b to (ꢁ)-MiPNO. The
absolute configurations of each enantiomer were first assigned
on the basis of our previous results with 5a leading to (R)-(ꢁ)-MiP-
NO. In the case of 7b, crystals suitable for X-ray diffraction analysis
could be obtained. The relative configuration of 7b was thus estab-
lished and confirmed the (R) stereochemistry for the imidazolidi-
none moiety in 7b. On the other hand, all crystals obtained from
compound 7a led to low-quality X-ray diffraction patterns, pre-
venting unit cell determination and structure elucidation.
Thus, the resolution via the O,O0-dibenzoyl-
L-tartaric acid
monoester led to (R)- and (S)-MiPNO in 57% and 38% yield, respec-
tively, starting from (rac)-MiPNO.
2.4. Crystal structures of racemic and enantiopure MiPNO 1
We noticed strong discrepancies between enantiopure MiPNO
and its racemic counterpart with regards to their physical proper-
ties. The melting point of (R)- or (S)-1 is 47 °C lower than that of
rac-1 (67 vs 114 °C). Compound rac-1 is much less soluble in
diethyl ether and THF. It is even possible to recover enantiopure
1 from a 90% ee sample by simple dissolution.33
To gain insight into these differences, a crystallographic analysis
of (R)-MiPNO was conducted and the results obtained for the race-
mate34 were re-examined, especially regarding the hydrogen-
bonding network in the crystal. The crystal packings proved to be
different. Thus, in the case of (R)-1, four distinct orientations of
the molecules can be found in the cell unit, each being either donor
or acceptor in a C–H. . .O interaction (Fig. 1).35 The hydrogen-bond
donor is an aldonitrone CH group and the acceptor a nitrone oxy-
gen atom (d(D–H) 0.95 Å, d(H. . .A) 2.27 Å, d(D. . .A) 3.20 Å; angle
Figure 3. Crystal structure of 4-methyl-3-oxo-1,4-diazaspiro[4.5]dec-1-ene 1-
oxide. The dashed lines represent the hydrogen bonds.

1270
M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
hydrochloride (200.7 g, 1.438 mol). Endothermic dissolution was
3. Conclusion
followed by a gentle exothermic reaction. The solution was kept
at room temperature for 3 h, then concentrated under reduced
pressure at 40 °C. Ethanol (200 mL) was added and evaporation
resumed; this step was repeated four times, leaving the amino
amide hydrochloride as a syrup (230 g, theo. 179 g). To this
crude material were added ethanol (120 mL), 3-methyl-2-buta-
none (230 mL, 2.16 mol), triethylamine (201 mL, 1.44 mol) and
activated 4 Å molecular sieves (beads, 380 g). The flask was fitted
with a reflux condenser and heated at 70 °C for 32 h without
stirring, The sieves were separated by filtration of the hot mix-
ture. The filtrate was concentrated under reduced pressure, and
precipitation took place. The crude white slurry was taken up
in ethyl acetate (800 mL), the solid triethylamine hydrochloride
was filtered off and the filtrate concentrated under reduced
We have shown here that the acylation of a secondary hydrox-
ylamine with a chiral carboxylic acid provides a straightforward
access to the enantiopure nitrone MiPNO 1. The hydroxylamine
is best prepared by the reduction of the racemic nitrone; recovery
of the enantiopure nitrone from the O,O0-dibenzoyl-
L-tartaric acid
monoester is effected in a single step. Therefore, both enantiomers
of MiPNO, a new chiral glycine synthon, are easily available in
enantiopure form on a multigram-scale, from a single, inexpensive
resolving agent. Furthermore, the examination of the crystal struc-
tures of (R)- and (rac)-1 led us to point out interesting properties of
cyclic aldonitrones as hydrogen-bond donors and acceptors.
4. Experimental
4.1. General
pressure to yield 177.7 g (theo. 154.7 g) of crude
orange oil.
