Diastereoselective synthesis of aryl and alkyl trans-glycidic amides from pseudoephedrine-derived sulfonium salt. Chemospecific exo-tet ring closure for morpholin-3-ones

Article abstract of DOI:10.1016/j.tet.2012.09.047

A regiospecific and high diastereoselective synthesis of trans-glycidic amides coming from a common pseudoephedrine sulfonium salt 2 precursor is presented. This is the first example in where the diastereoselectivity is controlled by a chiral noncyclic am

Full text of DOI:10.1016/j.tet.2012.09.047

Tetrahedron 68 (2012) 10252e10256
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective synthesis of aryl and alkyl trans-glycidic amides from
pseudoephedrine-derived sulfonium salt. Chemospecific exo-tet ring closure for
morpholin-3-ones
a
a
a
a
a
b
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David M. Aparicio , Dino Gnecco , Jorge R. Juarez , María L. Orea , Angel Mendoza , Noemí Waksman ,
b
c
a,
*
ꢀ
Ricardo Salazar , Marcos Fores-Alamo , Joel L. Teran
Centro de Química, Benemerita Universidad Autonoma de Puebla, Edif. 103H Complejo de Ciencias, C.U., 72570 Puebla, Pue., Mexico
Departamento de Química Analítica, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, 2316, Sucursal Tecnologico de Monterrey, N.L., 64841 Mexico
Facultad de Química, Universidad Nacional Autonoma de Mexico, 04510 Mexico, DF, Mexico
a
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ꢀ
b
c
ꢀ
ꢀ
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a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2012
Received in revised form 8 September 2012
Accepted 11 September 2012
Available online 20 September 2012
A regiospecific and high diastereoselective synthesis of trans-glycidic amides coming from a common
pseudoephedrine sulfonium salt 2 precursor is presented. This is the first example in where the dia-
stereoselectivity is controlled by a chiral noncyclic amide fragment. The epoxidation reaction provides
alkyl or aryl glycidic amides in good to excellent yields and exclusive trans selectivity. Finally, through of
a chemospecific 6-exo-tet ring closure of trans-epoxyamides we access to morpholin-3-ones densely
functionalized with excellent chemical and stereochemical yields.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
trans-Glycidic amides
Diastereoselective
Chemospecific
6-exo-tet Ring closure
Morpholin-3-ones
1. Introduction
aromatic trans-glycidic amides in good to excellent yields, however,
with very low diastereoselectivity.11
Glycidic amides are important building blocks in organic syn-
thesis. There are different methods for their preparation; via an
In order to improve the diastereomeric excess we turned our
attention to explore other chiral amines. In this sense, (S,S)-
(þ)-pseudoephedrine, which is a commercially and inexpensive
chiral available reagent, has provided excellent results as chiral
auxiliary in several CeC and CeX bond-forming reactions. Specif-
ically, amides derived from this amino alcohol have been employed
as nucleophiles via their corresponding enolates.12
oxidation route of the corresponding
a direct oxidation of tertiary allylamine,2 by a Darzens condensation
of
-haloacetamides,3 -diazoacetamides,4 ammoniumacetamides5
a,b
-unsaturated amide,1 by
a
a
with carbonyl compounds or by a condensation of an amide-
stabilized sulfonium ylide with an aldehyde.6
Specifically, amide-stabilized sulfonium ylides, have attracted
great attention because react with aldehydes to give glycidic am-
ides with high degree of trans selectivity.7 The induction of chirality
may be achieved either at the aldehyde,7b,8 at the sulfide frag-
ment,6c,d,9 or at the chiral cyclic sulfur ylide type.10
The reaction is general for aromatic aldehydes, but aliphatic
aldehydes gave more variable enantioselectivities and a mixture of
cis- and trans-isomers has been obtained.9b,10b
Taking into account this impressive precedent, herein we report
the first example in where, the asymmetric epoxidation is con-
trolled by a chiral acyclic amide fragment, precisely sulfur ylide
derived from (S,S)-(þ)-pseudoephedrine gives aliphatic and aro-
matic trans-glycidic amides in good to excellent yields and high
diastereoselectivity.
Finally, in order to demonstrate the valuable utility of these
glycidic amides, we make the chemospecific 6-exo-tet ring closure
obtaining the corresponding morpholin-3-one compounds densely
functionalized.
In this way, we previously reported that stabilized sulfur ylides
derived from (S)- or (R)-phenylethylamine afford aliphatic or
2. Results and discussion
Chiral sulfonium salt 2 was synthesized in two steps starting
from pseudoephedrine in 95% overall yield (Scheme 1).
