An efficient synthesis of aziridines from ephedrines

Article abstract of DOI:10.1016/j.tetasy.2010.05.007

The reaction of chlorodeoxyephedrine hydrochlorides with one, two, and three molar equivalents of base was studied. Isochlorodeoxypseudoepherines were identified and assigned by ¹H and ¹³C NMR data as intermediate compounds in the formation of cis-aziridines. Erythro and threo ephedrinethylethers were isolated as new compounds and analyzed by spectroscopic data. In addition, the erythro isomer was studied by X-ray diffraction.

Full text of DOI:10.1016/j.tetasy.2010.05.007

Tetrahedron: Asymmetry 21 (2010) 909–913
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient synthesis of aziridines from ephedrines
*
Alejandro Cruz , Itzia Irene Padilla-Martínez, Efrén V. García-Báez
Departamento de Ciencias Básicas de la Unidad Profesional Interdisciplinaria de Biotecnología del IPN, Av. Acueducto s/n Barrio la Laguna Ticomán, México, D.F. 07340, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of chlorodeoxyephedrine hydrochlorides with one, two, and three molar equivalents of base
was studied. Isochlorodeoxypseudoepherines were identified and assigned by 1H and 13C NMR data as
intermediate compounds in the formation of cis-aziridines. Erythro and threo ephedrinethylethers were
isolated as new compounds and analyzed by spectroscopic data. In addition, the erythro isomer was stud-
ied by X-ray diffraction.
Received 23 March 2010
Accepted 10 May 2010
Available online 22 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
aziridine (84%).7 This procedure was extended to pseudoephedrine
to form the cis-aziridine whereas norephedrine required three days
Ephedrines are very important substances in asymmetric syn-
thesis; they are widely used as building blocks in the synthesis
of heterocycles, as ligands for metallic or organometallic com-
plexes and as reagents or catalytic agents in organic chemistry.1
Due to their relevance in several areas, we are currently developing
synthetic methods to obtain heterocycles,2 which could be used as
chiral inductors or catalysts in asymmetric synthesis.
The intermediates that we had been using for the synthesis of
heterocycles derived from ephedrines or norephedrines 1 are the
hydrochlorides of chlorodeoxypseudoephedrines and chlorode-
oxynorpseudoephedrine 3.2a,b,d–f These hydrochlorides were ob-
tained from the chlorination reaction of ephedrine or
norephedrine 1 with thionyl chloride. The stereochemistry and
functional group effects on the chlorination reaction mechanisms
were revisited.3 Recently, we reported the synthesis of 2-imine-
heterocycles from chlorodeoxypseudoephedrines hydrochlorides 3
and heterocyanates2f to proceed through the cis-aziridinium 6,
Scheme 1. This intermediate explains the retention of configura-
tion in the heterocycle formed. In fact, this aziridinium intermedi-
ate has been proposed in other reactions carried out with retention
of the C-1 configuration.4
There are some procedures reported in the literature for the for-
mation of aziridines from ephedrines. (1) From the sulfate esters of
ephedrine and norephedrine, which are cyclized to a mixture of
aziridines (45:55 cis/trans) by treatment with hot aqueous potas-
sium hydroxide in 84% yield.5 (2) Pseudoephedrine was readily
converted to the corresponding cis-aziridine in a 74% yield by using
triphenylphosphine dibromide under mild conditions. In contrast,
ephedrine gave only a polymeric material.6 (3) Pfister treated
ephedrine with triphenylphosphine in the presence of diethylazo-
dicarboxylate in ether or THF for 2 h with good yields of the trans-
to give the corresponding trans-aziridine.8 (4) The corresponding
cis-aziridines were obtained in 65% yield from ephedrine9 and
norephedrine10 by stereospecific cyclization of the corresponding
chlorodeoxypseudoephedrine hydrochlorides 3 with NaOH 20%
aqueous solution. In this context, and in order to improve the
yields of aziridines, we performed a detailed study of this last reac-
tion by using bases such as NaOH, K2CO3, NH3, and Et3N in water,
ethanol, and chloroform as solvents.
