Preparation of chiral key intermediates of morpholine based neurokinin receptor antagonists by asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tet.2013.05.097

Abstract The preparation of optically active morpholine-2-aryl-2-allyl derivative from morpholine-2-aryl-3-ones is reported. The optically active tetrasubstituted stereocenter is introduced during a palladium promoted asymmetric allylic alkylation. The re

Full text of DOI:10.1016/j.tet.2013.05.097

Tetrahedron 69 (2013) 6424e6430
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of chiral key intermediates of morpholine based
neurokinin receptor antagonists by asymmetric allylic alkylation
a
,
,
,b,c
Jerome Keldenich c, Audrey Denicourt-Nowicki a c, Christophe Michon a
,
ꢀ ^
Francine Agbossou-Niedercorn a
,b,c,
*
a
ꢀ
Universite Lille Nord de France, F-59000 Lille, France
b CNRS, UCCS UMR 8181, F-59655 Villeneuve d’Ascq Cedex, France
c ENSCL, CCM-CCCF, Av. Mendeleïev, CS90108, F-59652 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2013
Received in revised form 20 May 2013
Accepted 21 May 2013
Available online 28 May 2013
The preparation of optically active morpholine-2-aryl-2-allyl derivative from morpholine-2-aryl-3-ones
is reported. The optically active tetrasubstituted stereocenter is introduced during a palladium promoted
asymmetric allylic alkylation. The resulting compounds are useful intermediates in the synthesis and
development of potent NK antagonists.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkylation
Palladium
Asymmetric catalysis
Heterocycle
1. Introduction
multistep sequences to access such potent antagonists,5 a few el-
egant approaches have been developed. Nishi et al. have applied
The neurokinins (also known as tachykinins) constitute a neu-
rotransmettor peptide family covering substance P (SP), neurokinin
A (NKA) and neurokinin B (NKB), which share the common
carboxy-terminal sequence Phe-X-Gly-Leu-Met-NH2. They are
widely spread in the central and peripheral nervous systems.1 Re-
lying on the affinity of natural neurokinins, three distinct 7-
the Sharpless asymmetric dihydroxylation reaction (AD) to prepare
homochiral diols (Scheme 1A).6 A subsequent recrystallization in
the presence of
D-(ꢀ)-tartaric acid afforded an optically pure 2-aryl-
transmembrane
G protein-coupled receptor types have been
identified: NK1 (SP-preferring), NK2 (NKA-preferring), NK3 (NKB-
preferring).2 The numerous forms of mammalian neurokinin as-
sume a large number of biological activities, including muscle
contraction and relaxation, vasodilatation, secretion, activation of
the immune system, pain transmission, and neurogenic in-
flammation. Thus, antagonists of these NK receptors have attracted
a great deal of interest as potent therapeutic agents.3 Some specific
morpholine based derivatives exhibit such properties and optically
active SSR240600, SSR144190, and SSR241586 have been described
to be active against depression, emesis, irritable bowel syndrome,
schizophrenia, and urinary trouble (Fig. 1).4 To implement the
tetrasubstituted stereogenic centre of optically active 2,20-di-
substituted morpholines, which are valuable intermediates in the
* Corresponding author. Fax: þ33 (0)3 20 43 65 85; e-mail address: franci-
ne.agbossou@ensc-lille.fr (F. Agbossou-Niedercorn).
Fig. 1. Examples of morpholine based NK antagonists.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.097

J. Keldenich et al. / Tetrahedron 69 (2013) 6424e6430
6425
2-ethanol-morpholine intermediate (Scheme 1B).7 Later on, Shi-
basaki disclosed an efficient trimethylsilylcyanation reaction to
convert a keto silylether into the corresponding cyano disilylether
(Scheme 1C).8
Scheme 2. Retrosynthetic analysis for 2,20 disubstituted morpholines.
Morpholinedione III was readily prepared from 2-(benzylamino)
ethanol.14 Thus, the reaction of commercially available 2-(benzy-
lamino)ethanol (1 equiv) and diethyloxalate (1 equiv) led to dione
compound III in 61% yield after purification. The subsequent re-
action of III with the corresponding freshly prepared arylmagne-
sium bromides 1aec (1.1 equiv) afforded the cyclic hemiketals 2aec
in 65e83% yield. Then, compounds 2aec were allowed to
react with methyl iodide (1.5 equiv) in the presence of NaH
(1.5 equiv).15 After workup, the cyclic ketals 3aec were isolated in
62e89% yield.
MgBr
X
1a-c
EtO
O
OEt EtOH
O
O
N
O
X
+
Ph
THF 0 °C then
reflux, 5h
HO
NHCH2Ph
O
0°C
III
61%
65-83%
O
N
O
O
MeO
N
O
HO
N
Ph
Ph
H
Ph
O
NaH, MeI
O
TiCl4, Et3SiH
- 78°C, 3h
65-81%
THF
50 °C, 2h
62-89%
X
X
X
2a-c
3a-c
IIa-c
X
X
X
Scheme 1. Different routes to access the benzylic stereocenter of arylmorpholine
precursors.
X=H, a; F, b; Cl, c
Scheme 3. Synthesis of morpholinones.