2 as an
In a 1-L flask fitted with a reflux condenser, a thermometer and
a 250-mL dropping funnel, were introduced 99.5 g of crude 2. A
solution of Na2WO4ꢀ2H2O (10.23 g, 31 mmol) in 20 mL water was
added; the temperature rose from 18 to 24 °C. The flask was placed
in an ice-salt bath, and H2O2 (217 g of 30% solution in water,
1.9 mol) was added dropwise over 45 min, so that the pot temper-
ature was kept below 30 °C. At the end of the addition, the ice bath
was replaced by a water bath (18 °C) and stirring was continued.
The reaction was moderately exothermic for the first 3 h and a
precipitate formed. After 5 h, filtration of the reaction mixture pro-
duced 82.8 g of crude nitrone 1. The water phase was placed in a 1-
L Erlenmeyer flask with magnetic stirring, cooled with an ice bath
and treated with MnO2 (3.5 g) to decompose the excess H2O2. After
the end of the intense frothing, the water phase was filtered on pa-
per, and then extracted with 5 ꢂ 200 mL ethyl acetate. The solid
nitrone was dissolved in the gathered organic phases, and the solu-
tion was washed with brine (50 mL), dried over MgSO4, and con-
centrated to a pale yellow solid (78.6 g). Recrystallization in ethyl
acetate (75 mL)/cyclohexane (200 mL) yielded pure 1 (pale yellow
crystals, 72.51 g, 0.427 mol) in 53% yield from glycine ethyl ester
hydrochloride.
Non-aqueous reactions were performed under a positive pres-
sure of dry nitrogen in oven-dried glassware equipped with a mag-
netic stirrer bar. Standard inert atmosphere techniques were used
in handling all air and moisture sensitive reagents. Tetrahydrofuran
was distilled over sodium benzophenone ketyl. Technical grade eth-
anol, methanol, dichloromethane (stabilized with amylene) and
ethyl acetate were purchased from Carlo Erba reagents and used
without further purification. All reagent-grade chemicals were pur-
chased from either Acros or Aldrich chemical companies and used
without purification unless otherwise stated. Reactions were mon-
itored by thin layer chromatography (TLC) using commercial alu-
minium-backed silica gel plates (Merck, Kieselgel 60 F254). TLC
spots were viewed under ultraviolet light and by heating the plate
after treatment with an appropriate staining solution (KMnO4, basic
TTC (2,3,5-triphenyltetrazolium chloride) for hydroxylamines).
Product purification by filtration over silica gel was performed
using Macherey Nagel Silica Gel 60 M (230–400 mesh). Melting
points (mp) were determined in capillary tubes with a Büchi B-
540 apparatus (heating rate 5 °C/min) and are given uncorrected.
Optical rotations [a] were measured on a Perkin Elmer 341 polarim-
eter, the corresponding concentration is given in g per 100 cm.3
Infrared spectra (IR) were recorded on a Nicolet ‘Magna 550’ spec-
trometer using ATR (Attenuated Total Reflexion) or a Nicolet Im-
pact-400 Fourier transform infrared spectrometer from a thin
film; data are reported in reciprocal centimetres (cmꢁ1). 1D and
2D NMR spectra were recorded on either a Bruker Advance 300 or
Advance 400 spectrometer. Chemical shifts (d) are given in ppm
using internal references or TMS as external reference for CDCl3.
Multiplicities are declared as follows: s (singlet), d (doublet), hept
(heptuplet), m (multiplet), qq (quadruplet of quadruplet). Coupling
constants (J) are given in Hertz. Low Resolution Mass Spectra
(LRMS) were recorded on a Bruker Daltonics Esquire 3000 Plus
ion-trap spectrometer (ESI) or a Thermo Fischer Scientific Polaris
Q spectrometer, using ammonia/isobutene–63:37 for chemical ion-
ization. High Resolution Mass Spectra (HRMS) were recorded on a
Thermoquest Orbitrap spectrometer at the LCOSB, UMR 7613, Uni-
versité Pierre et Marie Curie, Paris. Experimental errors for HRMS
data are estimated between 1 and 2 ppm. Elemental analysis were
performed at the Service d’Analyse Elémentaire du Département
de Chimie Moléculaire, Grenoble.