2. Results and discussion
2.1. Chlorination reaction of ephedrine hydrochlorides
To obtain the threo and erythro isomers of chlorodeoxyephed-
rines 3, 4 as starting materials for the synthesis of cis- and trans-
aziridines, the stereoselective chlorination with SOCl2 was used.
It is well known that the reaction of ephedrine or norephedrine
hydrochlorides 1 with thionyl chloride at room temperature pro-
ceeds stereoselectively with inversion of the C-1 configuration
(SN2 mechanism) to give the corresponding hydrochlorides of chlo-
rodeoxypseudoephedrines 3, respectively, Scheme 1. However, the
same reaction with the hydrochlorides of pseudoephedrines 2 gives
a 60:40 mixture of threo/erythro chlorodeoxystereoisomers 3/4,
respectively,3 Scheme 2. In order to improve the stereoselectivity,
we carried out the same chlorination reaction of pseudoephedrine
stereoisomers 2 at 0 °C. Under these conditions, only the corre-
sponding threo chlorodeoxystereoisomers 3 were stereoselectively
obtained (SNi mechanism).
On the other hand, we found that the pure threo isomer 3 can be
transformed to a 60:40 mixture of the threo/erythro stereoisomers
when it is heated (80–90 °C) in DMSO-d6 solution for five hours in
the NMR tube. This transformation has also been observed when a
60:40 mixture of these hydrochlorides are acidified with HCl to
obtain a 35:65 ratio.3
* Corresponding author. Tel.: +15557296000/56323; fax: +15557296000/56325.
E-mail addresses: alecruz@ipn.mx, alcralmx@hotmail.com (A. Cruz).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.007

910
A. Cruz et al. / Tetrahedron: Asymmetry 21 (2010) 909–913
X = O, S, Se
_
_
OH
C6H5
H3C
C6H5
H3C
Cl
+
+
Cl
+
C6H5
H3C
C6H5
H
SOCl2
_
X
MXCN
_
+
NH2
N
+
NH2Cl
NH2Cl
N
R
R
H3C
R
R
1
3
6
a
b
R = CH3
R = H
Scheme 1. Aziridinium 6 as intermediate to obtain 2-iminium heterazolidines.
Chlorodeoxyephedrine hydrochloride 4a was separated by frac-
On the basis of these results, compound 3a was refluxed in
anhydrous ethanol for 24 h in the presence of two molar equiv-
alents of K2CO3 as base. Bicarbonate and KCl were filtered off,
ethanol removed under vacuum, cis-ziridine 9a was extracted
with chloroform and the 1H NMR spectrum of the remaining
solid showed a mixture of two compounds in a 2:1 proportion.
The major compound was identified as the corresponding hydro-
chloride 3a. For the minor compound, the 1H chemical shift of
the methyne protons H-1 (doublet) and H-2 (doublet of quartet)
appears at 4.09 and 4.83 ppm, respectively. The multiplicity of
these signals is inter-changed in position compared with that
of the major compound 3a. In addition, the same coupling
constant values for H-1 (doublet) were measured for both
compounds (approx. 10 Hz). On the other hand, the C–Me
absorption at 1.28 ppm in the minor compound is characteristic
of a methyl group on a carbon bearing a chlorine atom.4a These
results allowed us to identify the formation of the isochlorode-
oxypseudoephedrine hydrochloride 8a as the minor compound,
whose formation is explained by chloride opening on the C3 of
the aziridinium intermediate 6a, Scheme 3. Under these condi-
tions cis-aziridine 9a, hydrochloride 3a, and isohydrochloride
8a are formed through acid-base equilibria of aziridinium 6a
with chlorodeoxypseudoephedrine 5a or isochlorodeoxypseudo-
ephedrine 7a. In addition, a new solid precipitated from the
chloroform solution, its NMR spectrum is in agreement with
pseudoephedrinylthylether hydrochloride 10a, formed by the
ethanolysis of the aziridinium intermediate 6a.