In the mean time, Onaka described an enantioselective epoxi-
dation reaction of a homoallylic alcohol (Scheme 1D).9 Finally,
Next, a Lewis acid promoted silane reduction of ketals 3aec
furnished morpholinones IIaec. Thus, ketals 3aec were reacted
with Et3SiH (3 equiv) in the presence of TiCl4 (6 equiv) in
dichloromethane providing compounds IIaec in 65e81% yield
(Scheme 3).15 The preparation of IIaec could also be achieved in
a one step procedure from 2aec under similar conditions (3 h,
ꢀ78 ꢁC, 69e73%).
Cossy recently reported a powerful approach to convert an
ketoester into a -nitro alcohol through an organo-catalysed Henry
reaction (Scheme 1E).10
a-
b
For several years, our laboratory has been interested in the ap-
plication of asymmetric allylic alkylation to prepare quaternary
stereocenters.11,12 We applied this methodology to the preparation
of morpholines and piperidines exhibiting tetrasubstituted ster-
eocenters.13 Herein, we report our development of the asymmetric
allylic alkylation to access chiral key 2,20-substituted morpholinone
intermediates (Scheme 1).
In order to find the most appropriate conditions for the palla-
dium catalysed allylic alkylation of II, we first carried out experi-
ments to screen different bases in the presence of the diphosphine
ligand DPPB (1,4-bis(diphenylphosphino)butane) and allylpalla-
dium chloride dimer as the precatalyst (Scheme 4 and Table 1).
Among the various bases tried, the best catalytic conditions were
found by using a combination of n-BuLi and TMEDA (entry 7, 9, 16)
in conjunction with the palladium complex.
Hence, the combined use of THF and a bidentate ligand like
TMEDA proved to be crucial breaking down n-BuLi aggregates to
form monomers and dimers and thereby increasing significantly
their basicity.16 Afterwards, asymmetric allylic alkylation reactions
of IIaec were then studied in the presence of BINAP or one of the
Trost ligands and allylpalladium chloride dimer (Fig. 2 and Table 2).
2. Results and discussion
The synthesis of chiral intermediates I (R¼H, F, Cl) was meant
from asymmetric allylation of II. This morpholinone could be ob-
tained easily from morpholinedione III prepared from 2-(benzyla-
mino)ethanol (Scheme 2). We focused thus on the preparation of
optically active I.
The three substrates IIaec needed for the asymmetric allylic
alkylation reactions were prepared easily in a few steps (Scheme 3).

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J. Keldenich et al. / Tetrahedron 69 (2013) 6424e6430
Table 2
Asymmetric allylation of IIaeca
Entry
Substrate
IIa
Ligand
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
(R,R)-BINAP
45
50
65
88
90
89
84
95
93
90
83
20
40
51
26
54
60
10
46
64
83
16
(R,R)-DACH-phenyl Trost
(R,R)-DACH-naphthyl Trost
(R,R)-BINAP
(R,R)-DACH-phenyl Trost
(R,R)-DACH-naphthyl Trost
(R,R)-Anden-phenyl Trost
(R,R)-BINAP
(R,R)-DACH-phenyl Trost
(R,R)-DACH-naphthyl Trost
(R,R)-Anden-phenyl Trost
IIb
IIc
Scheme 4. Palladium catalysed allylation of morpholinones.
9
10
11
Table 1
a
Reactions were carried out in the presence of [Pd(h
3-C3H5)Cl]2 (1 mol %), chiral
Variation of the base and additives in the alkylation of IIaeca
ligand (2.2 mol %) in THF (0.15 M). The addition of the base and TMEDA was done at
ꢀ78 ꢁC and the reaction carried out at 20 ꢁC for 12 h.
Entry
Substrate
Base (equiv)
Additive (equiv)
Yield (%)b
b
Isolated yield.
1
2
3
4
IIa
LDA (1.5)
71
45
0
c
Determined by 13C NMR with Eu(hfc)3 or chiral HPLC.
LiHMDS (1.5)
(ꢀ)sparteine
NaH
2
5
6
7
8
sec-BuLi (2)
sec-BuLi (2)
n-BuLi (1.5)
n-BuLi (1.5)
n-BuLi (1.5)
LDA (1.5)
LiHMDS (1.5)
(ꢀ)-sparteine
NaH
0
ZnCl2 (1.3)
TMEDA (1)
25
95
11
95
68
49
0
6
0
27
95
IIb
IIc
9
TMEDA (1)
d
10
11
12
13
14
15
16c
d
d
d
sec-BuLi (2)
sec-BuLi (2)
n-BuLi (1.5)
d
ZnCl2 (1.3)
TMEDA (1)
a
Reactions were carried out in the presence of [Pd(
(2.2 mol %) in THF at room temperature during 4 h.
h
3-C3H5)Cl]2 (1 mol %), DPPB
b
Isolated yield.
c
Addition of the base at ꢀ78 ꢁC and reaction carried out at room temperature for
12 h.
Fig. 3. Ortep view of compound Ic with ellipsoids drawn at 50% probability level.17
In order to convert the most interesting chiral allyl intermediate
Ic to aldehyde 5c, we carried out, first, the reduction of morpholi-
none Ic with lithium aluminium hydride in a 70% yield (Scheme 5).