* Corresponding author. Tel.: þ52 222 229 5500x7277; fax: þ52 222 229 5551;
ꢀ
e-mail address: joel.teran@correo.buap.mx (J.L. Teran).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.047

D.M. Aparicio et al. / Tetrahedron 68 (2012) 10252e10256
10253
As the determination of the absolute or relative stereochemistry
at epoxide function proved to be difficult at this stage, the regio-
specific 6-exo-tet ring closure was tested following the procedure
previously described by us based on the in situ sodium alkoxide
formation accessing to the morpholinone ring.11b
Firstly, trans-epoxyamide 3 was treated with sodium in anhy-
drous tetrahydrofuran giving the desired cyclic compound after
30 min. The NMR analysis of the crude reaction showed exclusively
the presence of the corresponding diastereomeric mixture of
morpholin-3-ones 13a/13b in a 95:5 ratio and 95% yield (entry 1,
Table 3). Diastereomers were easily separated by chromatographic
column. Fortunately, the major diastereoisomer 13a crystallized,
enabling the determination of its absolute configuration and the
confirmation of the presence of the morpholinone ring by X-ray
diffraction analysis (Fig. 1).15
Scheme 1.
With chiral sulfonium salt 2 in hand we proceeded to investigate
the asymmetric epoxidation with benzaldehyde (Table 1).
Table 1
Effect of the base, solvent, temperature, and time on conversion
Table 3
Intramolecular 6-exo-tet ring-closure reaction
Entry Base Solvent
Temperature (ꢀC) Time (h) Yield (%) dea (%)
1
2
3
4
5
6
KOH THF
KOH THF/H2O 0 ꢀC to rt
0 ꢀC to rt
36
24
12
24
72
24
60
80
85
73
50
95
90
90
90
90
90
90
KOH EtOH
KOH DCM
0
ꢀC
0 ꢀ
C
DBU
DBU
THF
DCM
0
0
ꢀC to rt
ꢀC to rt
Entry
trans-Epoxyamide
Time
(min)
Ratio of
Product
Isolated
a
Calculated by HPLC analysis of the crude reaction mixture (Chiralcel OD column,
a/ba
yield of ab (%)
UV detector, n-hexane/2-propanol 50:50, tR for the major diastereoisomer,
5.67 min, tR for the minor diastereoisomer 6.35 min, flow rate 1.00 mL/min).
1
2
3
4
5
6
7
8
9
3
4
5
6
7
8
9
10
11
12
30
30
20
25
30
30
10
25
20
25
9.5:0.5
9:1
8.5:1.5
9.5:0.5
9.5:0.5
8:2
9:1
9:1
8.5:1.5
7:3
13
14
15
16
17
18
19
20
21
22
81
77
72
76
78
58
80
40
70
33
Diverse reaction conditions were tested giving in general good
to excellent yields. The best result was obtained when sulfonium
salt 2 was treated with DBU as a base, in DCM, benzaldehyde
(2 equiv) from 0 ꢀC to room temperature, giving the desired epox-
yamide in 95% (entry 6, Table 1). Exclusive formation of trans-ad-
ducts was confirmed by the magnitude of the coupling constants
(J¼2.1 and 1.6 Hz).13 1H NMR determination of diastereomeric ra-
tios was complicated by the presence of E versus Z amide rotamers
in solution.12b,14 However, HPLC analysis of the crude reaction
showed a deꢁ90% in all entries.
10
a
Determined by 1H NMR of the unpurified reaction mixture.
Isolated yield of the major diastereoisomer.
b
The asymmetric epoxidation of chiral sulfonium salt 2 with
several aromatic aldehydes was then investigated giving in all en-
tries good to excellent yields despite of the presence of deactivating
or activating groups at aromatic ring (Table 2, entries 1e4) or the
presence of chlorine atoms (entries 5 and 6). The asymmetric
epoxidation with aliphatic aldehydes was tested giving exclusively
the trans-adducts in good yields (entries 7e9).
Table 2
Fig. 1. X-ray ORTEP diagram of compound 13a.
Asymmetric epoxidation with aromatic and aliphatic aldehydes
As a correlation, we concluded that the morpholinone comes
from the (S,R)-epoxyamide, this is the mainly diastereoisomer
formed in the asymmetric epoxidation process (Scheme 2).