When the same reaction was carried out with chlorodeoxynor-
pseudoephedrine hydrochloride 3b, only cis-aziridine 9b was ex-
tracted with chloroform and the corresponding mixture of
hydrochlorides 3b and isohydrochloride 8b in a 2:1 proportion
was identified in the remaining solid. The corresponding nor-
pseudoephedrinethyl ether 10b was not observed.
To avoid ethanolysis, chloroform was used in the reaction of
chlorodeoxypseudo-hydrochlorides 3a or 3b with two or three mo-
lar equivalents of K2CO3. In both cases, the 1H NMR spectra showed
compounds 3/8 in a mixture with the corresponding cis-aziridine 9
in a 1:1:2 proportion, respectively.
tional crystallization from a 60:40 mixture of threo/erythro chloro-
deoxy-hydrochlorides 3a/4a, in the last crop of crystals of an
ethanolic solution. However, chlorodeoxynorephedrine 4b could
not be separated from 3b by this procedure.
C6H5
H3C
Cl
Cl
+
OH
+
C6H5
H3C
C6H5
H3C
SOCl2
r.t
+
_
_
_
+
NH2Cl
NH2Cl
NH2Cl
R
R
R
2
3
4
Scheme 2. Chlorodeoxyephedrine hydrochlorides from the chlorination reaction of
pseudoephedrines 2.
2.2. Study of chlorodeoxyephedrines reaction with bases
It is known that the reaction of chlorodeoxypseudoephedrine
hydrochlorides 3 with 20% aqueous NaOH affords the correspond-
ing cis-aziridine 9 in 65% yield.10 In order to improve this result, we
decided to carry out the same reaction but using ammonia, sodium
hydroxide, potassium carbonate, or triethylamine in ethanol or
chloroform with one, two, or three molar equivalents of the corre-
sponding base to detect the intermediates: some results are sum-
marized in Table 1.
Table 1
Proportion of products from the reaction of chlorodeoxypseudoephedrine 2at with
bases
Moles of base
Solvent
Reaction
time (h)
1a/2a
3a
8a
9a
10a
6 NH3/H2O
1 NaOH
2 K2CO3
2 or 3 K2CO3
3 K2CO3
EtOH (96%)
EtOH (96%)
EtOH
CHCl3
EtOH
8 (reflux)
30/10
10/0
10
57
20
20
0
0
0
10
20
0
50
33
50
40
80
0
0
20
0
24 (stirring)
72 (reflux)
72 (reflux)
72 (reflux)
0
0
0
20
Compound 3a was reacted with an excess of aqueous ammonia
(27%) in refluxing ethanol for 8 h. NH4Cl was filtered off, ethanol
evaporated, and cis-aziridine 9a (50%) was separated with chloro-
form from the ethanolic residue, and hydrochloride 3a (10%) in a
mixture with ephedrine 1a/pseudoephedrine 2a hydrochlorides
(30%/10%) was identified in the solid residue as a result of partial
hydrolysis of compound 3a because of the presence of water.
The hydrolyzing role of water was confirmed when chlorode-
oxypseudo-hydrochlorides 3a or 3b were refluxed in water for 8
hours to obtain a stereoisomeric mixture of the corresponding
ephedrines 1a/2a or norephedrines 1b/2b in a 60:40 proportion,
respectively.
Finally, the best results were obtained when the reactions
were carried out with three molar equivalents of the base in
refluxing anhydrous ethanol by 72 h. From hydrochloride 3a,
cis-aziridine 9a (80%) in mixture with the free ether 10a (20%)
was obtained. From hydrochloride 3b, only cis-aziridine 9b was
obtained in 96% yield. From a 60:40 mixture of threo/erythro
chlorodeoxy-hydrochlorides 3b/4b, a mixture of cis/trans-aziri-
dines in the initial proportion was detected. When this mixture
was kept for a month in a chloroform solution, only the cis iso-
mer was observed by NMR.