The allyl moiety of the corresponding morpholine 4c was then
oxidized in a two steps procedure using N-methylmorpholine-N-
oxide along with a catalytic amount of osmium tetroxide followed
by addition of sodium periodate. After workup, the aldehyde 5c was
isolated in 79% yield and the synthesis of SSR240600 may be per-
formed in a few steps.
Fig. 2. Chiral Trost ligands used.
O
N
O
N
O
Ph
Ph
LiAlH4 (2.5 equiv)
Whether yields were average to good for all substrates, enan-
tioselectivities were rather modest to average in most cases. The
highest optical purities were obtained with DACH-Naphthyl Trost
ligand (entries 3, 6, 10), the two other Trost ligands as well as BINAP
being not well designed for this transformation. With a 83% ee for Ic
(entry 9), reagent IIc afforded the highest enantioselectivity.
The absolute configuration of Ic, which was the most promising
intermediate of the series, could be determined by X-ray structure
determination of a single crystal.17 The allyl derivative Ic obtained
from the (R,R)-DACH-Napthyl ligand has a (R)-configuration similar
to the C2 stereocenter of the morpholine heterocycle in SSR240600
(Fig. 3).
THF, reflux, 2h
70%
Cl
4c
Cl
Ic
Cl
Cl
i) NMO (3 equiv)
OsO4 (1 mol%)
THF/H2O 1:1, rt, 2h
O
N
OHC
Ph
ii) NaIO4 (2 equiv)
acetone/H2O 3:1, rt, 2h
Cl
79%
5c
Cl
Scheme 5. Synthesis of chiral aldehyde 5.

J. Keldenich et al. / Tetrahedron 69 (2013) 6424e6430
6427
3. Conclusion
After complete crystallization, 2a was isolated through filtration as
a white powder (4.71 g, 83%). Mp 106 ꢁC; Rf (ethyl acetate) 0.85; 1H
NMR (300 MHz CDCl3) 3.17 (1H, m, CHaHbN), 3.63 (1H, m, CHaHbN),
3.87 (1H, m, CHaHbO), 4.28 (1H, ddd, J 11.9,11.0 and 3.2 Hz, CHaHbO),
4.49 (1H, d, J 14.4 Hz, CHaHbPh), 4.65 (1H, d, J 14.4 Hz, CHaHbPh),
7.22e7.64 (10H, m, Haryl); 13C NMR (75 MHz CDCl3) 46.4, 50.4, 58.9,
97.1, 126.3, 127.8, 128.0, 128.1, 128.3, 128.6, 128.9, 135.9, 140.9, 168.0.
Anal. Calcd for C17H17NO3 C, 72.07; H, 6.05; N, 4.94. Found C, 71.90;
H, 6.00; N, 5.00.
In summary, we have developed a promising route to chiral 2,20-
substituted morpholinones, which are key intermediates of potent
neurokinin antagonists, exhibiting a tetrasubstituted stereocenter.
To access the desired (R)-configuration of such building blocks, the
palladium catalysed asymmetric allylic alkylation proved to be an
interesting methodology and the highest selectivities were up to
83% ee. Further investigations are under way to apply this meth-
odology to the preparation of lactams bearing also a quaternary
stereocenter.13c
4.4. 4-Benzyl-2-(3,4-difluorophenyl)-2-hydroxy-morpholin-
3-one (2b)
4. Experimental section
A solution of 4-bromo-1,2-difluorobenzene (3.09 g, 1.81 mL,
16 mmol) in THF (15 mL) was added dropwise over magnesium
turnings (0.39 g, 16 mmol) at room temperature under vigorous
stirring. The mixture was stirred during 3 h at room temperature.
The resulting solution was then transferred to a THF (10 mL) so-
lution of morpholinedione III (3.01 g, 14.6 mmol). The reaction
mixture was heated under reflux during 5 h. After cooling, HCl
(30 mL, 1 M) was added. The product was extracted with
dichloromethane (2ꢂ30 mL). The combined organic phases were
washed with brine (30 mL) and dried over anhydrous MgSO4. After
filtration and concentration under reduced pressure, hexane was
added until precipitation started. After complete crystallization
(24 h), the isolated solid was purified through silica gel column
chromatography (ethyl acetate) providing 2b as a white solid
(3.11 g, 66%). Rf (ethyl acetate) 0.75; 1H NMR (300 MHz CDCl3) 3.19
(1H, br d, J 11.0 Hz, CHaHbN), 3.66 (1H, ddd, J 15.0, 11.0, and 4.0 Hz,
CHaHbN), 3.92 (1H, m, CHaHbO), 4.31 (1H, ddd, J 15.0, 11.0, and
3.1 Hz, CHaHbO), 4.46 (1H, d, J 14.4 Hz, CHaHbPh), 4.68 (1H, d, J
14.4 Hz, CHaHbPh), 7.13e7.33 (8H, m, Haryl); 13C NMR (75 MHz
CDCl3) 46.5, 50.6, 59.0, 65.5, 116.2 (dd, J 13.8 and 5.9 Hz), 116.84 (dd,
J 14.3 and 5.8 Hz),122.9,128.1,128.3,128.6, 129.0,129.2,135.7,138.0,
148.3 (dd, J 11.2 and 3.5 Hz), 153.4 (dd, J 12.1 and 5.3 Hz), 167.5; 19F
NMR (282 MHz CDCl3) ꢀ137.7 (d, J 21.0 Hz), ꢀ137.8 (d, J 21.0 Hz).