4.3. Preparation of rac-1-hydroxy-2-isopropyl-2,3-dimethyl-
imidazolidin-4-one 3 by the reduction of MiPNO with BH3ꢀDMS
In a 25-mL flask under a nitrogen atmosphere, nitrone rac-1
(317 mg, 1.86 mmol) was dissolved in anhydrous THF (5 mL). A
commercial solution of borane dimethylsulfide complex in THF
(2 M, 1.21 mL, 2.42 mmol) was slowly added and the mixture
was stirred for 20 min at room temperature (20 °C). The reaction
mixture was stirred with methanol (10 mL) until the end of
dihydrogen evolution and concentrated under reduced pressure.
This operation was repeated three times to give pure
3
(320 mg, 1.86 mmol, quantitative yield) as a pale yellow oil. Fur-
ther purification by flash chromatography (cyclohexane/ethyl
acetate–30:70) yielded
84% yield).
a colourless oil (269 mg, 1.56 mmol,
4.4. Characterization data for rac-2-isopropyl-2,3-dimethyl-2,3-
dihydro-imidazol-4-one 4
Yellow oil; Rf 0.29 (ethyl acetate); IR (thin film): 2972, 2929,
2881, 1697, 1599, 1428; dH (400 MHz; CDCl3) 7.80 (1H, s), 2.84
(3H, s), 2.05 (1H, qq, J = 6.8, 7.2 Hz), 1.40 (3H, s), 1.11 (3H, d,
J = 6.8 Hz), 0.48 (3H, d, J = 7.2 Hz); dC (100 MHz; CDCl3) 163.1,
159.7, 91.9, 33.8, 25.6, 22.1, 17.6, 15.3; LRMS (DCI) m/z: 155.3
(100, (M+H)+), 183.4 (28, (M+C2H5)+), 195.3 (8, (M+C3H5)+); HRMS
(ESI+) m/z: found, 177.09945 (M+Na); C8H14N2ONa requires
177.09983.
Compounds 1, 2, 3, 5a were previously described in the
literature.6
4.2. Preparation of rac-2-isopropyl-2,3-dimethyl-1-oxy-2,
3-dihydro-imidazol-4-one (MiPNO, 1) on a 75 g scale
In a 1-L flask under magnetic stirring, methylamine (40% in
water, 300 mL, 3.5 mol) was added to solid glycine ethyl ester

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
1271
4.5. Resolution via the O,O0-dibenzoyl-
L-tartaric acid monoester
71.0, 70.7, 57.9, 34.8, 26.1, 17.2, 16.8, 15.5; LRMS (ESI+) m/z: 513
(21, (M+H)+), 535 (100, (M+Na)+), 1025 (6, (2 M+H)+), 1047 (12,
(2 M+Na)+); Anal.: found, C61.26; H5.50; N5.73; C26H28N2O9 re-
quires C60.94; H5.51; N5.47.
4.5.1. Synthesis of O,O0-dibenzoyl-
A mixture of -tartaric acid (150.09 g, 1.00 mol) and benzoyl
L
-tartaric anhydride 643
L
Compound 7b mp: 140 °C (dec); ½a D20
¼ ꢁ54:0 (c 1.08, EtOH); Rf
ꢃ
chloride (405 mL, 3.49 mol) was heated for 2 h at 125 °C in the
presence of a catalytic amount of DMAP (100 mg) (Caution! The
apparatus should be equipped with a hydrogen chloride trap).