The same results were observed when Et3N was used instead of
Na2CO3 using ethanol as solvent.
When hydrochloride 3a was reacted with one molar equivalent
of NaOH in stirring ethanol for 24 h at room temperature, cis-aziri-
dine 9a (33%) and hydrochloride 3a (57%), in a mixture with
ephedrine 1a (10%) as the hydrolysis product, were observed.
The 1H and 13C NMR spectral data of the corresponding cis-azir-
idines 9a and 9b showed the characteristic chemical shift reported
in the literature.8,10 However, a Hetcor experiment was recorded to
unequivocally assign the close signals, 47.7 to N–CH3 and 47.5 ppm

A. Cruz et al. / Tetrahedron: Asymmetry 21 (2010) 909–913
911
C6H5
H3C
Cl
C6H5
H3C
Cl
+
Base
HCl
_
C6H5
H3C
O
+
CH2CH3
_
NH2Cl
R
NH
R
NH2Cl
5
3
R
EtOH
R = CH3
Base
a R = CH3
R = H
C6H5
10
b
H
_
Cl
+
N
R
R
6
H3C
C6H5
R
_
N
R
HCl
H
N
C6H5
H3C
C6H5
NH2Cl
+
H3C
Base
HCl
9
Cl
H3C
Cl
7
8
Scheme 3. Intermediates involved to get cis-aziridines 9 from chlorodeoxypseudoephedrine hydrochlorides 3.
to C-2. It is interesting to note that C-2 and C-3 resonances are
3. Conclusions
shifted to high frequencies by approximately 10 ppm when N–H
is changed by N-methyl group.
The chlorination reaction of pseudoephedrines 2a or 2b with
SOCl2 at 0 °C stereoselectively afforded chlorodeoxypseudoephed-
rines 3a or 3b, respectively. However, when the same chlorination
reactions were carried out at 25 °C, a 40:60 mixture of the erythro/
threo isomers were obtained by thermal isomerization.
The reaction of the hydrochlorides 3a and 3b with three molar
equivalents of a mild base in anhydrous ethanol affords the corre-
sponding cis-aziridine in 80% and 96% yields, respectively. Solvoly-
sis is the main side reaction which lowers the aziridine yield.
However, the ethanolysis byproduct 10at is easily separated from
chloroform solutions. In the same conditions our attempts to ob-
tain trans-aziridines from 4a lead to the novel compound 10ae,
suggesting the fast ethanolysis of the incipiently formed trans-azi-
ridine 9at. The molecular structure of 10ae was confirmed by X-
ray.