Anal. Calcd for C17H15F2NO3 C, 63.95; H, 4.74; N, 4.39. Found C,
63.86; H, 4.78; N, 4.43.
4.1. General remarks
All solvents were dried using standard methods, distilled over
CaH2 and stored over molecular sieves (4 A). H, 13C, and 19F NMR
spectra were recorded on a Bruker Avance spectrometer at 300,
75.5, and 282 MHz, respectively. The chemical shifts of the 1H NMR
and 13C are reported relative to the residual signal of CDCl3. 19F NMR
chemical shifts are referenced externally relative to CFCl3
(ꢀ63 ppm). All coupling constants (J) are reported in Hertz (Hz). All
commercially chemicals were used as received without further
purification. Thin layer chromatography was performed on Merck
pre-coated 0.20 mm silica gel Alugram Sil 60 G/UV254 plates and
visualization effected with short wavelength UV light (254 nm).
Flash chromatography was carried out with Macherey silica gel
(Kielselgel 60). Melting points were determined using a Barnstead
Electrothermal (BI 9300) apparatus and were uncorrected. Infrared
spectra were recorded on a ThermoScientific-Nicolet 6700 spec-
trometer; the samples being prepared with KBr powder. HPLC
analysis was performed on a Thermo Finnigan apparatus using
Daicel ChiralpakÔ IA column and a diode array detector set to 200,
220 and 254 nm. HRMS analyses were performed at CUMA-Pharm.
Dept.-University Lille Nord de-France. Elemental analyses were
performed by the Service Central d’Analyses, CNRS, Solaize.
1
ꢁ
4.2. 4-Benzyl-morpholine-2,3-dione (III)
4.5. 4-Benzyl-2-(3,4-dichlorophenyl)-2-hydroxy-morpholin-
3-one (2c)
A solution of diethyloxalate (32 g, 0.22 mol) in ethanol (15 mL)
was added dropwise at 0 ꢁC to a solution of 2-(benzylamino)eth-
anol (11.35 g, 75 mmol) in ethanol (50 mL). The mixture was stirred
at 0 ꢁC for 1 h, at room temperature for 2 h, and finally at reflux for
1 h. After cooling, the product was precipitated from the crude
reaction mixture through addition of petroleum ether providing III
as a white solid (27.34 g, 61%). Mp 94 ꢁC; 1H NMR (300 MHz CDCl3)
3.53 (1H, dd, J 5.4 and 5.2 Hz, CHaHbN), 3.55 (1H, dd, J 5.4 and
5.2 Hz, CHaHbN), 4.41 (1H, dd, J 6.0 and 5.1 Hz, CHaHbO), 4.43 (1H,
dd, J 6.0 and 5.1 Hz, CHaHbO), 4.69 (2H, s, CH2Ph), 7.26e7.32 (5H, m,
Haryl); 13C NMR (75 MHz CDCl3) 44.0, 50.6, 65.5, 128.5, 128.6, 129.1,
134.6, 153.8, 156.9. Anal. Calcd for C11H11NO3C, 64.20; H, 5.35; N,
6.90. Found C, 64.38; H, 5.40; N, 6.82%.
A solution of 1-bromo-3,4-dichlorobenzene (6.14 g, 27 mmol) in
THF (25 mL) is added dropwise on magnesium turnings (0.66 g,
27 mmol) at roomtemperature. The formed Grignard reagent is then
added to a solution of morpholinedione III (5 g, 24 mmol) in THF
(25 mL). The reaction mixture was stirred at reflux for 5 h. After
addition of HCl (45 mL,1 M), the product was extracted with CH2Cl2
(2ꢂ45 mL). The combined organic phases were washed with brine
(45 mL) and dried over anhydrous MgSO4. The solvent was evapo-
rated under reduced pressure to give the crude product, which was
recrystallized in hexane and then purified by flash chromatography
(ethyl acetate) providing 2c as a white solid (6.80 g, 65%). Rf (ethyl
acetate) 0.75; 1H NMR (300 MHz CDCl3) 3.19 (1H, d, J 11.2 Hz,
CHaHbN), 3.66 (1H, td, J 11.2 and 4.1 Hz, CHaHbN), 3.91 (1H, d, J
11.9 Hz, CHaHbO), 4.31 (1H, td, J 11.9 and 4.1 Hz, CHaHbO), 4.46 (1H, d,
J 14.4 Hz, CHaHbPh), 4.68 (1H, d, J 14.4 Hz, CHaHbPh), 7.1e7.42 (8H, m,
Haryl); 13C NMR (75 MHz CDCl3) 46.3, 50.5, 59.1, 65.3, 109.7e110.7,
123e121, 129.4, 131.7, 161.0. Anal. Calcd for C17H15Cl2NO3: C, 57.97;
H, 4.29; N, 3.98. Found C, 58.22; H, 4.33; N, 4.04.
