Totally diastereoselective addition of aryl Grignard reagents to the nitrone-based chiral glycine equivalent MiPNO

Article abstract of DOI:10.1016/j.tetasy.2011.07.022

The reaction of the chiral nitrone MiPNO (2-isopropyl-2,3-dimethyl-1-oxy-2, 3-dihydro-imidazol-4-one) with Grignard reagents is totally diastereoselective. Using simple and functionalized arylmagnesium reagents, enantiopure hydroxylamines were obtained in fair to good yields, which in turn could be easily transformed into new chiral ketonitrones. The preparation of enantiopure l-phenylglycine derivatives is also described.

Full text of DOI:10.1016/j.tetasy.2011.07.022

Tetrahedron: Asymmetry 22 (2011) 1274–1281
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Totally diastereoselective addition of aryl Grignard reagents
to the nitrone-based chiral glycine equivalent MiPNO
⇑
⇑
Maryse Thiverny, Daniel Farran, Christian Philouze, Véronique Blandin , Pierre Y. Chavant
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:
Received 5 May 2011
Accepted 25 July 2011
The reaction of the chiral nitrone MiPNO (2-isopropyl-2,3-dimethyl-1-oxy-2,3-dihydro-imidazol-4-one)
with Grignard reagents is totally diastereoselective. Using simple and functionalized arylmagnesium
reagents, enantiopure hydroxylamines were obtained in fair to good yields, which in turn could be easily
transformed into new chiral ketonitrones. The preparation of enantiopure
also described.
L-phenylglycine derivatives is
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Several other
a
-carbonyl aldonitrones, both cyclic3,4 and acy-
clic,5 have been described in the literature and their reactivity in
1,3-dipolar cycloaddition reactions studied. However, little atten-
tion has been paid to their reactivity toward the nucleophilic addi-
tion of organometallic reagents.6 To the best of our knowledge, the
only report concerns the patented addition of organomagnesium
We recently reported that chiral nitrone 1 (2-isopropyl-2,3-di-
methyl-1-oxy-2,3-dihydro-imidazol-4-one, aka MiPNO)1 exhibits
a high degree of facial differentiation in 1,3-dipolar cycloaddition
reactions. Both enantiomers of MiPNO are available on a multi-
gram-scale through a rapid, 3-stage sequence (Scheme 1): selective
reduction into the corresponding racemic hydroxylamine/resolu-
and organolithium reagents to a menthol-derived cyclic
a-alkyla-
minocarbonyl nitrone.7 Our work on related ketonitrones has
shown that the presence of an acidic proton on the carbon atoms
tion of the hydroxylamine with O,O0-dibenzoyl-
L-tartaric anhydride
via the formation of covalent diastereomers/one-pot removal of
at the a-position of the nitrone group is detrimental to the nucle-
the chiral auxiliary and oxidation into a nitrone.2
ophilic addition reaction.8 Alkynylzinc reagents react smoothly on
the electrophilic carbon atom, whereas deprotonation can occur
with more basic organometallic species. We thus wondered
whether synthetically useful yields of hydroxylamine adducts
could be obtained in the reaction of Grignard reagents with MiPNO
1 and whether high diastereoselectivities could be achieved.
Given its structure, MiPNO 1 is a nitrone-based chiral glycine
equivalent, and we have demonstrated in the case of 1,3-dipolar
cycloaddition reactions that the products can be transformed into
BzO
2 steps
no purification
O
BzO
O
O
*
*
N
N
N
N
quant.
OH
O
O
O
rac-MiPNO 1
c
-hydroxy
nature of the nitrone carbon atom, we would have access to other
-amino acids. We chose to focus our study on the reaction of MiP-
NO 1 with arylmagnesium reagents, as the adducts should be pre-
cursors of arylglycines, -amino acids that cannot be easily
a
-amino acids.1 By taking advantage of the electrophilic
1) separation
2) H2O2 / NaHCO3
O
O
a
and
N
N
N
N
O
O
a
synthesized from the well-known chiral glycine enolate developed
1
1
(-)-(R)-
(+)-(S)-
by Seebach.9,10 Herein we report our investigation into this topic.
57% yield
38% yield
Scheme 1. Preparation of enantiopure MiPNO 1.
2. Results and discussion
2.1. Addition of Grignard reagents to MiPNO
A variety of aryl Grignard reagents were added to racemic or
enantiopure MiPNO 1 (Scheme 2 and Table 1), leading in all cases
to a single isomer of N-hydroxy imidazolidinone 2. The sole
⇑
Corresponding authors. Tel.: +33 476514803; fax: +33 476635983.
E-mail addresses: Veronique.Blandin@ujf-grenoble.fr (V. Blandin), Pierre-
Yves.Chavant@ujf-grenoble.fr (P.Y. Chavant).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.022

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
1275
Simple and electron-rich aryl Grignard reagents led to N-hydro-
xy imidazolidinones 2a–f in fair to good yields (entries 1–14). The
ortho-substituted (+)-2e (entry 12) was prepared from anisole via
ortho-lithiation followed by magnesium/lithium exchange. The di-
rect addition of the lithium species onto MiPNO caused degrada-
tion. The addition of a heteroaromatic group was possible, for
RMgX
HO
O
+
N
N
N
N
N
N
THF, -20 °C, 15 min
R
O
R
O
O
1
2
3
MiPNO
racemic or enantiopure
example
a-thienyl hydroxylamine 2g was isolated in high yield
(entries 15 and 16).
Scheme 2. Addition of Grignard reagents to racemic or enantiopure MiPNO 1
We were particularly interested in functionalized aryl Grignard
reagents bearing electron-withdrawing substituents. Such species
can be prepared from the corresponding aryl iodides by magne-
sium–iodine exchange according to the procedure reported by
(relative stereochemistry shown).
imidazolidinone-based impurities present in the reaction mixture
were unreacted MiPNO 1 and imine.
Table 1
Addition of Grignard reagents to MiPNO 1
Entry
Grignard reagenta
MiPNO
1:2:3 ratiob
Hydroxylamine 2
Isolated yield (%)
1
2
3
4
5:95:0
69
5:90:5c
51c
MgBr
rac-1
(R)-1
rac-2a
(ꢀ)-2a
B
A
0:79:21d
9:91:0
—
e
62
5
6
7
rac-1
(R)-1
(S)-1
0:97:3
7:90:3
rac-2b
(ꢀ)-2b
65
71
MgBr
3:95:2f
(+)-2b
75f
8
9
rac-1
(R)-1
5:92:3
1:94:5
rac-2c
(ꢀ)-2c
65
60
Me
MgBr
A
A
10
11
rac-1
(R)-1
3:91:6
1:94:5
rac-2d
(ꢀ)-2d
64
67
MeO
MgBr
MgBr
OMe
12
C
(S)-1
9:91:0
(+)-2e
72
13
14
rac-1
(R)-1
5:95:0
5:89:6
rac-2f
(ꢀ)-2f
65
65
N
S
MgBr
B
B
D
B
15
16
rac-1
(R)-1
7:90:3
4:94:2
rac-2g
(ꢀ)-2g
77
79
MgBr
17
18
rac-1
(R)-1
0:100:0
0:100:0
rac-2h
(ꢀ)-2h
84
89
I
MgCl
19
20
rac-1
(R)-1
6:87:7
8:86:6
rac-2i
(ꢀ)-2i
49
52
Br
MgBr
MgCl
F
e
21
D
rac-1
37:49:14
rac-2j
—
Br
F
22
23
rac-1
(R)-1
10:90:0
6:94:0
rac-2k
(ꢀ)-2k
71
78
F
MgCl
D
F
F
O
24
Dg
(R)-1
30:67:3
(ꢀ)-2l
46
MgCl
MeO
e
25
26
rac-1
(R)-1
—
—
rac-2m
(ꢀ)-2m
44
41
Ah
B
e
MgCl
MgBr
27
(S)-1
25:68:7
2n
40i
Preparation and amount of Grignard reagents. Method A: commercial source; 1.1 equiv. Method B: prepared from the aryl bromide and Mg0; 1.1 equiv. Method C:
a
prepared from anisole via ortho-lithiation followed by magnesium–lithium exchange; 1.5 equiv. Method D: prepared from the aryl iodide via magnesium–iodine exchange;
2.0 equiv.
b
The ratio of 1:2:3 was determined on the basis of the 1H NMR spectrum of the crude product.