The attempts to isolate the corresponding aziridinium interme-
diates 6a or 6b from the corresponding reaction of cis-aziridines
with HCl always led to the corresponding chlorodeoxypseudoderiv-
atives 3a or 3b, suggesting a fast hydrolysis in acid media. With the
aim of synthesizing the trans-aziridine 9at, the chlorodeoxyephe-
drine 4a was reacted with three molar equivalents of K2CO3 in
refluxing ethanol for 72 h. Under these conditions the erythro iso-
mer of the ether 10a was isolated as the only product. Compound
10ae crystallized from ethanol and its X-ray diffraction structure
was obtained, Figure 1. The molecular structure of 10ae showed
C-methyl and phenyl groups syn positioned and C-methyl and N-
methyl groups in a gauche conformation. Intermolecular NHꢀ ꢀ ꢀClꢁ
(2.21, 2.33 Å) and intramolecular Clꢁꢀ ꢀ ꢀHN (2.34 Å) and NHꢀ ꢀ ꢀO
(2.48 Å) distances are in the range for hydrogen bonding
interactions.3
4. Experimental
4.1. General
Melting points were measured on an Electrothermal IA appara-
tus and are uncorrected. 1H and 13C NMR spectra were recorded on
a Varian Mercury 300 MHz (1H, 300.08; 13C, 75.46 MHz). The spec-
tra were measured with tetramethylsilane as internal reference
following standard techniques. Crystallographic data (excluding
structure factors) for the structures in this paper have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC: 10ae, (748350). X-ray
diffraction cell refinement and data collection: CAD-4 EXPRESS;11
data reduction: JANA98;12 programs used to solve structure: SHEL-
XS-97;13 software used to prepare material for publication:
WinGX.14
4.2. (1S,2S)-Chlorodeoxypseudoephedrine hydrochloride 3a
To (1S,2S)-(+)-pseudoephedrine hydrochloride 2a (1.0 g,
4.96 mmol) on ice-water bath, SOCl2 (1.43 mL, 19.8 mmol) was
slowly added. After stirring for 5 h, excess of SOCl2 was removed
under vacuum. The resulting white solid was washed with acetone
and filtered (1.02 g, 94%); mp 198–200 °C; ½a D30
¼ þ10:5 (CH3OH, c
ꢂ
0.1), 1H NMR [d, ppm, DMSO-d6]: 9.45 (br, 2H, +NH2CH3), 7.4 (m,
5H, Ph), 5.45 (d, 1H, 3J = 9.4 Hz, C1-H), 3.96 (dq, 1H, J = 9.4,
6.7 Hz, C2-H), 2.60 (s, 3H, N–CH3), 1.03 (d, 3H, 3J = 6.7 Hz, C2–
CH3). 13C NMR [d, ppm, DMSO-d6]: 137.92 (Ci), 129.98 (Cp),
Figure 1. Molecular structure of compound 10ae. Some selected bond lengths (Å)
and bond/torsion angles (°): O1A–C1A, 1.422(5); O1A–C6A, 1.439(6); N4A–C2A,
1.501(5); N4A–C5A, 1.499(7); C1A–C2A, 1.531(6); C1A–C8A, 1.506(6); O1A–C1A–
C2A, 106.7(3); O1A–C1A–C8A, 113.7(3); C2A–C1A–C8A, 111.8(4); N4A–C2A–C1A,
109.1(3); N4A–C2A–C3A, 109.6(4).

912
A. Cruz et al. / Tetrahedron: Asymmetry 21 (2010) 909–913
129.71 (Co), 129.71 (Cm), 62.98 (C1), 58.93 (C2), 29.84 (N–CH3);
4.7. cis-(2S,3R)-1,2-Dimethyl-3-phenylaziridine 9a
13.59 (C2–CH3).