4.3. 4-Benzyl-2-phenyl-2-hydroxy-morpholin-3-one (2a)
A
solution of 4-benzyl-morpholine-2,3-dione III (4.10 g,
20 mmol) in THF (50 mL) was cooled to 0 ꢁC. Commercially avail-
able phenylmagnesium bromide (20 mL, 1 M in THF, 1.1 equiv) was
added dropwise. The reaction mixture was stirred at 0 ꢁC during 1 h
and then 3.5 h at room temperature. Hydrolysis of the medium was
carried out through addition of HCl (20 mL, 1 M). The product was
then extracted with dichloromethane (2ꢂ20 mL). The combined
organic phases were washed with brine and dried over anhydrous
MgSO4. After filtration and concentration under reduced pressure,
addition of hexane was performed until a precipitation started.
4.6. 4-Benzyl-2-phenyl-2-methoxy-morpholin-3-one (3a)
A suspension of NaH (1.2 g, 70% w/w dispersion in oil,
29.7 mmol, washed twice with dry n-pentane) in THF (50 mL) was
added dropwise to a solution of 2a (5.6 g, 19.9 mmol) and methyl

6428
J. Keldenich et al. / Tetrahedron 69 (2013) 6424e6430
iodide (4.22 g, 29.7 mmol) in THF (50 mL) over a period of 10 min.
After stirring of the mixture at 50 ꢁC for 2 h, water (35 mL) was
added slowly. The solvent was removed under reduced pressure.
The product was extracted with CH2Cl2 (2ꢂ50 mL). The combined
organic phases were washed with brine (30 mL) and dried over
anhydrous MgSO4. After evaporation of the solvent and silica gel
flash column chromatography (ethyl acetate/petroleum ether 1:1)
3a was obtained (3.63 g, 62%). Rf (ethyl acetate/petroleum ether
1:1) 0.41. 1H NMR (300 MHz CDCl3) 3.2 (4H, m, CHaHbN and OCH3),
3.65 (1H, ddd, J 12.1, 6.0, and 2.4 Hz, CHaHbN), 3.92 (1H, dd, J 11.7
and 4.3 Hz, CHaHbO), 4.24 (1H, m, CHaHbO), 4.23 (1H, d, J 14.3 Hz,
CHaHbPh), 4.83 (1H, d, J 14.3 Hz, CHaHbPh), 7.21e7.39 (8H, m, Haryl),
7.73 (2H, m, Haryl); 13C NMR (75 MHz CDCl3) 46.1, 49.7, 50.2, 58.1,
127.8, 128.1, 128.3, 128.8, 136.3, 136.8, 166.0. Anal. Calcd for
C18H19NO3 C, 72.71; H, 6.44; N, 4.71. Found C, 72.92; H, 6.50; N, 4.66.
3.97 (1H, ddd, J 12.1, 7.7, and 4.4 Hz, CHaHbO), 4.67 (2H, s, CH2Ph),
5.26 (1H, s, CHO), 7.32e7.50 (10H, m, Haryl); 13C NMR (75 MHz
CHCl3) 45.9, 49.8, 61.6, 79.4, 128.1, 127.7, 127.6, 128.2, 136.2, 138.3,
167.3. Anal. Calcd for C17H17NO2 C, 76.38; H, 6.41; N, 5.24. Found C,
76.52; H, 6.35; N, 5.29.
4.10. 4-Benzyl-2-(3,4-difluorophenyl)-morpholin-3-one (IIb)
Compound IIb was prepared following an identical procedure as
for the synthesis of IIa described above (1.72 g, 65%). Rf (ethyl ac-
etate/petroleum ether 1:2) 0.65; 1H NMR (300 MHz CDCl3) 3.27
(1H, ddd, J 12.5, 4.1, and 3.2 Hz, CHaHbN), 3.49 (1H, ddd, J 12.2, 8.4,
and 4.1 Hz, CHaHbN), 3.59 (1H, ddd, J 12.5, 8.4, and 4.4 Hz, CHaHbO),
3.99 (1H, ddd, J 12.2, 4.4, and 3.2 Hz, CHaHbO), 4.58 (1H, d, J 14.4 Hz,
CHaHbPh), 4.68 (1H, d, J 14.4 Hz, CHaHbPh), 5.18 (1H, s, CHO),
7.10e7.41 (8H, m, Haryl); 13C NMR (75 MHz CDCl3) 46.3, 50.3, 62.4,
78.4, 117.2 (dd, J 12.8 and 18.2 Hz), 124.2 (dd, J 6.4 and 3.9 Hz), 128.2,
128.6, 129.1, 134.4 (dd, J 5.7 and 3.6 Hz), 136.3, 148.0 (dd, J 11.3 and
3.1 Hz), 152.9 (dd, J 11.3 and 4.6 Hz), 167.1; 19F NMR (282 MHz,
CDCl3) ꢀ137.8 (d, J 21.0 Hz), ꢀ138.8 (d, J 21.0 Hz). Anal. Calcd for
C17H15F2NO2 C, 67.32; H, 4.98; N, 4.62. Found C, 67.50; H, 5.06; N,
4.66.