Entry
R
Product
Yield (%)
dea (%)
1
2
3
4
5
6
7
8
9
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
3,4-(CH3)2C6H3
2,6-ClC6H3
3,5-ClC6H3
Pr
4
5
6
7
8
9
10
11
12
85
93
90
83
75
80
73
75
84
80
70
94
94
60
80
86
70
33
Scheme 2.
i-Pr
i-Bu
Epoxyamides containing deactivating or activating groups at
aromatic ring were reacted with sodium, affording the corre-
sponding morpholinones in good to excellent yields. However,
epoxyamide 8 gave low yield; this result was attributed to the
Reaction conditions: aldehyde (2 equiv), 0 ꢀC to rt, 12 h.
a
Calculated by HPLC (Chiralcel OD column, UV detector, n-hexane/2-propanol
50:50, 1.00 mL/min).

10254
D.M. Aparicio et al. / Tetrahedron 68 (2012) 10252e10256
presence of chlorine atoms at ortho position, which represents
a combination of unfavorable steric and electronic effects (entry 6,
Table 3). Epoxyamides containing an aliphatic group gave the cor-
responding morpholinones in excellent yields.16
4.2. Synthesis of (D)-2-bromo-N-((1S,2S)-1-hydroxy-1-phenyl
propan-2-yl)-N-methylacetamide, 1
To a stirred solution of (1S,2S)-pseudoephedrine(2.5 g,15.1 mmol,
1.0 equiv) in DCM, at room temperature, was added an aqueous so-
lution of K2CO3 (4.18 g, 2 equiv) and bromoacetyl bromide
(15.1 mmol, 3.05 g,1.3 mL,1 equiv). The resulting mixture was stirred
for 1 h. After, the reactionwas quenched by the successive addition of
brine solution (25 mL) and the organic phase was separated, dried
over anhydrous Na2SO4, filtered, and the solvent was removed by
evaporation. The resulting mixture was purified via flash column
chromatography. Compound 1 was obtained as a white solid in a 95%
yield (spectroscopic details of the major rotamer of compound 1);
Finally, the diastereoselective outcomes in asymmetric epoxi-
dation reaction could be explains as follows. The addition of the
ylide onto the aldehyde results in a formation of reversible two
possible anti-betaine intermediates I and II, followed by the re-
versible rotation around the newly formed CeC bond giving the
transoid conformers I and II, in agreement with Aggarwal’s postu-
lated mechanism,9b in where the transoid II shows a greater steric
interactions between oxy and methyl groups destabilizing this
rotamer, while transoid I disposes the oxy and methyl groups in an
opposite side favoring the ring closure, giving the trans-(S,R)-di-
astereoisomer as a mayor compound (Scheme 3)
[
a
]
20 þ81.0 (c 1.0, CH2Cl2); IR (film) 3383, 1632, 1454, 1086 cmꢂ1. 1H
D
NMR (400 MHz, CDCl3)
d
1.00 (d, J¼7.2 Hz, 3H), 2.90 (s, 3H), 3.72 (d,
J¼10.4 Hz, 1H), 3.95 (qd, J¼7.2, 6.6 Hz, 1H), 4.11 (m, 1H), 4.16 (d,
J¼10.4 Hz, 1H), 4.53 (br, 1H), 7.26e7.39 (m, 5H); 13C NMR (100 MHz,
CDCl3)
d 13.8, 27.0, 59.4, 74.6, 75.3, 126.2, 127.9, 128.7, 141.2, 168.1.
HRMS (FAB): calcd for C12H16BrNO2: 285.0364; found: 285.0366.
4.3. Synthesisof (D)-(2-(((1S,2S)-1-hydroxy-1-phenylpropan-2-
yl)(methyl)amino)-2-oxoethyl)dimethylsulfonium bromide, 2
To a stirred solution of N-methylacetamide 1 (2.27 mmol,
0.65 g), in DCM (2 mL), at room temperature was added dimethyl
sulfide (0.35 g, 0.42 mL, 5.63 mmol). Then, the mixture was stirred
until total formation of the corresponding sulfonium salt (6 h).
Later, the excess of dimethyl sulfide was eliminated by evaporation,
and the solvent was removed under reduce pressure giving the
desired sulfonium salt 2 in a quantitative yield.
The NMR spectra show the presence of a rotameric mixture of E
versus Z isomers, only the major rotamer is described. [
a
]
20 þ69.1 (c
1.0, CH2Cl2); IR (film) 3378, 1633, 1453, 1045, 704 cmꢂ1D
.