(1S,2S)-Chlorodeoxypseudoephedrine hydrochloride 3a (1.0 g,
4.54 mmol) and K2CO3 (1.88 g, 13.64 mmol) were dissolved in
5 mL of anhydrous ethanol and refluxed during 72 h, the resulted
KHCO3 and KCl in suspension were filtered off and ethanol was
evaporated. The resulting mixture was dissolved in CHCl3. From
this solution compound 10a precipitated and was filtered off as a
white solid (0.1 g). Chloroform was eliminated to give the corre-
sponding aziridine 9a as viscous liquid (0.53 g, 80% yield):
4.3. (1R,2R)-Chlorodeoxynorpseudoephedrine hydrochloride 3b
Synthesized as 3a, (1R,2R)-(+)-norpseudoephedrine hydrochlo-
ride 2b (1.0 g, 5.33 mmol) to get 3b as a white solid (0.82 g, 74%),
mp 205–207 °C; ½a D33
ꢂ
¼ ꢁ10:4 (c 0.1, H2O); 1H NMR [d, ppm,
DMSO-d6]: 8.68 (br, 3H, +NH3), 7.45 (m, 5H, Ph), 5.26 (d, 1H,
3J = 9.7 Hz, C1-H), 3.83 (dq, 1H, J = 9.7, 6.7 Hz, C2-H), 1.03 (d, 3H,
3J = 6.7 Hz, C2–CH3). 13C NMR [d, ppm, DMSO-d6]: 138.08 (Ci),
129.9 (Cp), 129.65 (Co), 128.51 (Cm), 65.0 (C1), 52.92 (C2), 16.91
½
a 2D0
ꢂ
¼ ꢁ131 (c 0.8, EtOH) 1H NMR [d, ppm, CDCl3]: 7.25 (m, 5H,
Ph), 2.50 (s, 3H, N–CH3), 2.44 (d, 1H, 3J = 6.7 Hz, C2-H), 1.68 (dq,
1H, J = 6.7, 5.9 Hz, C2-H), 0.92 (d, 3H, 3J = 5.9 Hz, C2–CH3). 13C
NMR [d, ppm, CDCl3]: 137.76 (Ci), 128.11 (Co), 127.96 (Cm),
126.7 (Cp), 47.82 (C2), 47.71 (C3), 43.14 (N–CH3); 12.85 C3–CH3.
z/e (%): 146 (100), 147 (16), 148 (2).
C2–CH3; IR (KBr, m
max/cmꢁ1): 3420 (NH3), 3058, 3014 (Ar), 2996,
2974, 2958 (CH, CH3), 716, 692 (Cl); Elemental Anal. Calcd: C,
52.4461; H, 6.3570; N, 6.7956. Found: C, 53.1263; H, 6.4989; N,
7.5554.
4.4. (1R,2S)-Chlorodeoxyephedrine hydrochloride 4a
4.8. Threo-(1S,2S)-ephedrinylethylether hydrochloride 10a
Synthesized as 3a, (1R,2S)-(+)-ephedrine hydrochloride 1a
(1.0 g, 4.96 mmol) at room temperature to get 0.96 g (88%) of a
mixture of chlorodeoxy stereoisomers 4a/3a (40:60 erythro/threo).
The erythro chlorodeoxy hydrochloride 4a was separated from the
threo isomer 3a by a fractional crystallization from ethanol as a
white solid (0.2 g). 1H NMR [d, ppm, DMSO-d6]: 9.45 (br, 2H,
+NH2Me), 7.35 (m, 5H, Ph), 5.93 (d, 1H, 3J = 3.2 Hz, C1-H), 3.70
(dq, 1H, J = 3.2, 6.4 Hz, C2-H), 2.60 (s, 3H, N–CH3), 1.13 (d, 3H,
3J = 6.4 Hz, C2–CH3). 13C NMR [d, ppm, DMSO-d6]: 137.15 (Ci),
128.80 (Cp), 129.32 (Co), 128.04 (Cm), 63.45 (C1), 59.58 (C2),
31.19 (N–CH3); 10.63 (C2–CH3).
1H NMR [d, ppm, CDCl3]: 7.3 (m, 5H, Ph), 4.40 (d, 1H, 3J = 9.7 Hz,
C1-H), 3.31 (dq, J = 19.1, 7.0 Hz, 2H, O–CH2), 3.17 (dq, 1H, J = 9.7,
6.7 Hz, C2-H), 1.16 (t, J = 7.0 Hz, 3H, CH2CH3), 1.08 (d, 3H,
3J = 6.7 Hz, C2–CH3). 13C NMR [d, ppm, CDCl3]: 137.80 (Ci), 129.0
(Co), 128.99 (Cm), 127.82 (Cp), 82.65 (C1), 64.71 (C2), 60.59 (O–
CH2), 31.52 (N–CH3), 15.36 (CH2CH3), 13.72 (C2–CH3). z/e (%): 58
(100), 77 (9.6), 194 (18.4).