1.3 equiv of Grignard reagent were used.
2.0 equiv of Grignard reagent were used.
Not determined.
c
d
e
f
PhMgCl was used.
g
1.1 equiv of Grignard reagent were used.
h
i
i
The PrMgClꢁLiCl complex was used.
Hydroxylamine 2m was contaminated with its imine counterpart (10%).

1276
M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
Knochel and Cahiez,11 but their addition to nitrones has not yet
been investigated. The p-iodophenyl adduct 2h and pentafluor-
ophenyl adduct 2k were isolated in very good yields (entries 17–
18 and 22–23). On the other hand, the reaction of MiPNO 1 with
hindered o-bromo phenylmagnesium chloride was very sluggish
and was accompanied by imine formation to a large extent (entry
21). Better results were obtained in the case of an ester group at
the para-position (entry 24), although the corresponding hydroxyl-
amine 2l was isolated in modest yield. Since methyl 4-iodobenzo-
ate underwent a rapid magnesium-iodine exchange, we wondered
whether this exchange could be performed in the presence of MiP-
NO, that is, with in situ quenching.12 However, the addition of iso-
propylmagnesium chloride onto the mixture of MiPNO 1 and
methyl 4-iodobenzoate led only to the isopropyl adduct 2m and
not the aryl adduct 2l.
of ketonitrone 4c into hydroxylamine proved difficult. Nitrone 4c
was recovered unchanged after reaction with NaBH4, BH3ꢁTHF,
BH3ꢁDMS or BH3ꢁN,N-diethylaniline. Finally, the use of LiAlH4 al-
lowed the partial conversion (72%) of 4c into a new compound,
identified by 1H NMR and mass spectroscopy as N-hydroxy imi-
dazolidinone 20c.16 A 2D NOESY NMR experiment showed a dis-
tinct correlation between the protons of the methyl group and
the hydrogen atom introduced, which was consistent with a cis-
stereochemistry for 20c (Scheme 3). The chemical shifts for 20c
are clearly different compared to 2c (see Section 4). Thus, we could
confirm that 20c was indeed not present in the crude material from
the p-tolylmagnesium addition onto MiPNO (Table 1, entry 8) and
that the diastereoselectivity of this addition was above 98%.
2.3. Imine side product
Finally, we investigated the reaction of MiPNO with alkylmag-
nesium reagents (entries 25–27). Again, the reaction produced a
single diastereomer, albeit in modest yield.
As mentioned in Table 1, we supposed that the single imidazo-
lidinone-based side product in the crude materials was imine 3.
This was proven in the case of 3a by comparison with an authentic
sample prepared by 1,10-carbonyldiimidazole-mediated dehydra-
tion of hydroxylamine 2a (Scheme 4).7 Compounds 3a–l curiously
exhibited a very large difference in 1H NMR chemical shift between
the diastereotopic methyl groups of the isopropyl (0.60–0.70 ppm,
compare with 0.03–0.04 for hydroxylamines 2 or 0–0.07 for nitro-
nes 4). The separation of hydroxylamine 2 from 3 proved difficult,
thus affecting the yield.
2.2. Diastereoselectivity
The relative configuration of hydroxylamines 2 was determined
by 2D NOESY NMR experiments on the crude materials. Distinct
correlations between the protons of the isopropyl group and the
hydrogen atom on the imidazolidinone ring showed that the aryl
group was transferred anti to the bulky isopropyl group (the ob-
served correlations in the instance of rac-2c are depicted in
Scheme 3). In the case of p-anisyl adduct (ꢀ)-2d, crystals suitable
for X-ray diffraction analysis were obtained, and the trans-stereo-
chemistry was again confirmed (Fig. 1).
HO
N
N
N
N
CDI
O
O
DCM
rt, 2 h
46%
H
2a
rac-
rac-3a
Scheme 4. Preparation of authentic imine 3a from hydroxylamine 2a (relative
configuration shown).
Our attempts to suppress the formation of 3 were unsuccessful.
Changes in the hydrolysis protocol produced only non-significant
variations in the ratios. More interestingly, we noticed that a great-
er amount of 3 was obtained when a larger excess of arylmagne-
sium reagent was used (for instance, see Table 1, entries 1–3).
This suggests that imine 3 is formed before hydrolysis, with the ex-
cess Grignard reagent acting as a base.
Figure 1. ORTEP drawing of (ꢀ)-2d (H atoms omitted for clarity).13 The ellipsoids
are plotted at the 70% probability level.
The diastereoselectivity of the reaction appeared very high in all
runs. No other hydroxylamine could be detected by TLC14 in the
isolated or crude material, or in minor chromatography fractions.
The 1H NMR analysis of crude reaction mixtures showed only 1,
2, and 3. In order to prove the absence of the cis-diastereomer,
we prepared an authentic sample in the case of the p-tolyl adduct
(Table 1, entry 8). For this, hydroxylamine rac-2c was oxidized
with MnO2 into nitrone rac-4c in quantitative yield15 (Scheme 3;
we also quantitatively prepared ketonitrones 4a, b, f, g from 2a,
b, f, g by this very efficient procedure, see Section 4). The reduction
2.4. Enantioselective preparation of
L-phenylglycine derivatives
Arylglycines are a class of -amino acids that are difficult to
a
synthesize in enantiopure form due to the high acidity of the a-aryl
proton.17 Elegant approaches to the asymmetric construction of
the chiral center leading to arylglycine derivatives have been
H
H
H
H
nOe
nOe
HO
O
HO
N
N
N
N
N
N
MnO2
LiAlH4
H
DCM
rt, 15 min
quant.
H
O
O
O
THF
-20 °C, 30 min
72% conv.
H
2c
2'c
:
rac-
:
rac-
(2R*,5S*)
(2R*,5R*)
rac-4c
Scheme 3. Preparation of the opposite diasteromer 20c; NOESY correlations for each diastereomer (relative stereochemistry shown).

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
1277
disclosed18–20 but the subsequent obtention of the enantiopure
a
We investigated the transformation of N-hydroxy imidazolidi-
none (+)-2b into L-phenylglycine. The hydrolytic cleavage of the
yields. With both enantiomers of MiPNO 1 being equally accessi-
ble,2 both enantiomers of the adducts 2 are also equally accessible.
The hydroxylamines can be easily oxidized into new chiral ketoni-
trones 4. The transformation of the N-hydroxy imidazolidinone (+)-
-aryl amino acids remains challenging.21
two C–N bonds of the aminal was performed in 5 min under micro-
wave irradiation (Scheme 5). Under these conditions, no cleavage
of the amide C–N bond was observed; the sole side product, 3-
methyl-2-butanone was easily eliminated under reduced pressure
2b into L-phenylglycine shows that enantiopure arylglycine deriv-
atives, namely the N-hydroxy amino amide and the amino amide,
could be prepared via this methodology. N-Hydroxy amino acid
derivatives are particularly valuable compounds: their introduc-
tion in peptides allows the easy grafting of side chains on the pep-
tide backbone leading to other classes of pseudopeptides or
cyclized peptides.23
to give the N-hydroxy
in quantitative yield.
a-amino amide hydrochloride salt (S)-5ꢁHCl
Attempts to hydrolyze the amide group at the N-hydroxy
a-
amino amide stage resulted in partial degradation. The hydroxyl-
amine group was thus reduced first. The hydrogenation over Pd/
C of the crude (S)-5ꢁHCl quantitatively yielded the amine hydro-
chloric salt. However, some racemization occurred: the phenylgly-
cine derivative was recovered in 84% ee as determined by 1H NMR
analysis of 6 with (S)-O-acetylmandelic acid as a chiral solvating
agent.22 Performing the hydrogenolytic N–O bond cleavage in the
presence of excess HCl (1.6 additional equivalents) suppressed
the racemization (ee >98%, Scheme 5).