The solid residue was triturated two times in diethyl ether at room
temperature, and then dried under vacuum over P2O5 to give O,O0-
0.55 (ethyl acetate/ethanol–50:50); IR (ATR): 3672, 3562, 3069,
3031, 2965, 2952, 2882, 1787, 1781, 1723, 1646, 1448, 1245,
1095, 712; dH (400 MHz; (CD3)2SO) 8.03–8.02 (4H, m), 7.74–7.73
(2H, m), 7.62–7.59 (4H, m), 6.11 (1H, d, J = 2.8 Hz), 5.88 (1H, d,
J = 2.8 Hz), 4.02 (1H, d, J = 17.2 Hz), 3.61 (1H, d, J = 17.2 Hz), 2.64
(3H, s), 1.83 (1H, hept, J = 6.8 Hz), 1.16 (3H, s), 0.73 (3H, d,
J = 6.8 Hz), 0.68 (3H, d, J = 6.8 Hz); dC (100 MHz; (CD3)2SO) 168.4,
166.7, 164.1, 164.6, 134.4, 134.2, 129.5, 129.4, 129.2, 129.1,
128.3, 128.1, 88.6, 71.2, 70.8, 58.4, 34.8, 26.0, 17.0, 16.5, 16.0; LRMS
(ESI+) m/z: 513 (21, (M+H)+), 535 (100, (M+Na)+), 1025 (6,
(2M+H)+), 1047 (12, (2M+Na)+); Anal.: found, C60.60; H5.27;
N5.53. C26H28N2O9 requires C60.94; H5.51; N5.47.
dibenzoyl-L-tartaric anhydride 6 as a white solid (282 g, 829 mmol,
83%). Mp: 191.1–191.2 °C; ½a D25
ꢃ
¼ þ147 (c 1.07, acetone). Lit.44 mp:
188–189 °C; ½a 2D5
¼ þ153 (c 1.07, acetone).
ꢃ
4.5.2. Derivatization of hydroxylamine 3: synthesis of (2R,3R)-
2,3-bis-benzoyloxy-succinic acid mono-((S)-2-isopropyl-2,3-
dimethyl-4-oxo-imidazolidin-1-yl) ester 7a and (2R,3R)-2,3-
bis-benzoyloxy-succinic acid mono-((R)-2-isopropyl-2,3-dime-
thyl-4-oxo-imidazolidin-1-yl) ester 7b
4.5.4. Solubility measurements
In a 1-L round-bottomed flask under vigourous magnetic stir-
ring, crude hydroxylamine 3 (47.74 g, 277 mmol) was dissolved
in dichloromethane (380 mL). Next, DMAP (130 mg, 1.16 mmol)
was added, followed by anhydride 6 (94.32 g, 277 mmol). The reac-
tion was almost athermic, the anhydride dissolved and precipita-
tion took place. After 30 min, the reaction mixture was
concentrated.
A saturated solution of 7a (or 7b) in the solvent at 18 °C (inter-
nal temperature; glassware placed in a thermostated water bath)
was prepared and a precise volume of the supernatant was sam-
pled and concentrated.
Solubility of 7a in EtOAc: 7 mg/mL; in DCM: 41–48 mg/mL.
Solubility of 7b in EtOAc: 32–33 mg/mL; in DCM: 8 mg/mL.
4.5.5. (S)-2-Isopropyl-2,3-dimethyl-1-oxy-2,3-dihydro-
imidazol-4-one (S)-1 [(S)-MiPNO]
4.5.3. Separation of diastereomers 7a and 7b
The solid was transferred to a 2-L Erlenmeyer flask, suspended
in 1.5 L dichloromethane and stirred at 21 °C (room temperature)
for 30 min. The remaining solid was filtered and the cake was
rinsed with 100 mL dichloromethane. Filtration yielded 45.9 g of
a white solid (solid I, 7a/7b–5:95 as determined by 1H NMR),
and filtrate I. Solid I (entire quantity) was stirred in dichlorometh-
ane (47 mL) for 30 min and filtration yielded diastereopure 7b as a
white solid (solid I0, 43.2 g, 7a/7b > 1:99). The filtrate was added to
filtrate I.
Filtrate I (entire quantity) was concentrated under reduced
pressure to yield 98.1 g of a 63:37 mixture of diastereomers 7a/
7b which was triturated in ethyl acetate (1 L) for 30 min at 21 °C.
The remaining solid was filtered and the cake was rinsed with
50 mL ethyl acetate. Filtration yielded 47.7 g of diastereopure 7a
as a white solid (solid II, 7a/7b > 99:1), and filtrate II.