1H NMR
(400 MHz, CDCl3)
d
0.83 (d, J¼6.4 Hz, 3H), 2.87 (s, 3H), 3.01 (s, 3H),
3.09 (s, 3H), 3.90 (qd, J¼6.4, 9.2 Hz, 1H), 4.46 (d, J¼9.2 Hz, 1H), 5.22
(br, OH), 5.31 (br, 2H), 7.23e7.76 (m, 5H); 13C NMR (100 MHz,
CDCl3)
d 13.9, 24.8, 25.2, 27.1, 49.8, 59.1, 74.7, 126.8, 128.0, 128.4,
140.9, 164.2. HRMS (FAB): calcd for C14H22BrNO2S: 347.0555;
found: 347.0554.
Scheme 3. Suggested mechanism.
4.4. Representative procedure for asymmetric epoxidation of
(2-(((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)(methyl)amino)-
2-oxoethyl)dimethylsulfonium bromide 2 with benzaldehyde
3. Conclusion
We have shown that chiral non-racemic amide-stabilized sulfur
ylide 2 is a valuable starting material for the preparation of alkyl or
aryl trans-epoxyamides. These intermediates were utilized to build
in a high yielding, highly functionalized morpholin-3-ones. This
new, short, versatile, and scalable strategy opens the route to the
six-membered N,O-heterocycles for further pharmacological
investigations.
To a stirred solution of sulfonium salt 2 (0.35 g, 1.0 mmol) in
DCM (20 mL) at 0 ꢀC were added DBU (0.39 g, 2 equiv) and benz-
aldehyde (0.26 mL, 0.274g, 2 equiv). The resulting mixture was
stirred from 0 ꢀC to room temperature until the total consumption
of sulfonium salt 2 (24 h). Finally the reaction was quenched by
a successive addition of a brine solution. The organic phase was
separated, dried over anhydrous Na2SO4, filtered, and the solvent
was removed by evaporation. The resulting mixture was purified
via flash column chromatography. Compound 3 was obtained as
a colorless oil in a 95% yield. The NMR spectra show the presence of
a rotameric mixture of E versus Z isomers of each diastereomer.
4. Experimental section
4.1. General methods
Melting points are uncorrected. 1H NMR and 13C NMR spectra
were acquired on Varian VX400 (400 MHz), chemical shifts were
given on the delta scale as parts per million (ppm) with tetrame-
thylsilane (TMS) as internal standard. IR spectra were recorded on
Nicolet FT-IR Magna 750. Mass spectra were recorded on JEOL JEM-
AX505HA at a voltage of 70 eV. Optical rotations were measured on
PerkineElmer 341polarimeter at room temperature. Column
chromatography was performed on silica gel (60, 0.063e0.2 mm/
70e230 mesh ASTM). All reagents and solvents were analytically
pure.
4.5. Representative procedure for intramolecular 6-exo-tet
ring-closure reaction
To a solution of the corresponding trans-diastereomeric mixture
of epoxyamide (0.38mmol) in anhydrous THF (6 mL) at room tem-
peraturewasadded Na (14e18 mg). The resulting mixturewasstirred
untilthe totalconversion of the startingmaterial (30 min). Finally, the
reaction mixture was filtered and quenched by addition of a brine
solution, and the organic phase was separated, dried over anhydrous
Na2SO4, filtered, and the solvent was removed by evaporation. The

D.M. Aparicio et al. / Tetrahedron 68 (2012) 10252e10256
10255
resulting diastereomeric mixture was purified via flash column
chromatography. Only the mayor diastereoisomer is described.
CH2Cl2); IR (film) 3381, 1634, 1432, 1125, 763 cmꢂ1
(400 MHz, CDCl3)
.
1H NMR
d
1.08 (d, J¼6.8 Hz, 3H), 2.98 (s, 3H), 3.49 (qd,
J¼6.8, 9.6 Hz, 1H), 4.16 (d, J¼7.6 Hz, 1H), 4.22 (d, J¼9.6 Hz, 1H), 4.97
4.5.1. (þ)-(2R,5S,6S)-2-((R)-Hydroxy(phenyl)methyl)-4,5-dimethyl-
(d, J¼7.6 Hz, 1H), 5.48 (br, OH), 7.18e7.40 (m, 8H); 13C NMR
20
6-phenylmorpholin-3-one, 13a. Mp¼154e156 ꢀC; [
a]
þ100.3 (c
(100 MHz, CDCl3) d 15.7, 30.4, 58.6, 73.4, 78.3, 81.7, 125.9, 126.0,
D
1.0, CH2Cl2); IR (film) 3384, 1635, 1449, 699 cmꢂ1
.
1H NMR
127.0, 127.2, 127.6, 128.4, 128.7, 134.0, 137.3, 143.4, 169.4. HRMS
(FAB): calcd for C19H19NO3: 379.0742; found: 379.0740.