4. Experimental
4.1. General
Non-aqueous reactions were performed under a positive pres-
sure of N2 in oven-dried glassware equipped with a magnetic stir
bar. Standard inert atmosphere techniques were used in handling
all air and moisture sensitive reagents. Tetrahydrofuran (THF)
and diethyl ether (Et2O) were distilled over sodium benzophe-
none ketyl. Technical grade dichloromethane, ethanol and meth-
anol were purchased from Carlo Erba reagents and used without
further purification. All reagent-grade chemicals were purchased
from either Acros or Aldrich chemical companies (magnesium
turnings: Aldrich, ref. 20,090-5; Pd/C 10%: Fluka, ref. 15990)
and used without purification. GC analyses were performed on
a Shimadzu C17 apparatus equipped with a flame ionization
detector and a BPX1 column (15 m ꢂ 0.25 mm, SGE; He). Thin
layer chromatography (TLC) was performed using commercial
aluminium-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, ninhydrine for amines, basic TTC (2,3,5-triphenyltetrazo-
lium chloride) for hydroxylamines). Product purification by col-
umn chromatography was performed using Macherey Nagel
Silica Gel 60 M (230–400 mesh). Microwave irradiation experi-
ments were conducted in a CEM Discover S-Class apparatus (sin-
gle mode technology). Melting points (mp) were determined in
capillary tubes with a Büchi B-540 apparatus and are uncor-
O
HCl•HOHN
HO
HCl 12M, EtOH
NHMe
N
N
µw, 130 °C, 5 min
O
quant.
5
(S)- •HCl
2b
(+)-
O
HCl
HCl•H2N
H2, Pd/C, MeOH
NHMe
rt, 16 h
quant.
6
(S)- •HCl
ee > 98%
Scheme 5. Transformation of N-hydroxy imidazolidinone (+)-2b into enantiopure
L
-phenylglycine derivatives.
We have previously performed the epimerization-free hydroly-
sis of a similar amide group on a related compound produced via a
1,3-dipolar cycloaddition reaction between MiPNO 1 and cyclohex-
ene.1 When the same conditions (HClaq 6 M, microwave irradiation,
150 °C) were applied, amino amide (S)-6 was converted into phen-
ylglycine 7 in 10 min (Scheme 6). However the enantiomeric ex-
cess of the amino acid was only 60% as determined by HPLC
analysis. With lower reaction temperatures, longer reaction times
were required for complete conversion and the extent of racemiza-
tion could not be reduced.
rected. Optical rotations [a] were measured on a Perkin Elmer
341 polarimeter, the corresponding concentration is given in g
per 100 cm3. Infrared spectra (IR) were recorded on a Nicolet
‘Magna 550’ spectrometer using ATR (Attenuated Total Reflexion)
or a Nicolet Impact-400 Fourier transform infrared spectrometer
from a thin film. Data are reported in reciprocal centimeters
(cmꢀ1). 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 ref-
erence for CDCl3. Multiplicities are declared as follows: s (sin-
glet), d (doublet), t (triplet), hept (heptuplet), m (multiplet), dd
(doublet of doublet), tt (triplet of triplet), qq (quadruplet of qua-
druplet). Coupling constants (J) are given in Hertz. Low Resolu-
tion Mass Spectra (LRMS) were recorded on a Bruker Daltonics
O
O
HCl•H2N
H2N
NHMe
OH
HCl 6M,µw, 130-150 °C
10-20 min
quant.
Esquire 3000 Plus ion-trap spectrometer (ESI) or
a Thermo
Fischer Scientific Polaris Q spectrometer, using ammonia/isobu-
tene—63:37 for chemical ionization. High Resolution Mass Spec-
6
L-7
ee < 60%
(S)- •HCl
ee > 98%
tra (HRMS) were recorded on
a
Thermoquest Orbitrap
Scheme 6. Amide group hydrolysis.
spectrometer at the LCOSB, UMR 7613, Université 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. Crystal data were collected on a Bruker
3. Conclusions
The reaction of the chiral glycine equivalent MiPNO 1 with Grig-
nard reagents is totally diastereoselective and, with arylmagne-
sium reagents, gives the hydroxylamine adducts 2 in fair to good
AXS-Enraf-Nonius MACH3 diffractometer working at the Cu K
wavelength (1.54178 Å) and at 296 K.
a

1278
M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
4.2. Synthesis of hydroxylamines 2
C20H24N2O2 requires C, 74.05; H, 7.46; N, 8.64. Found: C, 74.06;
H, 7.54; N, 8.61.
4.2.1. Preparation of Grignard reagents
Method A: Commercial organomagnesium reagents.
4.2.3. (2R,5R)-1-Hydroxy-2-isopropyl-2,3-dimethyl-5-phenyl-
imidazolidin-4-one (ꢀ)-2b
Method B: The organomagnesium reagents were freshly pre-
pared by the slow addition of the corresponding bromides
(1.0 equiv) in THF (Et2O for 2-bromothiophene and 1-bromo-3-
methylbutane) onto magnesium turnings (1.3 equiv) previously
activated with 1,2-dibromoethane. p-Bromomagnesium bromide
was prepared by the dropwise addition (over 15 min) of p-dibro-
mobenzene (4.72 g, 20.0 mmol) in THF (30 mL) onto magnesium
turnings (486 mg, 20 mmol) that were previously activated with
The title compound was prepared as described for 2a (organo-
magnesium reagent: method A). Yield: 71%; beige solid, mp:
110 °C; ½a 2D5
¼ ꢀ108:2 (c 0.98, acetone); Rf 0.57 (ethyl acetate);
ꢃ
IR (thin film): 3297, 3063, 3020, 2985, 2959, 2933, 1681; dH
(400 MHz; CDCl3) 7.38–7.37 (4H, m), 7.34–7.31 (1H, m), 4.84
(1H, s), 4.83 (1H, s), 2.89 (3H, s), 2.34 (1H, hept, J = 7.2 Hz), 1.49
(3H, s), 1.15 (3H, d, J = 7.2 Hz), 1.12 (3H, d, J = 7.2 Hz); dC
(100 MHz; CDCl3) 169.3, 136.9, 129.0, 128.4, 128.1, 84.7, 71.0,
34.9, 27.0, 22.9, 18.8, 18.5; LRMS (ESI+) m/z: 249.1 (59, (M+H)+),
271.1 (100, (M+Na)+), 497.2 (5, (2M+H)+), 519.3 (67, (2M+Na)+);
HRMS (ESI+) m/z: found, 271.14183 (M+Na); C14H20N2O2Na re-
quires 271.14170; Anal. C14H20N2O2 requires C, 67.72; H, 8.12; N,
11.29. Found: C, 67.39; H, 8.15; N, 10.95.
a
crystal of iodine. The insoluble dimagnesium compound
precipitated in the reaction mixture.24 The organomagnesium
solutions were titrated prior to use according to Watson and
Eastham (1.05 M solution of isopropanol in toluene and
orthophenantroline).25
Method C: In an oven-dried, N2-flushed Schlenk vessel were
introduced magnesium turnings (182 mg, 7.50 mmol) and Et2O
(11 mL). 1,2-Dibromoethane (390
l
L, 4.50 mmol) was slowly
4.2.4. (2R,5R)-1-Hydroxy-2-isopropyl-2,3-dimethyl-5-p-tolyl-
imidazolidin-4-one (ꢀ)-2c
added and the reaction mixture was stirred at room temperature
until ethylene evolution ceased (2 h). The reaction mixture became
biphasic. In an oven-dried, N2-flushed Schlenk vessel, a solution of
t-BuLi in heptane (1.1 M, 2.05 mL, 2.25 mmol) was slowly added to
The title compound was prepared as described for 2a (organo-
magnesium reagent: method A), then recrystallized from cyclohex-
ane/ethyl acetate. Yield: 60%; white crystals, mp: 135 °C;
anisole (740
lL, 6.75 mmol) in THF (1 mL) at 0 °C. The reaction
½
a 2D5
ꢃ
¼ ꢀ115:0 (c 1.00, acetone); Rf 0.28 (cyclohexane/ethyl ace-
mixture was kept at this temperature for 2.5 h. This solution was
then added in two portions to the previously prepared pre-cooled
solution of MgBr2 (4.50 mmol) in Et2O (11 mL) at 0 °C. The result-
ing solution was stirred for 15 min before use.