4.7. 4-Benzyl-2-(3,4-difluorophenyl)-2-methoxy-morpholin-
3-one (3b)
Compound 3b was prepared following an identical procedure as
for the synthesis of 3a (1.45 g, 88%). Rf (ethyl acetate) 0.75. 1H NMR
(300 MHz CDCl3) 3.14 (3H, s, OCH3), 3.17 (1H, m, CHaHbN), 3.65 (1H,
ddd, J 11.9, 11.9 and 4.4 Hz, CHaHbN), 3.92 (1H, br dd, J 11.4 and
4.4 Hz, CHaHbO), 4.20 (1H, dd, J 11.9 and 3.0 Hz, CHaHbO), 4.24 (1H,
d, J 14.6 Hz, CHaHbPh), 4.83 (1H, d, J 14.6 Hz, CHaHbPh), 7.15e7.25
(6H, m, Haryl), 7.29e7.31 (2H, m, Haryl); 13C NMR (75 MHz CDCl3)
43.1, 45.9, 50.2, 51.6, 116.6 (dd, J 23.5 and 3.8 Hz), 117.6 (dd, J 26.4
and 2.0 Hz), 124.6 (dd, J 9.5 and 5.9 Hz), 127.8, 128.2, 128.7, 128.8,
133.9 (dd, J 8.1 and 5.0 Hz), 136.0, 148.0 (dd, J 11.6 and 4.3 Hz), 150.9
(dd, J 11.3 and 3.9 Hz), 171.1; dF (282 MHz CDCl3) ꢀ138.2 (d, J
21.0 Hz), ꢀ138.0 (d, J 21.0 Hz). Anal. Calcd for C18H17F2NO3 C, 64.86;
H, 5.14; N, 4.20. Found C, 64.98; H, 5.22; N, 4.28.
4.11. 4-Benzyl-2-(3,4-dichlorophenyl)-morpholin-3-one (IIc)
Compound IIc was prepared following the procedure reported
above for the synthesis of IIa (colourless oil, 3.43 g, 73%). Rf (ethyl
acetate/petroleum ether 1:2) 0.85; 1H NMR (300 MHz CDCl3) 3.24
(1H, ddd, J 12.4, 4.0, and 3.9 Hz, CHaHbN), 3.46 (1H, ddd, J 12.3, 8.1,
and 4.4 Hz, 1H, CHaHbN), 3.82 (1H, ddd, J 12.1, 8.3, and 3.7 Hz,
CHaHbO), 3.95 (1H, ddd, J 12.1, 4.4, and 4.1 Hz, CHaHbO), 4.53 (1H, d, J
14.5 Hz, CHaHbPh), 4.65 (1H, d, J 14.5 Hz, CHaHbPh), 5.15 (1H, s,
CHO), 7.23 (2H, m, Haryl), 7.31 (4H, m, Haryl), 7.40 (1H, d, J 8.4 Hz,
Haryl), 7.57 (1H, d, J 2.2 Hz, Haryl); 13C NMR (75 MHz CDCl3): 46.0,
50.2, 62.3, 78.3, 127.3, 128.0,128.4,132.5,132.6,136.1,137.6,166.8. IR
(KBr): 3094, 3025, 2988, 2960, 2921, 1684, 1653, 1484, 1472, 1448,
1199, 1030, 802, 749, 728 cmꢀ1. HRMS (ESI): m/z calcd for
C17H16O2NCl2 [MHþ]: 336.05526; found: 336.05510. Anal. Calcd for
C17H15Cl2NO2 C, 60.73; H, 4.50; N, 4.17. Found C, 60.85; H, 4.55; N,
4.23.
4.8. 4-Benzyl-2-(3,4-dichlorophenyl)-2-methoxy-morpholin-
3-one (3c)
Compound 3c was prepared following an identical procedure as
for the synthesis of 3a (1.47 g, 89%). Rf (ethyl acetate) 0.75; 1H NMR
(300 MHz CDCl3) 3.13 (3H, s, OCH3), 3.19 (1H, d, J 11.0 Hz, CHaHbN),
3.66 (1H, dd, J 11.2 and 4.07 Hz, CHaHbN), 3.91 (1H, d, J 11.9 Hz,
CHaHbO), 4.31 (1H, dd, J 11.0 and 3.1 Hz, CHaHbO), 4.46 (1H, d, J
14.6 Hz, CHaHbPh), 4.80 (1H, d, J 14.6 Hz, CHaHbPh), 7.15e7.42 (8H, m,
Haryl); 13C NMR (75 MHz CDCl3) 46.1, 49.3, 55.8, 58.1, 109.7e110.7,
121.0e129.4, 131.7, 133.5, 133.9, 136.8, 167.8. Anal. Calcd for
C18H17Cl2NO3 C, 59.03; H, 4.68; N, 3.82. Found C, 59.20; H, 4.63; N,
3.89.
4.12. General procedure for asymmetric allylic alkylation
In a Schlenk tube, the morpholine substrate (1 mmol) was dis-
solved in THF (4 mL). The solution was cooled to ꢀ78 ꢁC and n-BuLi
(0.45 mL, 1.5 mmol) and TMEDA (0.15 mL, 1.5 mmol) were added.
The solution was stirred at ꢀ78 ꢁC for 1 h and then charged with
a solution containing [Pd(allyl)Cl]2 (3.7 mg, 0.01 mmol), the se-
lected chiral ligand (0.022 mmol) and allyl acetate (0.16 mL,
1.5 mmol) in THF (2 mL). The reaction mixture was stirred under
nitrogen at ꢀ78 ꢁC for 2 h. The cooling bath was removed and the
reaction was allowed proceeding at room temperature for 12 more
hours. The reaction was followed by GPC (column BPX-5, 230 ꢁC).