(400 MHz, CDCl3)
d
1.03 (d, J¼6.4 Hz, 3H), 2.92 (s, 3H), 3.41 (qd,
J¼6.6, 9.2 Hz, 1H), 4.18 (d, J¼9.2 Hz, 1H), 4.23 (d, J¼7.2 Hz, 1H), 5.02
(d, J¼7.6 Hz, 1H), 5.30 (br, OH), 7.17e7.45 (m, 10H); 13C NMR
4.5.8. (2R,5S,6S)-2-((R)-1-Hydroxybutyl)-4,5-dimethyl-6-
20
(100 MHz, CDCl3)
d
15.7, 30.3, 58.5, 74.3, 78.8, 81.6, 127.2, 127.5,
phenylmorpholin-3-one, 20a. [
a]
þ58.8 (c 1.0, CH2Cl2); IR (film)
D
127.9, 128.4, 137.7, 140.0, 169.8. HRMS (FAB): calcd for C19H21NO3:
311.1521; found: 311.1520.
3417, 1632 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
0.89 (t, J¼7.2 Hz, 3H),
1.10 (d, J¼6.4 Hz, 3H), 1.49 (m, 3H), 1.68 (m, 1H), 2.97 (s, 3H), 3.89
(qd, J¼6.8, 7.2 Hz, 1H), 3.97 (m, 2H), 4.28 (d, J¼9.6 Hz, 1H), 4.61 (br,
4.5.2. (þ)-(2R,5S,6S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)-4,5-
OH), 7.28e7.41 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 14.0, 15.9, 18.1,
dimethyl-6-phenylmorpholin-3-one, 14a. [
a
]
D
20 þ91.6 (c 1.0, CH2Cl2);
30.2, 34.6, 58.6, 71.6, 78.9, 82.1,127.1,127.4,128.7,137.9,170.5. HRMS
(FAB): calcd for C16H23NO3: 277.1678; found: 277.1675.
IR (film) 3379, 1634, 1520, 1346 cmꢂ1
.
1H NMR (400 MHz, CDCl3)
d
1.03 (d, J¼6.8 Hz, 3H), 2.99 (s, 3H), 3.53 (qd, J¼6.8, 9.6 Hz,1H), 3.99
(d, J¼8.8 Hz, 1H), 4.10 (d, J¼9.6 Hz, 1H), 5.94 (br, OH), 5.99 (d,
J¼8.8 Hz, 1H), 7.15e7.37 (m, 6H), 7.52 (td, J¼1.2, 7.6 Hz, 1H), 7.65
(dd, J¼1.2, 8.0 Hz, 1H), 7.95 (dd, J¼1.6, 8.0 Hz, 1H); 13C NMR
4.5.9. (þ)-(2R,5S,6S)-2-((R)-1-Hydroxy-2-methylpropyl)-4,5-
dimethyl-6-phenylmorpholin-3-one, 21a. [
a
]
D
20 þ50.7 (c 1.0, CH2Cl2);
IR (film) 3418, 2955, 1634, 1108 cmꢂ1
.
1H NMR (400 MHz, CDCl3)
(100 MHz, CDCl3)
d
15.6, 30.4, 58.5, 68.2, 78.8, 82.4, 123.8, 126.9,
d
0.85 (d, J¼7.2 Hz, 3H), 0.97 (d, J¼6.8 Hz, 3H), 1.08 (d, J¼6.8 Hz, 3H),
127.3, 128.8, 132.6, 134.6, 136.9, 149.1, 170.1. HRMS (FAB): calcd for
C19H20N2O5: 356.1372; found: 356.1370.
2.04 (m, J¼2.8, 6.8 Hz, 1H), 2.95 (s, 3H), 3.57 (m, J¼7.2, 9.6 Hz, 1H),
3.79 (qd, J¼2.8, 8.4 Hz, 1H), 3.99 (d, J¼8.4 Hz, 1H), 4.25 (d, J¼9.6 Hz,
1H), 7.31e7.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 14.8, 15.9,
4.5.3. (þ)-(2R,5S,6S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)-4,5-
28.38, 30.3, 58.6, 75.3, 76.8, 82.2, 127.1, 128.4, 128.7, 137.9, 171.4.
HRMS (FAB): calcd for C16H23NO3: 277.1678; found: 277.1676.
dimethyl-6-phenylmorpholin-3-one, 15a. [
a]
20 þ83.3 (c 1.0, CH2Cl2);
D
IR (film) 3380, 1652, 1524, 1350 cmꢂ1
.