tate—60:40); IR (ATR): 3250, 3054, 2977, 2936, 2933, 1679; dH
(400 MHz; CDCl3) 7.26 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz),
4.80 (1H, s), 4.74 (1H, s), 2.89 (3H, s), 2.36 (3H, s), 2.32 (1H, qq,
J = 6.8, 7.2 Hz), 1.49 (3H, s), 1.14 (3H, d, J = 6.8 Hz), 1.11 (3H, d,
J = 7.2 Hz); dC (100 MHz; CDCl3) 169.7, 138.0, 134.0, 129.3, 129.1,
84.8, 71.0, 35.0, 27.1, 22.8, 21.3, 18.9, 18.6; LRMS (ESI+) m/z:
263.1 (95, (M+H)+), 285.1 (100, (M+Na)+), 301.1 (5, (M+K)+),
525.3 (5, (2M+H)+), 547.3 (35, (2M+Na)+). HRMS (ESI+) m/z: found,
Method D: The preparation was carried out in an oven-dried,
N2-flushed, 25 mL two-necked flask fitted with an internal ther-
mometer. To a ꢀ30 °C (liquid N2/EtOH bath) pre-cooled solution
of appropriate iodobenzene (3.30 mmol) in dry THF (3 mL) was
added dropwise a commercial solution of isopropylmagnesium
chloride–lithium chloride complex in THF (1.01 M, 2.96 mL,
3.00 mmol). The pot temperature raised to ꢀ20 °C and was kept
at this temperature until the I/Mg exchange was complete (as
checked by GC analysis of reaction aliquots; conditions: 2 min at
75 °C, then 75–280 °C at 10 °C per min and 4 min at 280 °C, inter-
nal standard: dodecane) at which point the reagent was used
immediately.
287.15731 (M+Na);
15H22N2O2 requires C, 68.68; H, 8.46; N, 10.68. Found: C, 69.00;
H, 8.60; N, 10.86.
C15H22N2O2Na requires 287.15735; Anal.
C
4.2.5. (2R,5R)-1-Hydroxy-2-isopropyl-5-(4-methoxy-phenyl)-
2,3-dimethyl-imidazolidin-4-one (ꢀ)-2d
The title compound was prepared as described for 2a (organo-
magnesium reagent: method A), then recrystallized from cyclohex-
ane/dichloromethane. Yield: 67%; beige solid, mp: 147 °C;
4.2.2. (2R,5R)-5-Biphenyl-4-yl-1-hydroxy-2-isopropyl-2,3-dimeth-
yl-imidazolidin-4-one (ꢀ)-2a
½
a 2D5
ꢃ
¼ ꢀ104:1 (c 1.04, acetone); Rf 0.32 (cyclohexane/ethyl ace-
tate—50:50); IR (thin film): 3354, 3054, 2985, 2963, 2933, 1691;
dH (400 MHz; CDCl3) 7.29 (2H, d, J = 8.8 Hz), 6.90 (2H, d,
J = 8.8 Hz), 4.79 (1H, s), 4.67 (1H, s), 3.80 (3H, s), 2.90 (3H, s),
2.32 (1H, qq, J = 6.8, 7.2 Hz), 1.49 (3H, s), 1.14 (3H, d, J = 6.8 Hz),
1.11 (3H, d, J = 7.2 Hz); dC (100 MHz; CDCl3) 169.9, 159.7, 130.4,
128.9, 114.0, 84.8, 70.6, 55.4, 35.1, 27.1, 22.5, 18.9, 18.6; LRMS
(ESI+) m/z: 279.1 (15, (M+H)+), 301.1 (100, (M+Na)+), 579.3 (84,
(2M+Na)+); HRMS (ESI+) m/z: found, 301.15152 (M+Na);
The reaction was performed in an oven-dried, nitrogen-flushed,
25 mL cylindrical three-necked flask fitted with an internal ther-
mometer. Nitrone (R)-1 (170 mg, 1.0 mmol) was dissolved in anhy-
drous THF (2 mL). The reaction mixture was cooled to ꢀ20 °C
(liquid N2/EtOH bath) and a solution of organomagnesium reagent
in THF (1.1 mmol, method B) was added. During the addition, the
temperature was kept below ꢀ20 °C. After 15 min, a saturated
aqueous solution of NH4Cl (2 mL) was added, followed by ethyl
acetate (10 mL) and water (2 mL). The aqueous layer was separated
and extracted with ethyl acetate (15 mL). The gathered organic lay-
ers were washed with brine (10 mL), dried over anhydrous Na2SO4,
filtered, and the solvents were removed under reduced pressure.
The resulting crude material was purified by flash chromatography
(cyclohexane/ethyl acetate—70:30) to yield hydroxylamine 2a.
C15H22N3O2Na requires 301.15226; Anal. C15H22N2O3 requires C,
64.73; H, 7.97; N, 10.07. Found: C, 64.40; H, 8.06; N, 9.91. The rel-
ative configuration of (ꢀ)-2d was determined by X-ray crystallog-
raphy of an analytical sample recrystallized in ethanol (pale yellow
crystals).
a = 10.448(4),
C
15H22N2O3, M = 278.35 g molꢀ1
b = 7.451(2),
,
monoclinic, P21,
b = 97.63(4)°,
c = 20.442(6) Å,
V = 1577.2(8) Å3, Z = 4, Dx = 1.172 g cmꢀ3. A total of 3497 reflec-
tions were collected; 3445 independent reflections (Rint = 0.0455).
The structure was solved by direct methods with SIR9226 and re-
fined against F by least-squares method implemented by TeXsan.27
The C, N, and O atoms were refined anisotropically by the full ma-
trix least-squares method. The H atoms were set geometrically and
recalculated before the last refinement cycle. There are two inde-
pendent molecules in the asymmetric unit. These two molecules
are linked by a hydrogen bond. The final R values obtained for
Yield: 62%; white solid, mp: 182 °C; ½a D25
¼ ꢀ123:9 (c 0.96, ace-
ꢃ
tone); Rf 0.62 (ethyl acetate); IR (thin film): 3345, 3050, 3028,
2963, 2937, 1682; dH (400 MHz; CDCl3) 7.60–7.58 (4H, m), 7.46–
7.41 (4H, m), 7.34 (1H, tt, 4J = 2.0, 3J = 7.4 Hz), 4.89 (1H, s), 2.92
(3H, s), 2.35 (1H, qq, J = 6.8, 7.2 Hz), 1.51 (3H, s), 1.17 (3H, d,
J = 6.8 Hz), 1.13 (3H, d, J = 7.2 Hz); dC (100 MHz; CDCl3) 169.5,
141.3, 141.1, 136.1, 129.5, 128.9, 127.4, 127.3, 84.9, 70.9, 35.1,
27.2, 23.0, 19.0, 18.6; LRMS (DCI) m/z: 325.2 (100, (M+H)+); Anal.

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
1279
3022 reflections with I > 2
r
(I) and 361 parameters are R1 = 0.0643,
(2H, d, J = 8.2 Hz), 4.77 (1H, s), 4.76 (1H, s), 2.88 (3H, s), 2.33 (1H,
qq, J = 6.8, 7.2 Hz), 1.50 (3H, s), 1.15 (3H, d, J = 6.8 Hz), 1.12 (3H,
d, J = 7.2 Hz); dC (100 MHz; CDCl3) 169.0, 137.5, 136.7, 130.9,
94.0, 84.9, 70.5, 35.1, 27.1, 22.9, 18.9, 18.5; LRMS (ESI+) m/z:
375.1 (45, (M+H)+), 397.1 (79, (M+Na)+), 749.0 (3, (2M+H)+),
771.1 (100, (2M+Na)+); HRMS (ESI+) m/z: found, 397.03914
(M+Na); C14H19IN2O2Na requires 397.03834; Anal. C14H19IN2O2 re-
quires C, 44.94; H, 5.12; N, 7.49. Found: C, 45.05; H, 5.17; N, 7.56.
wR2 = 0.1008 and for all 3445 unique reflections R1 = 0.0702,
wR2 = 0.1033. The data have been deposited at the Cambridge Crys-
tallographic Data Centre (Reference No. CCDC 819593).