In a 250-mL Erlenmeyer flask were introduced NaHCO3 (14.0 g,
165 mmol), water (35 mL) and a 30% aqueous solution of hydrogen
peroxide (18.7 g, 165 mmol). Under vigourous stirring, solid 7a
(8.52 g, 16.5 mmol) was added in one portion. Frothing and disso-
lution then took place. After 20 min stirring, MnO2 (0.3 g) was
added portion-wise (brisk frothing). After 5 min the water phase
was extracted six times with 50 mL ethyl acetate. The gathered or-
ganic layers were dried over Na2SO4 and concentrated to yield (S)-
1 (1.65 g), that crystallized upon standing. The solid was stirred in
25 mL diethyl ether. The solution was filtered and concentrated to
yield 1.61 g of (S)-1 (>98% ee, 57% yield). An analytical sample of
(S)-1 was obtained by recrystallization from ethanol: mp: 67.0–
67.1 °C; ½a 2D5
¼ þ16:5 (c 2.0, EtOH).
ꢃ
4.5.6. Recovery of resolving agent 6
Filtrate II (entire quantity) was concentrated under reduced
pressure to yield 51.1 g of a 32:68 mixture of diastereomers 7a/
7b which was triturated in dichloromethane (340 mL) for 30 min
at 21 °C. The remaining solid was filtered and the cake was rinsed
with 20 mL dichloromethane. Filtration yielded 11.9 g of diastereo-
pure 7b as a white solid (solid III, 7a/7b > 1:99), and filtrate III.
Filtrate III (entire quantity) was concentrated under reduced
pressure to yield 39.07 g of a 50:50 mixture of diastereomers 7a/
7b. The addition of ethyl acetate (25 mL), overnight standing at
room temperature, and filtration yielded only 3.38 g of a 88:12
mixture of 7a/7b, which was not processed further. After concen-
tration, the filtrate did not crystallize.
The water layers from the liberation of (S)-1 were acidified to
pH 1 and extracted with 2 ꢂ 100 mL ethyl acetate; the gathered or-
ganic layers were dried over Na2SO4 and concentrated under re-
duced pressure to yield O,O0-dibenzoyl-
L-tartaric acid (6.45 g) as
a thick oil. To a suspension of crude O,O0-dibenzoyl-
L-tartaric acid
(6.45 g, 18 mmol) in cyclohexane (100 mL) was added acetyl chlo-
ride (6.28 g, 80 mmol). The reaction mixture was stirred for 9 h at
50 °C and concentrated. The residue was taken up in Et2O (40 mL)
and the white solid was filtered off to yield O,O0-dibenzoyl-
L-tar-
taric anhydride 6 (3.98 g, 11.7 mmol, 65%). The specific rotation
was identical to that of the sample used for the resolution of
MiPNO.
Global yield of diastereopure 7a: 67% (white solid, 47.7 g).
Global yield of diastereopure 7b: 77% (white solid, 55.1 g).
4.5.7. (R)-2-Isopropyl-2,3-dimethyl-1-oxy-2,3-dihydro-imidazol-
4-one (R)-1 [(R)-MiPNO]
Compound 7a: mp: 146–150 °C (dec); ½a D20
¼ ꢁ52:0 (c 1.26,
ꢃ
CHCl3); Rf 0.55 (ethyl acetate/ethanol–50:50); IR (ATR): 3085,
2977, 2942, 2885, 1796, 1721, 1646, 1623, 1243, 1093, 726; dH
(400 MHz; (CD3)2SO) 8.04-8.02 (4H, m), 7.76–7.73 (2H, m), 7.63–
7.59 (4H, m), 6.01 (1H, d, J = 2.8 Hz), 5.97 (1H, d, J = 2.8 Hz), 3.93
(1H, d, J = 17.2 Hz), 3.32 (1H, d, J = 17.2 Hz), 2.69 (3H, s), 1.91
(1H, hept, J = 6.8 Hz), 1.35 (3H, s), 0.89 (3H, d, J = 6.8 Hz), 0.77
(3H, d, J = 6.8 Hz); dC (100 MHz; (CD3)2SO) 168.3, 166.9, 164.1,
164.5, 134.4, 134.2, 129.5, 129.4, 129.2, 129.1, 128.3, 128.0, 88.9,
Compound (R)-1 was prepared as described for (S)-1 starting
from 7b (8.47 g). Yield: 74% (2.07 g, >98% ee). An analytical sample
of (R)-1 was obtained by recrystallization from ethanol: mp: 66.6–
66.7 °C; ½a 2D5
¼ ꢁ16:2 (c 2.0, EtOH).