1H NMR (400 MHz, CDCl3)
d
1.08 (d, J¼6.8 Hz, 3H), 2.97 (s, 3H), 3.51 (qd, J¼6.8, 9.6 Hz, 1H), 4.18
4.5.10. (þ)-(2R,5S,6S)-2-((R)-1-Hydroxy-3-methylbutyl)-4,5-
(d, J¼7.6 Hz, 1H), 4.21 (d, J¼9.6 Hz, 1H), 5.10 (d, J¼7.6 Hz, 1H), 5.67
(d, J¼2.4 Hz, 1H), 7.25e7.41 (m, 6H), 7.76 (d, J¼7.6 Hz, 1H), 8.03 (m,
dimethyl-6-phenylmorpholin-3-one, 22a. [
a
]
D
20 þ54.3 (c 1.0, CH2Cl2);
IR (film) 3418, 2958, 1633, 1110 cmꢂ1
.
1H NMR (400 MHz, CDCl3)
1H), 8.37 (t, J¼2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
15.5, 30.2,
d
0.90 (d, J¼6.4 Hz, 3H), 0.94 (d, J¼6.4 Hz, 3H),1.09 (d, J¼6.0 Hz, 3H),
58.2, 73.2, 78.3, 81.6, 122.5, 127.1, 128.3, 133.4, 137.2, 142.0, 169.2.
HRMS (FAB): calcd for C19H20N2O5: 356.1372; found: 356.1371.
1.46 (m, 2H), 1.91 (m, 1H), 2.96 (s, 3H), 3.59 (m, 1H), 3.96 (d,
J¼6.8 Hz, 1H), 4.04 (m, 1H), 4.27 (d, J¼9.6 Hz, 1H), 7.29e7.40 (m,
5H); 13C NMR (100 MHz, CDCl3)
d 15.8, 21.1, 23.7, 30.2, 41.5, 58.5,
4.5.4. (þ)-(2R,5S,6S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)-4,5-
70.0, 79.3, 82.1, 127.3, 128.6, 128.7, 137.8, 170.3. HRMS (FAB): calcd
for C17H25NO3: 291.1834; found: 291.18933.
20
dimethyl-6-phenylmorpholin-3-one, 16a. [
a
]
þ119.6 (c 1.0,
CH2Cl2); IR (film) 3393, 1646, 1524, 1344 cmꢂD1. 1H NMR (400 MHz,
CDCl3)
d
1.08 (d, J¼6.0 Hz, 3H), 2.98 (s, 3H), 3.52 (qd, J¼6.0, 9.6 Hz,
Acknowledgements
1H), 4.17 (d, J¼7.6 Hz, 1H), 4.20 (d, J¼9.6 Hz, 1H), 5.11 (d, J¼7.6 Hz,
1H), 5.71 (br, OH), 7.23e7.35 (m, 5H), 7.60 (d, J¼8.6 Hz, 2H), 8.07 (d,
We are grateful to CONACyT (Project CB-2010-154104) for fi-
nancial support, D.M.A.S. thanks CONACyT for the scholarship
(169011). We thank Dra. Gabriela Huelgas of the Universidad de las
J¼8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 15.7, 30.4, 58.6, 73.5,
78.3, 81.9, 122.7, 127.1, 128.4, 128.7, 137.2, 147.2, 147.4, 169.4. HRMS
(FAB): calcd for C19H20N2O5: 356.1372; found: 356.1370.
ꢀ
Americas Puebla, for HPLC chromatographic analyses.
4.5.5. (þ)-(2R,5S,6S)-2-((R)-(3,4-Dimethylphenyl)(hydroxy)methyl)-
20
4,5-dimethyl-6-phenylmorpholin-3-one, 17a. [
a
]
þ61.6 (c 1.0,
References and notes
D
CH2Cl2); IR (film) 3385, 1642, 1575, 1120, 770 cmꢂ1
.
1H NMR
ꢀ~
ꢀ
1. Díez, D.; Nunez, M. G.; Antoon, A. B.; García, P.; Moro, R. F.; Garrido, N. M.;
Marcos, I. S. Curr. Org, Synth. 2008, 5, 189; Nemoto, T.; Kakei, H.; Gnanadesikda,
V.; Tosaki, S.-Y.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544.