4.2.6. (2S,5S)-1-Hydroxy-2-isopropyl-5-(2-methoxy-phenyl)-2,3-
dimethyl-imidazolidin-4-one (+)-2e
The title compound was prepared as described for 2a except
that the solution of nitrone (S)-1 (255 mg, 1.50 mmol) in THF
(3 mL) was added to the organomagnesium reagent obtained from
4.2.10. (2R,5R)-5-(4-Bromo-phenyl)-1-hydroxy-2-isopropyl-2,3-
dimethyl-imidazolidin-4-one (ꢀ)-2i
method C. Yield: 72%; white solid, mp: 160 °C; ½a D25
¼ þ61:7 (c
ꢃ
1.04, acetone); Rf 0.55 (ethyl acetate); IR (ATR): 3391, 3018,
2968, 2838, 1666; dH (400 MHz; CDCl3) 7.30–7.25 (2H, m), 6.93
(1H, t, J = 7.0 Hz), 6.87 (1H, d, J = 8.0 Hz), 5.97 (1H, br s), 5.15 (1H,
s), 3.78 (3H, s), 2.83 (3H, s), 2.19 (1H, qq, J = 6.8, 7.2 Hz), 1.04
(3H, s), 1.03 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 7.2 Hz); dC
(100 MHz; CDCl3) 170.2, 158.6, 132.1, 129.7, 124.2, 120.6, 111.1,
86.0, 66.5, 55.7, 34.9, 27.2, 20.2, 18.8, 18.4; LRMS (ESI+) m/z:
279.2 (100, (M+H)+), 301.2 (71, (M+Na)+), 579.3 (54, (2M+Na)+);
HRMS (ESI+) m/z: found, 301.15175 (M+Na); C15H22N2O3Na re-
quires 301.15226. Anal. C15H22N2O3 requires C, 64.73; H, 7.97; N,
10.07. Found: C, 65.05; H, 8.10; N, 10.08.
The title compound was prepared as described for 2a (organo-
magnesium reagent: method B). Yield: 52%; white solid, mp:
153 °C; ½a 2D5
¼ ꢀ106:9 (c 1.38, acetone); Rf 0.67 (ethyl acetate);
ꢃ
IR (thin film): 3336, 3054, 2985, 1693; dH (400 MHz; CDCl3) 7.49
(2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 4.79 (1H, s), 4.78 (1H,
s), 2.88 (3H, s), 2.33 (1H, qq, J = 6.8, 7.2 Hz), 1.50 (3H, s), 1.15
(3H, d, J = 6.8 Hz), 1.12 (3H, d, J = 7.2 Hz); dC (100 MHz; CDCl3)
168.9, 136.1, 131.6, 130.6, 122.3, 84.9, 70.5, 35.1, 27.2, 23.1, 18.9,
18.6; LRMS (ESI+) m/z: 327.1 (100, (M+H)+), 329.1 (92, (M+H)+),
349.1 (92, (M+Na)+), 351.1 (93, (M+Na)+), 655.1 (5, (2M+H)+),
677.1 (43, (2M+Na)+), 679.1 (20, (2M+Na)+); HRMS (ESI+) m/z:
found, 349.05286 and 351.05049 (M+Na); C14H19BrN2O2Na re-
quires 349.05221 and 351.05017.
4.2.7. (2R,5R)-5-(4-Dimethylamino-phenyl)-1-hydroxy-2-isoprop-
yl-2,3-dimethyl-imidazolidin-4-one (ꢀ)-2f
The title compound was prepared as described for 2a (organo-
magnesium reagent: method B). The resulting crude material was
purified by trituration in boiling ethyl acetate to yield hydroxyl-
4.2.11. (2R,5R)-1-Hydroxy-2-isopropyl-2,3-dimethyl-5-penta-
fluorophenyl-imidazolidin-4-one (+)-2k
The title compound was prepared as described for 2a except
that the solid nitrone (R)-1 (255 mg, 1.50 mmol) was added in
one portion to the solution of organomagnesium reagent obtained
from method D (2.0 equiv) cooled to ꢀ30 °C. Yield: 78%; white so-
amine (ꢀ)-2f (65%) as a beige solid. mp: 184 °C; ½a D25
¼ ꢀ111:3 (c
ꢃ
1.10, acetone); Rf 0.34 (ethyl acetate/cyclohexane—70:30); IR
(ATR): 3251, 3006, 2987, 2965, 2796, 1679; dH (400 MHz; CDCl3)
7.20 (2H, d, J = 8.8 Hz), 6.72 (2H, d, J = 8.8 Hz), 4.96 (1H, s), 4.74
(1H, s), 2.93 (6H, s), 2.88 (3H, s), 2.28 (1H, qq, J = 6.8, 7.2 Hz),
1.41 (3H, s), 1.11 (3H, d, J = 6.8 Hz), 1.08 (3H, d, J = 7.2 Hz); dC
(100 MHz; CDCl3) 170.3, 150.8, 130.2, 124.3, 112.8, 84.8, 70.7,
40.8, 35.1, 27.1, 22.2, 18.9, 18.6; LRMS (ESI+) m/z: 292.2 (100,
(M+H)+), 314.2 (14, (M+Na)+), 583.4 (9, (2M+H)+), 605.3 (13,
(2M+Na)+); Anal. C16H25N3O2 requires C, 65.96; H, 8.65; N, 14.43.
Found: C, 65.75; H, 8.97; N, 14.48.
lid, mp: 178 °C; ½a D25
¼ þ14:8 (c 0.94, acetone); Rf 0.22 (cyclohex-
ꢃ
ane/ethyl acetate—70:30); IR (thin film): 3331, 2976, 2985, 2938,
1693, 1003; dH (400 MHz; CDCl3) 5.21 (1H, s), 4.86 (1H, s), 2.92
(3H, s), 2.28 (1H, hept, J = 7.2 Hz), 1.49 (3H, s), 1.15 (3H, d,
J = 7.2 Hz), 1.10 (3H, d, J = 7.2 Hz); dC (100 MHz; CDCl3) 167.1,
146.4 (d, J = 190 Hz), 141.5 (d, J = 190 Hz), 137.6 (d, J = 187 Hz),
111.2, 86.3, 62.0, 35.3, 27.1, 22.2, 18.4, 18.2; dF (282 MHz; CDCl3)
ꢀ141.2 (br), ꢀ153.7 (tt, 4J = 2.3 Hz, 3J = 21.4 Hz), ꢀ162.4 (td,
5J = 8.1 Hz, 3J = 21.4 Hz); LRMS (ESI+) m/z: 339.1 (34, (M+H)+),
361.1 (100, (M+Na)+), 699.2 (20, (2M+Na)+); HRMS (ESI+) m/z:
found, 361.09507 (M+Na); C14H15F5N2O2Na requires 361.09459.
4.2.8. (2R,5R)-1-Hydroxy-2-isopropyl-2,3-dimethyl-5-thiophen-
2-yl-imidazolidin-4-one (ꢀ)-2g
The title compound was prepared as described for 2a (organo-
magnesium reagent: method B). Yield: 79%; pink solid, mp:
4.2.12. (2R,5R)-1-Hydroxy-5-(4-methoxycarbonylphenyl)-2-iso-
propyl-2,3-dimethylimidazolidin-4-one (ꢀ)-2l28
118 °C; ½a 2D5
¼ ꢀ64:9 (c 1.24, acetone); Rf 0.62 (ethyl acetate); IR
ꢃ
(thin film): 3338, 3111, 3067, 2963, 2933, 1688; dH (300 MHz;
CDCl3) 7.28 (1H, dd, J = 1.2, 5.1 Hz), 7.15 (1H, dd, J = 1.2, 3.5 Hz),
7.01 (1H, dd, J = 3.5, 5.1 Hz), 5.12 (1H, s), 4.97 (1H, s), 2.89 (3H,
s), 2.30 (1H, hept, J = 9.2 Hz), 1.49 (3H, s), 1.13 (3H, d, J = 9.2 Hz),
1.10 (3H, d, J = 9.2 Hz); dC (100 MHz; CDCl3) 168.5, 140.0, 127.3,
127.1, 125.7, 85.1, 66.8, 35.1, 27.2, 22.2, 18.8, 18.5; LRMS (ESI+)
m/z: 255.0 (25, (M+H)+), 277.1 (100, (M+Na)+), 293.0 (17,
(M+K)+), 531.2 (67, (2M+Na)+); HRMS (ESI+) m/z: found,
277.09861 (M+Na); C12H18N2O2SNa requires 277.09812; Anal.