The reaction mixture was quenched with a NH4Cl saturated solu-
tion (5 mL) and water (10 mL). The organic phase was extracted
with ethyl acetate (3ꢂ15 mL). The combined organic phases were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified through silica gel col-
umn chromatography (ethyl acetate/petroleum ether 1:1) affording
the allyl derivative. The enantiomeric excess was determined by 13C
NMR with Eu(hfc)3 or by HPLC methods.
4.9. 4-Benzyl-2-phenyl-morpholin-3-one (IIa)
At ꢀ78 ꢁC and under nitrogen, TiCl4 (14.7 g, 8.53 mL, 69 mmol,
6 equiv) was added, via cannula and dropwise, to a solution of
dichloromethane (20 mL) containing compound 3a (4.07 g,
13.7 mmol). Then, a solution of triethylsilane (4.01 g, 6.2 mL,
34.5 mmol, 3 equiv) in dichloromethane (10 mL) was added
atd78 ꢁC under nitrogen. The reaction mixture was stirred during
3 h at ꢀ78 ꢁC and then 30 min at room temperature after removal of
the cold bath. The reaction was quenched by slow addition of water
(18 mL). The desired product was extracted with dichloromethane
(2ꢂ30 mL). The combined organic phases were dried over anhy-
drous Na2SO4. After removal of the solvent under reduced pressure,
IIa was obtained as a colourless oil. After purification though silica
gel column chromatography (ethyl acetale/petroleum ether 1:2),
IIa was isolated as a white solid (2.96 g, 81%). Mp 65 ꢁC; Rf (ethyl
acetate/petroleum ether 1:1) 0.85; 1H NMR (300 MHz CDCl3) 3.28
(1H, ddd, J 12.1, 4.3, and 4.4 Hz, CHaHbN), 3.48 (1H, ddd, J 12.2, 7.7,
and 4.4 Hz, CHaHbN), 3.83 (1H, ddd, J 12.2, 7.7, and 4.3 Hz, CHaHbO),
4.13. 2-Allyl-4-benzyl-2-phenyl-morpholin-3-one (Ia)
65% yield. 1H NMR (300 MHz CDCl3) 2.64 (1H, m, CHaHbCH]
CH2), 2.99 (2H, m, CHaHbN and CHaHbCH]CH2), 3.53 (1H, m,

J. Keldenich et al. / Tetrahedron 69 (2013) 6424e6430
6429
CHaHbN), 3.77 (2H, m, CH2O), 4.67 (2H, s, CH2Ph), 5.11 (2H, m, CH]
CH2), 5.84 (1H, m, CH]CH2), 7.25e7.37 (8H, m, Haryl), 7.67e7.70
(2H, m, Haryl); 13C NMR (75 MHz CDCl3) 46.5, 46.7, 50.2, 59.4, 84.0,
126.3, 127.7, 127.8, 128.3, 128.5, 128.8, 133.4, 136.6, 140.9, 168.8.
Anal. Calcd for C20H21NO2 C, 78.15; H, 6.89; N, 4.56. Found C, 78.30;
H, 6.97; N, 4.50.
53.9, 58.9, 62.1, 63.3, 77.0, 118.6, 126.5, 127.5, 128.5, 120.3, 129.4,
130.1, 130.5, 137.8, 143.6.
To a solution of intermediate 4c (0.750 g, 2.2 mmol) in THF/H2O
(v/v: 1:1) (30 mL) was added dropwise OsO4 (0.20 mL of a solution
of 4% OsO4 in H2O, 0.02 mmol). The resulting black solution was
then stirred for 5 min before addition of NaIO4 (1.87 g, 8.7 mmol) in
little portions over a period of 2 h. After an additional stirring pe-
riod of 2 h, addition of a saturated solution of Na2S2O3 (26 mL),
stirring of 30 min, dilution with Et2O (40 mL) and washing with
brine (26 mL), extraction by Et2O, drying (MgSO4) and evaporation
gave a yellow oil, which was purified by silica gel flash chroma-
tography (ethyl acetate/petroleum ether 1:1), to give a colourless
4.14. 2-Allyl-4-benzyl-2-(3,4-difluoro-phenyl)-morpholin-3-
one (Ib)
89% yield. 1H NMR (300 MHz CDCl3) 2.59 (1H, dd, J 14.1 and
7.0 Hz, CHaHbCH]CH2), 2.93 (1H, dd, J 14.1 and 7.0 Hz, CHaCHbCH]
CH2), 3.02 (1H, m, CHaHbN), 3.53 (1H, ddd, J 11.7, 11.2, and 4.5 Hz,
CHaHbN), 3.7 (1H, ddd, J 11.5, 11.2, and 3.2 Hz CHaHbO), 3.84 (1H, m,
CHaCHbO), 4.61 (1H, d, J 14.4 Hz, CHaHbPh), 4.67 (1H, d, J 14.4 Hz,
CHaHbPh), 5.1 (2H, m, CH]CH2), 5.8 (1H, m, CH]CH2), 7.1e7.6 (8H,
m, Haryl); 13C NMR (75 MHz CDCl3) 46.5, 46.8, 50.4, 59.7, 83.1, 115.5
(d, J 19.1 Hz), 117.0 (d J 17.1 Hz), 119.1, 122.5 (dd, J 3.5 and 1.5 Hz),
127.9, 128.3, 128.9, 132.7, 136.4, 138.0, 148.4 (dd, J 29.2 and 12.2 Hz),
151.7 (dd, J 27.0 and 12.7 Hz), 168.4; 19F NMR (282 MHz CDCl3)
ꢀ137.5 (d, J 21.3 Hz), ꢀ139.7 (d, J 21.3 Hz). Anal. Calcd for
C20H19F2NO2 C 69.96; H 5.58; N 4.08. Found C, 69.45; H, 5.67; N, 3.99.