(400 MHz, CDCl3)
d
1.06 (d, J¼6.6 Hz, 3H), 2.19 (s, 3H), 2.21 (s, 3H),
2.95 (s, 3H), 3.45 (m, J¼6.6, 9.2 Hz, 1H), 4.20 (d, J¼9.2 Hz, 1H), 4.25
(d, J¼7.5 Hz, 1H), 4.95 (d, J¼7.5 Hz, 1H), 5.18 (br, OH), 7.01e7.42 (m,
€
ꢀ
2. Fuentes, L.; Osorio, U.; Quintero, L.; Hopfl, H.; Vazquez-Cabrera, N.; Sartillo-
Piscil, F. J. Org. Chem. 2012, 77, 5515.
8H); 13C NMR (100 MHz, CDCl3)
d 15.9, 19.4, 19.7, 29.6, 58.7, 74.3,
3. For a review, see: Rosen, T. In Comprehensive Organic Synthesis; Trost, B. M.,
Feming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 409; For
communications, see: Tung, C. C.; Speziale, A. J.; Frazier, H. W. J. Org. Chem.
1963, 28, 1514; Arai, S.; Tokumaru, K.; Aoyama, T. Tetrahedron Lett. 2004, 45,
1845.
4. He, Li.; Liu, W. J.; Ren, L.; Lei, T.; Gong, L. Z. Adv. Synth. Catal. 2010, 352, 1123;
Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley: New York, NY, 1998; Liu, W.-J.; Lv, B.-
D.; Gong, L.-Z. Angew. Chem., Int. Ed. 2009, 48, 6503; Lopez-Herrera, F. J.; Sar-
abia-García, F.; Pino-Gonzalez, M. S. Tetrahedron Lett. 1994, 35, 2933.
5. Waser, M.; Herchi, R.; Muller, N. Chem. Commun. 2011, 2170; Herchl, R.; Stif-
tinger, M.; Waser, M. Org. Biomol. Chem. 2011, 9, 7021.
6. (a) Illa, O.; Arshad, M.; Ros, A.; McGarrigle, E. M.; Aggarwal, V. K. J. Am. Chem.
Soc. 2010, 132, 1828; (b) McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.;
Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007, 107, 5841; (c) Aggarwal, V. K.;
Hynd, G.; Picoul, W.; Vasse, J. L. J. Am. Chem. Soc. 2002, 124, 9964; (d) Zhou,
Y.-G.; Hou, X.-L.; Dai, L.-X.; Xia, L. J.; Tang, M.-H. J. Chem. Soc., Perkin Trans. 1
1999, 77.
78.9, 81.7, 124.9, 127.4, 128.3, 128.5, 135.7, 137.5, 138.0, 170.1. HRMS
(FAB): calcd for C21H25NO3: 339.1834; found: 339.1832.
4.5.6. (þ)-(2R,5S,6S)-2-((R)-(2,6-Dichlorophenyl)(hydroxy)methyl)-
20
4,5-dimethyl-6-phenylmorpholin-3-one, 18a. [
a]
þ51.5 (c 1.0,
D
CH2Cl2); IR (film) 3385, 1642, 1575, 1120, 770 cmꢂ1
.
1H NMR
ꢀ
(400 MHz, CDCl3)
d
1.10 (d, J¼6.8 Hz, 3H), 3.03 (s, 3H), 3.52 (m,
ꢀ
€
J¼6.8, 9.6 Hz, 1H), 4.25 (d, J¼9.6 Hz, 1H), 5.03 (d, J¼9.6 Hz, 1H), 5.71
(s, OH), 5.80 (d, J¼9.6 Hz, 1H), 6.98 (t, J¼8 Hz, 1H), 7.18e7.34 (m,
7H); 13C NMR (100 MHz, CDCl3)
d 15.7, 30.4, 59.0, 71.4, 74.4, 81.7,
127.1,127.4,128.0,128.3,128.9,133.7,137.8,171.0. HRMS (FAB): calcd
for C19H19NO3: 379.0742; found: 379.0740.
4.5.7. (þ)-(2R,5S,6S)-2-((R)-(3,5-Dichlorophenyl)(hydroxy)methyl)-
ꢀ
7. (a) Ratts, K. W.; Yao, A. N. J. Org. Chem. 1966, 31, 1689; (b) Valpuesta Fernandez,
M.; Durante-Lanes, P.; Lopez-Herrera, F. J. Tetrahedron 1990, 46, 7911.
20
ꢀ
4,5-dimethyl-6-phenylmorpholin-3-one, 19a. [
a
]
þ115.7 (c 1.0,
D

10256
D.M. Aparicio et al. / Tetrahedron 68 (2012) 10252e10256
ꢀ
ꢀ
8. (a) Sarabia, F.; Martína-Galvez, F.; García-Castro, M.; Chammaa, S.; Sanchez-
Paquette, L. A., Ed.; Wiley Interscience: New York, NY, 2003; p 485; For other
examples, see: (d) Iza, A.; Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2006,
4065; (e) Vicario, J. L.; Rodriguez, M.; Badía, D.; Carrillo, L.; Reyes, E. Org. Lett.