The title compound was prepared as described for 2a except
that a solution of nitrone (R)-1 (340 mg, 2.0 mmol) in THF (3 mL)
was added to the solution of organomagnesium reagent obtained
from method D (1.1 equiv). Yield: 46%; white solid, mp: 162 °C;
½
a 2D5
ꢃ
¼ ꢀ82:9 (c 1.00, acetone); Rf 0.67 (ethyl acetate); IR (ATR):
3424, 2987, 2959, 1715, 1686; dH (400 MHz; CDCl3) 7.95 (2H, d,
J = 8.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 5.69 (1H, s), 4.83 (1H, s), 3.89
(3H, s), 2.84 (3H, s), 2.32 (1H, hept, J = 7.1 Hz), 1.47 (3H, s), 1.13
(3H, d, J = 7.1 Hz), 1.10 (3H, d, J = 7.1 Hz); dC (100 MHz; CDCl3)
169.0, 167.2, 142.2, 129.6 (2C), 128.7, 84.9, 70.7, 52.2, 35.0, 27.1,
23.2, 18.9, 18.5; LRMS (ESI+) m/z: 307.1 (M+H)+, 329.1 (M+Na)+.
C12H18N2O2S requires C, 56.67; H, 7.14; N, 11.02. Found: C,
56.99; H, 7.44; N, 11.18.
4.2.9. (2R,5R)-1-Hydroxy-5-(4-iodo-phenyl)-2-isopropyl-2,3-di-
methyl-imidazolidin-4-one (ꢀ)-2h
4.2.13. (2R,5R)-1-Hydroxy-2,5-diisopropyl-2,3-dimethylimid-
azolidin-4-one (–)-2m
The title compound was prepared as described for 2a except
that the solid nitrone (R)-1 (255 mg, 1.50 mmol) was added in
one portion to the solution of organomagnesium reagent obtained
from method D (2.0 equiv) cooled to ꢀ30 °C. Yield: 89%; white so-
The title compound was prepared as described for 2a using
iPrMgClꢁLiCl (method A). Yield: 41%; white solid, mp: 126 °C;
½
a 2D5
ꢃ
¼ ꢀ1:7 (c 1.06, acetone); Rf 0.26 (cyclohexane/ethyl ace-
tate—60:40); IR (thin film): 3284, 2965, 2933, 1675; dH
(400 MHz; CDCl3) 4.69 (1H, s), 3.66 (1H, d, J = 3.6 Hz), 2.80 (3H,
s), 2.25 (1H, qq, J = 6.8, 7.2 Hz), 2.17–2.13 (1H, m), 1.41 (3H, s),
1.07 (3H, d, J = 6.8 Hz), 1.05 (3H, d, J = 6.8 Hz), 1.04 (3H, d,
lid, mp: 151 °C; ½a D25
¼ ꢀ104:8 (c 1.14, acetone); Rf 0.26 (cyclohex-
ꢃ
ane/ethyl acetate—60:40); IR (thin film): 3345, 3054, 2976, 2959,
2933, 1682; dH (400 MHz; CDCl3) 7.69 (2H, d, J = 8.2 Hz), 7.14

1280
M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
J = 7.2 Hz), 0.95 (3H, d, J = 6.8 Hz); dC (100 MHz; CDCl3) 170.6, 84.4,
71.4, 35.0, 29.2, 26.6, 23.6, 19.2, 18.8, 18.5, 17.7; LRMS (ESI+) m/z:
215.1 (100, (M+H)+), 237.1 (54, (M+Na)+), 253.1 (6, (M+K)+), 429.2
(10, (2M+H)+), 451.3 (29, (2M+Na)+); HRMS (ESI+) m/z: found,
237.15760 (M+Na); C11H22N2O2Na requires 237.15735.
7.71 (2H, m), 7.66–7.64 (2H, m), 7.48–7.44 (2H, m), 7.37 (1H, tt,
4J = 0.3, 3J = 7.6 Hz), 3.11 (3H, s), 2.44 (1H, qq, J = 6.8, 7.2 Hz), 1.74
(3H, s), 1.04 (3H, d, J = 7.2 Hz), 0.99 (3H, d, J = 6.8 Hz); dC
(100 MHz; CDCl3) 163.1, 143.4, 140.4, 130.5, 129.0, 128.05,
128.00, 127.3, 127.0, 125.0, 91.2, 35.2, 26.7, 21.6, 16.4, 15.7; LRMS
(ESI+) m/z: 323.2 (100, (M+H)+), 345.2 (94, (M+Na)+), 645.4 (3,
(2M+H)+), 667.3 (42, (2M+Na)+); Anal. C20H22N2O2 requires C,
74.51; H, 6.88; N, 8.69. Found: C, 74.56; H, 6.96; N, 8.63.
4.2.14. (2S,5S)-1-Hydroxy-2-isopropyl-2,3-dimethyl-5-(3-meth-
yl-butyl)-imidazolidin-4-one 2n
The title compound was prepared as described for 2a starting
from (S)-MiPNO (organomagnesium reagent: method B). Hydrox-
ylamine 2n (white solid, 40% yield) was contaminated with its
imine counterpart (10%). Rf 0.59 (ethyl acetate); dH (400 MHz;
CDCl3) 4.82 (1H, br s), 3.72 (1H, t, J = 6.4 Hz), 2.80 (3H, s), 2.11
(1H, qq, J = 6.8, 7.2 Hz), 1.80–1.71 (2H, m), 1.58–1.51 (1H, m),
1.45–1.25 (2H, m), 1.42 (3H, s), 1.03 (3H, d, J = 7.2 Hz), 0.99 (3H,
d, J = 6.8 Hz), 0.91 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6.4 Hz); dC
(100 MHz; CDCl3) 172.2, 86.3, 66.5, 35.4, 35.2, 28.4, 27.1, 26.5,
22.8, 22.6, 19.7, 18.8, 18.3; LRMS (ESI+) m/z: 243.2 (100, (M+H)+),
265.2 (62, (M+Na)+), 485.3 (3, (2M+H)+), 507.3 (42, (2M+Na)+).
4.4.2. rac-2-Isopropyl-2,3-dimethyl-1-oxy-5-phenyl-2,3-
dihydro-imidazol-4-one rac-4b
The title compound was prepared as described for 4a starting
from hydroxylamine rac-2b (1.35 g, 5.47 mmol). Yield: 95%, beige
solid; dH (400 MHz; CDCl3) 8.79–8.77 (2H, m), 7.48–7.46 (3H, m),
3.09 (3H, s), 2.44 (1H, qq, J = 6.8, 7.2 Hz), 1.73 (3H, s), 1.03 (3H, d,
J = 7.2 Hz), 0.98 (3H, d, J = 6.8 Hz).
4.4.3. rac-2-Isopropyl-2,3-dimethyl-1-oxy-5-p-tolyl-2,3-
dihydro-imidazol-4-one rac-4c
The title compound was prepared as described for 4a starting
from hydroxylamine rac-2c (262 mg, 1 mmol). Yield: quant.;
brown solid; dH (400 MHz; CDCl3) 8.70 (2H, d, J = 8.1 Hz), 7.28
(2H, d, J = 8.1 Hz), 3.08 (3H, s), 2.42 (1H, hept, J = 7.0 Hz), 2.40
(3H, s), 1.71 (3H, s), 1.02 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz).
4.2.15. Complementary data for racemic hydroxylamines 2
Compound rac-2a: white solid, mp: 162 °C; rac-2b: yellow oil
that solidified upon standing, mp: 95 °C; rac-2c: beige solid, mp:
128 °C; rac-2d: white solid, mp: 139 °C; rac-2f: yellow solid, mp:
155 °C; rac-2g: beige solid, mp: 108 °C; rac-2h: white solid, mp:
135 °C; rac-2i: white solid, mp: 103 °C; rac-2k: white solid, mp:
155 °C; rac-2m: beige solid, mp: 85 °C.