oil (0.66 g, 79%). [
a
]
20 þ102 (c 11.0 mM, CH2Cl2, for 83% ee). 1H NMR
D
(300 MHz CDCl3) 2.48 (1H, d, J 11.7 Hz, NCHaHbC), 2.54 (2H, t, J
4.9 Hz, CH2NCH2), 2.63 (1H, dd, J 15.7 and 2.3 Hz, CHaHbCHO), 2.83
(1H, br d, J 12.6 Hz, NCHaHbC), 3.04 (1H, br dd, J 15.7 and 3.1 Hz,
CHaHbCHO), 3.42 (1H, d, J 13.1 Hz, CHaHbPh), 3.59 (1H, d, J 13.1 Hz,
CHaHbPh), 3.75 (1H, m, CHaHbO), 3.85 (1H, m, CHaHbO), 7.17 (1H, dd,
J 8.4 and 2.4 Hz), 7.33 (5H, m, Haryl), 7.43 (2H, 2d, J 5.7, J 5.3, Haryl),
9.62 (1H, t, J 3.0 Hz, HC]O); 13C NMR (75 MHz CDCl3) 53.5, 59.7,
59.8, 62.2, 63.1, 75.9, 125.7, 127.7, 128.6, 128.7, 129.2, 130.6, 131.7,
132.9, 137.4, 142.8, 200.7.
IR (KBr): 3028, 2965, 2873, 2766,1722,1469,1461,1138, 818, 791,
747 cmꢀ1. MS (ESI): m/z 320.0597 [MHþꢀCH2CHO], 364.0859
[MHþ], 396.1117 [MHþþCH3OH]. HRMS (ESI): m/z calcd for
C19H20Cl2NO2 [MHþ]: 364.08656; found: 364.08585.
4.15. 2-Allyl-4-benzyl-2-(3,4-dichloro-phenyl)-morpholin-3-
one (Ic)
20
90% yield. [
a]
ꢀ32 (c 2.8 mM, CH2Cl2, for 83% ee). 1H NMR
D
Acknowledgements
(300 MHz CDCl3) 2.59 (1H, dd, J 14.3 and 6.7 Hz, CHaHbCH]CH2),
2.94 (1H, dd, J 14.3 and 7.1 Hz, CHaHbCH]CH2), 3.03 (1H, ddd, J 11.8,
3.3, and 1.8, CHaHbN), 3.54 (1H, dd, J 11.3, 11.7, and 3.5 Hz, CHaHbO),
3.70 (1H, ddd, J 11.4, 11.1, and 3.3 Hz, CHaHbO), 3.85 (1H, m,
CHaHbN), 4.62 (1H, d, J 14.3 Hz, CHaHbPh), 4.68 (1H, d, J 14.6 Hz,
CHaHbPh), 5.10 (2H, m, CH]CH2), 5.78 (1H, m, CH]CH2), 7.29 (5H,
m, Haryl), 7.43 (1H, d, J 8.1 Hz, Haryl), 7.58 (1H, dd, J 8.5 and 2.3 Hz,
Haryl), 7.81 (1H, d, J 2.0 Hz, Haryl); 13C NMR (75 MHz CHCl3) 46.4,
46.6, 50.4, 59.7, 83.1, 119.3, 126.0, 127.9, 128.3, 128.5, 128.9, 130.4,
132.0, 132.6, 132.7, 136.3, 141.3, 168.1. IR (KBr): 3075, 3029, 2924,
1653, 1484, 1465, 1190, 1030, 995, 920, 825, 786, 727 cmꢀ1. HRMS
(ESI): m/z calcd for C20H20Cl2NO2 [MHþ]: 376.0870; found:
376.0870. Anal. Calcd for C20H19Cl2NO2 C, 63.84; H, 5.09; N, 3.72.
Found C, 63.92; H, 5.14; N, 3.68. HPLC (DAICEL CHIRALPAK OJ-H,
We are grateful to Sanofi-Aventis with Prof. B. Castro and Dr. G.
Ricci for supporting this work (Ph-D fellowships to J.K and A.N).
Support from CNRS is also greatly appreciated. Dr. P. Roussel and Dr.
F. Capet are thanked for the X-ray diffraction analysis. Mrs. N. Duhal
(CUMA, Pharm. Dept., Univ. Lille Nord de France) is thanked for
mass analyses.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.097.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
hexane/i-PrOH¼9/1, 0.3 mL/min, 200 nm) tR (major,
R
enantiomer)¼41.4 min, tR (minor, S enantiomer)¼49.4 min.
References and notes
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