2004, 6, 3171; (f) Smitrovich, J. H.; Boice, G. N.; Qu, C.; Dimichelle, L.; Nelson, T.
D.; Huffman, M. A.; Murry, J.; McNamara, J.; Reider, P. J. Org. Lett. 2002, 4, 1; (g)
Hutchison, P. C.; Heightman, T. D.; Procter, D. J. Org. Lett. 2002, 4, 4583; (h)
Vicario, J. L.; Badía, D.; Carrillo, L. J. Org. Chem. 2001, 66, 5801; (i) Vicario, J. L.;
Badía, D.; Carrillo, L. J. Org. Chem. 2001, 66, 9030; (j) Anakabe, E.; Vicario, J. L.;
Badía, D.; Carrillo, L.; Yoldi, V. Eur. J. Org. Chem. 2001, 4343; (k) Myers, A. G.;
Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207; (l) Vicario, J. L.; Badía,
D.; Domínguez, E.; Rodríguez, M.; Carrillo, L. J. Org. Chem. 2000, 65, 3754; (m)
Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
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Ruiz, A.; Tejon-Blanco, J. F. J. Org. Chem. 2008, 73, 8979; (b) Lopez-Herrera, F. J.;
Sarabia-García, F. R.; Pino-Gonzalez, M. S. Recent Res. Dev. Org. Chem. 2000, 4,
465; (c) Heras-Lopez, A. M.; Pino-Gonzalez, M. S.; Sarabia-García, F.; Lopez-
Herrera, F. J. J. Org. Chem. 1998, 63, 9630; (d) Valpuesta Fernandez, M.; Durante
Lanes, P.; Lopez-Herrera, F. J. Tetrahedron 1993, 49, 9547; (e) Lopez Herrera, F. J.;
Pino Gonzalez, M. S.; Sarabia García, F.; Heras Lopez, A.; Ortega Alcantara, J. J.;
Pedraza Cebrian, M. G. Tetrahedron: Asymmetry 1996, 7, 2065.
9. (a) Aggarwal, V. K.; Richardson. J. Chem. Commun. 2003, 2644; (b) Aggarwal, V.
K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.; Ohara, D.; Picoul, W.;
Robiette, R.; Smith, C.; Vasse, J. L.; Winn, C. L. J. Am. Chem. Soc. 2006, 128, 2105.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
10. (a) Sarabia, F.; Chammaa, S.; García-Castro, M.; Martín-Galvez, F. Chem. Com-
mun. 2009, 5763; (b) Sarabia, F.; Vivar-García, C.; García-Castro, M.; Martín-
Ortiz, J. J. Org. Chem. 2011, 76, 3139.
13. For description of trans-epoxides coming from aromatic aldehydes see: (a)
ꢀ
Aggarwal, V. K.; Hebach, C. Org. Biomol. Chem. 2005, 3, 1419; (b) Lopez-Herrera,
ꢀ
ꢀ
ꢀ
ꢀ
11. (a) Aparicio, D. M.; Teran, J. L.; Gnecco, D.; Galindo, A.; Juarez, J. R.; Orea, M. L.;
F. J.; Heras-Lopez, A. M.; Pino-Gonzalez, M. S.; García, F. S. J. Org. Chem. 1996, 61,
ꢀ
Mendoza, A. Tetrahedron: Asymmetry 2009, 20, 2764; (b) Aparicio, D. M.; Teran,
8839.
ꢀ
J. L.; Roa, L. F.; Gnecco, D.; Juarez, J. R.; Orea, M. L.; Mendoza, A.; Flores-Alamo,
14. Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656;
Chain, W. J.; Myers, A. G. Org. Lett. 2007, 9, 355.
M.; Micouin, L. Synthesis 2011, 14, 2310.
12. For the first use of pseudoephedrine as chiral auxiliary, see: (a) Myers, A. G.;
Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361; (b) Myers,
A. G.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496; For a review, see: (c) Myers, A. G.; Charest, M. G. In Handbook of
Reagents for Organic Synthesis: Chiral Reagents for Asymmetric Synthesis;
15. Crystal structure of compound 13a was deposited at the Cambridge Crystallo-
graphic Data Centre. Deposit number: CCDC 885086.
16. We assumed that in all morpholinones the majority diastereoisomers have the
same stereochemistry than morpholinone 13a, because they have the same
optical rotation sign.