4.4.4. rac-5-(4-Dimethylamino-phenyl)-2-isopropyl-2,3-
dimethyl-1-oxy-2,3-dihydro-imidazol-4-one rac-4f
The title compound was prepared as described for 4a from
hydroxylamine rac-2f (100 mg, 343 lmol). Yield: quant.; yellow
4.3. rac-5-Biphenyl-4-yl-2-isopropyl-2,3-dimethyl-2,3-dihydro-
imidazol-4-one rac-3a
solid; dH (300 MHz; CDCl3) 8.83 (2H, d, J = 9.2 Hz), 6.76 (2H, d,
J = 9.2 Hz), 3.07 (3H, s), 3.04 (6H, s), 2.44 (1H, qq, J = 6.9, 7.2 Hz),
1.70 (3H, s), 1.02 (3H, d, J = 7.2 Hz), 0.95 (3H, d, J = 6.9 Hz).
In a 25-mL flask under an N2 atmosphere, hydroxylamine rac-2a
(481 mg, 1.48 mmol) was dissolved in dichloromethane (2 mL) and
1,10-carbonyldiimidazole (384 mg, 2.37 mmol) was added. The
reaction mixture was stirred for 2 h at room temperature after
which a 0.25 M aqueous solution of hydrochloric acid (8 mL) was
added. After decantation, the aqueous layer was extracted three
times with dichloromethane (10 mL). The gathered organic layers
were washed with a saturated solution of NaHCO3, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography (silica gel, cyclohex-
ane/ethyl acetate—70:30) gave imine rac-3a as a beige solid
4.4.5. rac-2-Isopropyl-2,3-dimethyl-1-oxy-5-thiophen-2-yl-2,3-
dihydro-imidazol-4-one rac-4g
The title compound was prepared as described for 4a from
hydroxylamine rac-2g (110 mg, 432 lmol). Yield: quant.; yellow
oil; dH (400 MHz; CDCl3) 8.52 (1H, d, J = 4.2 Hz), 7.58 (1H, d,
J = 4.8 Hz), 7.23 (1H, dd, J = 4.2, 4.8 Hz), 3.10 (3H, s), 2.41 (1H, hept,
J = 6.8 Hz), 1.73 (3H, s), 0.99 (6H, d, J = 6.8 Hz).
4.5. (2R⁄,5S⁄)-1-Hydroxy-2-isopropyl-2,3-dimethyl-5-p-tolyl-
imidazolidin-4-one rac-20c
(209 mg, 682 lmol, 46%). Rf 0.62 (ethyl acetate); dH (400 MHz;
CDCl3) 8.54 (2H, d, J = 8.4 Hz), 7.70 (2H, d, J = 8.4 Hz), 7.65 (2H, d,
J = 7.2 Hz), 7.47 (2H, t, J = 7.2 Hz), 7.38 (1H, t, J = 7.2 Hz), 2.98
(3H, s), 2.18 (1H, hept, J = 6.8 Hz), 1.53 (3H, s), 1.24 (3H, d,
J = 6.8 Hz), 0.58 (3H, d, J = 6.8 Hz); dC (100 MHz; CDCl3) 163.0,
162.4, 144.2, 140.6, 130.0, 129.00, 128.95, 128.0, 127.35, 127.30,
87.7, 34.7, 26.1, 22.5, 17.9, 15.7; LRMS (ESI+) m/z: 307.2 (100,
(M+H)+), 329.2 (21, (M+Na)+), 635.3 (60, (2M+Na)+).
In a 25 mL flask, nitrone 4c (210 mg, 0.81 mmol) was dissolved
in anhydrous THF (10 mL). The reaction mixture was cooled to
ꢀ20 °C (liquid N2/EtOH bath) and LiAlH4 (31 mg, 0.81 mmol) was
added. After 30 min at ꢀ20 °C, the medium was diluted with
Et2O (20 mL), carefully hydrolyzed with a saturated aqueous
Na2SO4 solution (10 mL) and filtered. The organic layer was sepa-
rated, dried over anhydrous MgSO4, and concentrated under re-
duced pressure to afford an inseparable mixture of the desired
compound and the starting material. A selected set of peaks
belonging to the title compound from the 1H NMR and LRMS of
the crude material are as follows: dH (400 MHz; CDCl3) 7.27 (2H,
d, J = 8.1 Hz), 7.17 (2H, d, J = 8.1 Hz), 4.96 (1H, s), 4.42 (1H, s),
2.79 (3H, s), 2.34 (3H, s), 1.95 (1H, hept, J = 7.1 Hz), 1.44 (3H, s),
1.08 (3H, d, J = 7.1 Hz), 0.96 (3H, d, J = 7.1 Hz); LRMS (ESI+) m/z:
263.1 (100, (M+H)+), 285.1 (20, (M+Na)+), 525.3 (40, (2M+H)+),
547.3 (70, (2M+Na)+).
4.4. Preparation of ketonitrones 4 from hydroxylamines 2
4.4.1. rac-5-Biphenyl-4-yl-2-isopropyl-2,3-dimethyl-1-oxy-2,3-
dihydro-imidazol-4-one rac-4a
In a 10 mL flask, hydroxylamine rac-2a (204 mg, 629 lmol) was
dissolved in dichloromethane (4 mL). Manganese dioxide (219 mg,
2.52 mmol, 4 equiv) was added. The reaction mixture was stirred
at room temperature for 15 min, then diluted with ethyl acetate
(4 mL), and anhydrous MgSO4 was added. The solids were filtered
over Celite and thoroughly rinsed with ethyl acetate. The gathered
filtrates were concentrated under reduced pressure to yield nitrone
rac-4a as a white solid in quantitative yield. An analytical sample
was recrystallized from cyclohexane/ethyl acetate: white crystals,
mp: 101 °C; Rf 0.62 (ethyl acetate); IR (thin film): 3059, 3033,
2967, 2924, 1702, 1557; dH (400 MHz; CDCl3) 8.89 (2H, m), 7.73–
4.6. Synthesis of L-phenylglycine
4.6.1. (S)-2-Hydroxyamino-N-methyl-2-phenyl-acetamide
hydrochloride (S)-5ꢁHCl
In a 10 mL microwave vial were introduced hydroxylamine (+)-
2b (743 mg, 3 mmol), a 12 M aqueous solution of hydrochloric acid

M. Thiverny et al. / Tetrahedron: Asymmetry 22 (2011) 1274–1281
1281
Florke, U.; Altenbach, H.-J. Org. Lett. 2001, 3, 1375–1378; (c) Baldwin, S. W.;
Long, A. Org. Lett. 2004, 6, 1653–1656.
(1.25 mL, 15 mmol) and ethanol (5 mL). The reaction mixture was
heated for 5 min at 130 °C under microwave irradiation. Removal
of the solvents under reduced pressure yielded (S)-5ꢁHCl (yellow
oil, quantitative). dH (400 MHz; CD3OD) 7.58–7.56 (2H, m), 7.50–
7.48 (3H, m), 5.05 (1H, s), 2.77 (3H, s); dC (100 MHz; CD3OD)
167.7, 131.5, 130.5, 130.3, 130.1, 58.5, 26.5; LRMS (ESI+) m/z:
148.0 (71), 163.0 (97, (M+HꢀH2O)+), 181.0 (100, (M+H)+), 203.0
(51, (M+Na)+).
4. Six-membered ring: (a) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Sakamoto, M. Chem. Commun. 1996, 1861–1862; (b) Baldwin, S.
W.; Young, B. G.; McPhail, A. T. Tetrahedron Lett. 1998, 39, 6819–6822; (c)
Heaney, F.; Fenlon, J.; O’Mahony, C.; McArdle, P.; Cunningham, D. J. Chem. Soc.,
Perkin Trans. 1 2001, 3382–3392; (d) Wang, P.-F.; Gao, P.; Xu, P.-F. Synlett 2006,
1095–1099.
5. Recent examples: (a) Romeo, G.; Iannazzo, D.; Piperno, A.; Romeo, R.; Corsaro,
A.; Rescifina, A.; Chiacchio, U. Mini-Rev. Org. Chem. 2005, 2, 59–77; (b) Manzoni,
L.; Arosio, D.; Belvisi, L.; Bracci, A.; Colombo, M.; Invernizzi, D.; Scolastico, C. J.
Org. Chem. 2005, 70, 4124–4132; (c) Tamura, O.; Mita, N.; Imai, Y.; Nishimura,
T.; Kiyotani, T.; Yamasaki, M.; Shiro, M.; Morita, N.; Okamoto, I.; Takeya, T.;
Ishibashi, H.; Sakamoto, M. Tetrahedron 2006, 62, 12227–12236; (d) Cordero, F.