ꢃ
4.5.8. HPLC determination of the ee
The enantiomeric purity of 1 was determined by chiral HPLC on a
Daicel Chiralpak AD-RH column, 4.6 ꢂ 100 mm, eluent acetonitrile/

1272
M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
water 70/30, 0.5 mL/min, retention time 5.9 min for (S)-MiPNO and
6.9 min for (R)-MiPNO.
by TeXsan.52 C, N, and O atoms were refined anisotropically by the
full matrix least-squares method. H atoms were set geometrically
and recalculated before the last refinement cycle. The final R values
4.6. X-Ray crystal structure determination
obtained for 1373 reflections with I > 2r (I) and 119 parameters
are R1 = 0.0425, wR2 = 0.0857 and for all 1927 unique reflections
R1 = 0.0763, wR2 = 0.1365. The data have been deposited at the
Cambridge Crystallographic Data Centre (Reference No. CCDC
823684).
4.6.1. Diastereomer 7b: (2R,3R)-2,3-bis-benzoyloxy-succinic acid
mono-((R)-2-isopropyl-2,3-dimethyl-4-oxo-imidazolidin-1-yl)
ester
Data for the crystal structure of compound 7b (recrystallized
from ethanol) were collected on a Bruker AXS-Enraf-Nonius Kap-
Acknowledgements
pa-CCD diffractometer working at the Mo-K
a wavelength
(0.71073 Å) using the program Collect.45 The temperature was
maintained at 200 K using a 700 series Cryostream cooling device.
The unit cells determinations were performed using Dirax46 and
the data were integrated with EvalCCD.47 C26H28N2O9, M =
We are grateful to the Université Joseph Fourier and the CNRS
for financial support. We thank Lucille Garcia, Céline Plantevin
and François Vibert for their support.
512.50 g molꢁ1
,
trigonal, P32, a = 12.439(1), b = 12.439(1),
References
c = 14.846(4) Å, V = 1989.3(3) Å3, Z = 3, Z0 = 1, Dx = 1.283 g cmꢁ3. A
total of 12690 reflections were measured and 2746 unique
(Rint = 0.0718) were used in all calculations. The final R values were:
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R1 = 0.0368 and wR2 = 0.0768 for I > 2
r (I) and R1 = 0.0505 and
wR2 = 0.0847 for all data. The structure was solved with one mole-
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A
2. Baldwin, S. W.; Long, A. Org. Lett. 2004, 6, 1653–1656.
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The space group discrimination between P31 and P32 was achieved
according to the prior knowledge of compound configuration. All
non-hydrogen atoms were refined with anisotropic thermal param-
eters. All hydrogen atoms were positioned with idealized geometry
using the riding model proposed in Shelx97 with C–H = 0.93 Å or
0.96 Å, and N–H = 0.86 Å, and with Uiso(H) = 1.2Ueq(C-aromatic)
and 1.5Ueq(C-methyl). The data have been deposited at the Cam-
bridge Crystallographic Data Centre (Reference No. CCDC 819651).
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864–872. The stereochemistry of the cycloadducts was furthermore confirmed
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7. Thiverny, M.; Farran, D.; Philouze, C.; Blandin, V.; Chavant, P. Y. Tetrahedron:
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8. The less expensive aqueous methylamine solution (40% w/w) can be used
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Serizawa, M.; Fujinami, S.; Ukaji, Y.; Inomata, K. Tetrahedron: Asymmetry 2008,
19, 921–931.