M.; Bonollo, S.; Machetti, F.; Brandi, A. Eur. J. Org. Chem. 2006, 3235–3241; (e)
Weselin´ ski, Ł.; Słyk, E.; Jurczak, J. Tetrahedron Lett. 2011, 52, 381–384.
6. For carbon radical addition reactions to chiral glyoxylic nitrones, see: (a) Ueda,
M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T. Chem. Commun. 2003, 426–
427; (b) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T. J. Org. Chem.
2005, 70, 6653–6660; (c) Ueda, M.; Miyabe, H.; Nonoguchi, N.; Miyata, O.;
Tamura, O.; Naito, T. Heterocycles 2009, 79, 739–751; (d) For nucleophilic
addition of pyrroles to chiral glyoxylic nitrones, see: Berini, C.; Minassian, F.;
Pelloux-Léon, N.; Denis, J.-N.; Vallée, Y.; Philouze, C. Org. Biomol. Chem. 2008, 6,
2574–2586; (e) Berini, C.; Minassian, F.; Pelloux-Léon, N.; Denis, J.-N. Org.
Biomol. Chem. 2008, 7, 4512–4516.
7. Altenbach, H.-J.; Kottenhahn, M.; Vogt, A.; Matthäus, M.; Grundler, A.; Hahn,
M.-G. US 6 018 050, 2000: the exemplified hydroxylamine adducts were
obtained in 11–83% yield.
8. (a) Cantagrel, F.; Pinet, S.; Gimbert, Y.; Chavant, P. Y. Eur. J. Org. Chem. 2005,
2694–2701; (b) Pernet-Poil-Chevrier, A.; Cantagrel, F.; Le Jeune, K.; Philouze, C.;
Chavant, P. Y. Tetrahedron: Asymmetry 2006, 17, 1969–1974; (c) Thiverny, M.
Ph. D. Dissertation, Université de Grenoble, 2010.
4.6.2. (S)-2-Amino-N-methyl-2-phenyl-acetamide
hydrochloride (S)-6ꢁHCl
The above crude hydrochloride salt of N-hydroxy amino amide
(S)-5ꢁHCl was taken up in methanol (7 mL). A 12 M aqueous solu-
tion of HCl (370 lL, 4.5 mmol) and Pd/C 10% (200 mg) were added.
The reaction mixture was stirred under an atmospheric pressure of
H2 at room temperature for 16 h, then filtered through Celite and
concentrated to give (S)-6ꢁHCl (yellow oil, quantitative). Peaks cor-
responding to two rotamers were distinguishable in the NMR spec-
tra. dH (400 MHz; CD3OD) 7.51–7.46 (5H, m), 4.92 (1H, s), 2.76 and
2.75 (3H, s); dC (100 MHz; CD3OD) 169.3, 134.5, 130.9, 130.3,
129.1, 57.8 and 57.6, 26.6 and 26.5; LRMS (ESI+) m/z: 148.0 (36,
(M+HꢀNH3)+), 165.1 (100, (M+H)+), 187.0 (42, (M+Na)+), 351.2 (9,
(2M+Na)+). The enantiomeric purity of the free amino amide
(>98%) was determined by 1H NMR analysis (CDCl3, 400 MHz) of
6 with (S)-(+)-O-acetylmandelic acid as a chiral solvating agent;22
the separation between the two N-methyl signals was 0.05 ppm
[upfield signal for the (S)-enantiomer].
9. Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277–5292.
10. The addition of arynes to the chiral enolate derived from Schölkopf’s bislactim
ether has been described very recently: Jones, E. P.; Jones, P.; Barrett, A. G. M.
Org. Lett. 2011, 13, 1012–1015.
11. (a) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed.
4.6.3. (S)-Amino-phenyl-acetic acid (
In a 10 mL microwave vial were introduced the hydrochloride
mol) and a 6 M
aqueous solution of hydrochloric acid (1 mL). The reaction mixture
was heated for 10 min at 150 °C under microwave irradiation. After
concentration of the reaction mixture, the crude hydrochloride salt
of amino acid was adsorbed onto a DOWEX 50W-X8 ion-exchange
column. After washing with H2O and then ethanol until neutrality,
elution with a 1 M aqueous solution of NH4OH and concentration
L-phenylglycine) L-7
1998, 37, 1701–1703; For
a review, see: (b) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A.
Angew. Chem., Int. Ed. 2003, 42, 4302–4320; For iPrMgClꢁLiCl, see: (c)
Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336.
12. Demory, E.; Blandin, V.; Einhorn, J.; Chavant, P. Y. Org. Process Res. Dev. 2011,
15, 710–716.
13. Image obtained using the Mercury software: Macrae, C. F.; Bruno, I. J.;
Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.;
Taylor, R.; Van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466–470.
14. Secondary hydroxylamines can be efficiently detected by TLC by reaction with
basic triphenyltetrazolium chloride.
15. Manganese dioxide-mediated oxidation of hydroxylamines into nitrones:
Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001, 42, 6503–
6505.
16. The conversion of nitrone 4c and product composition were determined on the
basis of the 1H NMR spectrum of the crude material. The main product (>96%)
was hydroxylamine 20c; traces of diastereomer 2c and imine 3c were detected.
It should be noted that using more than 1 equiv LiAlH4 resulted in some
degradation.
salt of the amino amide (S)-6ꢁHCl (138 mg, 688
l
under vacuum gave the free amino acid L-7 (98 mg, 649 lmol,
94% yield) as a white solid. IR (ATR): 3114, 2980, 2800, 1606,
1577, 1495, 1391; dH (400 MHz; 1 N LiOD in D2O) 7.39–7.29 (5H,
m), 4.32 (1H, s); dC (100 MHz; 1 N LiOD in D2O) 178.9, 139.8,
129.0, 127.2, 128.1, 60.0; LRMS (ESI+) m/z: 135.0 (63,
(M+HꢀNH3)+), 152.0 (100, (M+H)+); HRMS (ESI+) m/z: found,
152.07048 (M+H); C8H10NO2 requires 152.07061. The enantio-
17. For a review on the asymmetric synthesis of arylglycines, see: Williams, R. M.;
Hendrix, J. A. Chem. Rev. 1992, 92, 889–917.
18. For a review on the catalytic asymmetric synthesis of a-amino acids, including
meric purity of the amino acid L-7 (60%) was determined by chiral
arylglycines, see: Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584–4671.
19. For a review on the catalytic enantioselective Strecker reaction, see: Gröger, H.
Chem. Rev. 2003, 103, 2795–2827.
20. For the metal-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl
imino esters, see: Rhodium: (a) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am.
Chem. Soc. 2006, 128, 6304–6305; Palladium: (b) Dai, H.; Lu, X. Org. Lett. 2007,
9, 3077–3080.
HPLC on a Chirex 3126 (D)-penicillamine column, 150 ꢂ 4.6 mm,
eluent methanol/2 mM CuSO4 in water—20:80, 1 mL/min, reten-
tion times: 11.05 min for the (S)-enantiomer and 19.18 min for
the (R)-enantiomer.
Acknowledgments
21. A small amount of racemization is often observed, even under mild conditions;
see Ref.10 for a recent example.
22. Benson, S. C.; Cai, P.; Colon, M.; Haiza, M. A.; Tokles, M.; Snyder, J. K. J. Org.
Chem. 1988, 53, 5335–5341.
23. (a) Maire, P.; Blandin, V.; Lopez, M.; Vallée, Y. Synlett 2003, 671–674; (b)
Lawrence, J.; Cointeaux, L.; Maire, P.; Vallée, Y.; Blandin, V. Org. Biomol. Chem.
2006, 3125–3141; (c) Lawrence, J.; Jourdan, M.; Vallée, Y.; Blandin, V. Org.
Biomol. Chem. 2008, 6, 4575–4581.
24. Schiemenz, G. P. Org. Synth. 1973, Coll. Vol. 5, 496–499.
25. Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165–168.
26. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Crystallogr.
1993, 26, 343–350.
The authors thank Beatrice Gennaro for her assistance in NMR
and Emilien Demory for his support. We are grateful to Université
Joseph Fourier and the CNRS for financial support.
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28. Note added in proof: X-ray structure of (–)-2l is also available: CCDC 836864.