4.6.2. (R)-MiPNO 1
Data for the crystal structure of compound (R)-1 (recrystallized
from ethanol) were collected on
MACH3 diffractometer working at the Cu-K
(1.54178 Å) and at 296 K. C8H14N2O2, M = 170.21 g molꢁ1, mono-
clinic, P21, a = 6.803(2), b = 11.399(4), c = 12.260(3) Å,
a
Bruker AXS-Enraf-Nonius
a
wavelength
11. (a) Palling, D.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 4869–4876; (b) Fina, J.
O.; Edwards, N. J. Int. J. Chem. Kinetics 1973, 5, 1–26.
b = 92.48(2)°, V = 949.8(5) Å3, Z = 4, Dx = 1.191 g cmꢁ3. A total of
2042 reflections were collected; 2011 independent reflections
(Rint = 0.0454). The structure was solved by direct methods with
SIR9251 and refined against F by least square method implemented
by TeXsan.52 C, N, and O atoms were refined anisotropically by the
full matrix least-squares method. H atoms were set geometrically
and recalculated before the last refinement cycle. There are two
independent molecules in the asymetric unit. The final R values ob-
12. Murray, R. W.; Singh, M. Synthetic Commun. 1989, 19, 3509–3522.
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tained for 1767 reflections with I > 2
r
(I) and 217 parameters are
18. When performed in methanol, the oxidation of amines with H2O2 or UHP and
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1996, 37, 6025–6028; (b) Murray, R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org.
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R1 = 0.0615, wR2 = 0.0844 and for all 2011 unique reflections
R1 = 0.0653, wR2 = 0.0858. The data have been deposited at the
Cambridge Crystallographic Data Centre (Reference No. CCDC
819649).
20. Probably
the
hydroxamic
acid
(1-hydroxy-2-isopropyl-2,3-
4.6.3. 4-Methyl-3-oxo-1,4-diazaspiro[4.5]dec-1-ene 1-oxide 8
Data for the crystal structure of compound 8 were collected on a
Bruker AXS-Enraf-Nonius CAD4 diffractometer working at the Cu-K
dimethylimidazolidine-4,5-dione) from the overoxidation: Murahashi, S.;
Oda, T.; Sugahara, T.; Masui, Y. J. Org. Chem. 1990, 55, 1744–1749.
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23. See for instance: Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem. 2005, 70,
4954–4961.
24. Wilkinson, H. S.; Tanoury, G. J.; Wald, S. A.; Senanayake, C. H. Org. Process Res.
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25. Zheng, Q. Y.; Darbie, L. G.; Cheng, X.; Murray, C. K. Tetrahedron Lett. 1995, 36,
2001–2004.
a
wavelength (1.54178 Å) and at 296 K. C9H14N2O2, M = 182.22,
monoclinic, P21/a, a = 11.213(2), b = 9.824(3), c = 8.631(3) Å,
b = 98.11(2)°, V = 941.3(4) Å3, Z = 4, Dx = 1.286 g cmꢁ3. A total of
2195 reflections were collected; 1927 independent reflections
(Rint = 0.0227). The structure was solved by direct methods with
SIR9251 and refined against F by least square method implemented
26. Balagam, B.; Richardson, D. E. Inorg. Chem. 2008, 47, 1173–1178.

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1266–1273
1273
27. Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001, 42, 6503–
6505.
28. Review: Synoradzki, L.; Bernas´, U.; Rus´kowski, P. Org. Proc. Prep. Int. 2008, 40,
Bierer, L.; Jager, V. Z. Kristallogr. -New Cryst. Struct. 2003, 218, 107–108; (f)
Jasinski, M.; Mloston, G.; Mucha, P.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
2007, 90, 1765–1780; (g) Fujii, T.; Ogawa, K.; Saito, T.; Kobayashi, K.; Itaya, T.;
Date, T.; Okamura, K. Chem. Pharm. Bull. 1995, 43, 53–62.
39. See for instance: Laurence, C.; Graton, J.; Berthelot, M.; Besseau, F.; Le Questel,
J.-Y.; Luçon, M.; Ouvrard, C.; Planchat, A.; Renault, E. J. Org. Chem. 2010, 75,
4105–4123.
163–200.
29. The ratio of 7a/7b was determined on the basis of the 1H NMR spectrum of the
mixture in CD3OD (complete dissolution).
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