4.9. cis-(2R,3S)-2-Methyl-3-phenylaziridine 9b
Synthesized as 10a, (1R,2R)-chlorodeoxynorpseudo-ephedrine
hydrochloride 3b (1.0 g, 4.85 mmol) and K2CO3 (2.0 g,
14.55 mmol), aziridine 9b precipitate as white solid (0.62 g, 96%
4.5. (1S,2R)-Chlorodeoxynorephedrine hydrochloride 4b
yield): mp 61 °C, (lit.10 68 °C); ½a D20
ꢂ
¼ þ69:1 (c 4.43 ꢃ 10ꢁ3, CHCl3),
This compound was identified when the threo chlorodeoxy
hydrochloride 3b in DMSO-d6 solution is heated (80–90 °C) for five
hours in the NMR tube to get a 60:40 mixture of the 3b/4b
stereoisomers.
{lit.10
½
a 2D5
ꢂ
¼ ꢁ74 (c 3, EtOH)}; IR (KBr) 3218, 1600 cmꢁ1
;
1H NMR
[d, ppm, CDCl3]: 7.26 (m, 5H, Ph), 3.18 (d, 1H, 3J = 6.4 Hz, C2-H),
2.34 (dq, 1H, C2-H, 3J = 6.4, 5.6 Hz), 0.88 (d, 3H, 3J = 5.6 Hz, C2–
CH3). 13C NMR [d, ppm, CDCl3]: 137.86 (Ci), 128.11 (Co), 128.02
(Cm), 126.83 (Cp), 37.33 (C2), 32.39 (C3), 13.83 C3–CH3. z/e (%):
1H NMR [d, ppm, DMSO-d6]: 8.8 (br, 3H, +NH3), 7.45 (m, 5H, Ph),
5.65 (d, 1H, 3J = 4.4 Hz, C1-H), 3.70 (dq, 1H, J = 4.4, 6.4 Hz, C2-H),
1.17 (d, 3H, 3J = 6.4 Hz, C2–CH3). 13C NMR [d, ppm, DMSO-d6]:
135.63 (Ci), 129.93 (Cp), 129.65 (Co), 128.51 (Cm), 64.76 (C1),
52.51 (C2), 13.72, (C2–CH3).
132 (100), 133 (12), 77 (19.25), 28 (53.2). IR (KBr,
m
max/cmꢁ1):
3308 (NH), 3060, 3026 (Ar), 2992, 2958, 2926 (CH, CH3); Elemental
Anal. Calcd: C, 81.1600; H, 8.3239; N, 10.5161. Found: C, 81.0615;
H, 8.3238; N, 11.1770.
4.6.
4.10. Erythro-(1R,2S)-ephedrinylethylether 10ae
The isochlorodeoxy-derivatives 8a and 8b were identified as
intermediates in a solid mixture with the corresponding chlorode-
oxy-derivatives 3a and 3b when the reactions of the corresponding
chlorodeoxy-hydrochlorides 3a or 3b were reacted with two molar
equivalents of K2CO3 in refluxing chloroform for 72 h.
Sythesized as 10a, (1R,2S)-chlorodeoxyephedrine hydrochloride
4a (0.2 g, 0.11 mmol) and K2CO3 (0.046 g, 0.33 mmol) to get ether
10ae as white solid (0.2 g, 96% yield): mp = 185–186 °C;
½
a 2D0
ꢂ
¼ ꢁ68:5 (c 3.08 ꢃ 10ꢁ3, EtOH) 1H NMR [d, ppm, CDCl3]: 7.30
(m, 5H, Ph), 4.98 (d, 1H, 3J = 2.9 Hz, C1-H), 3.51 (dq, J = 7.0,
4.7 Hz, 2H, O–CH2), 3.27 (dq, 1H, J = 2.9, 6.7 Hz, C2-H), 1.26 (t,
J = 7.0 Hz, 3H, CH2CH3), 1.21 (d, 3H, 3J = 6.7 Hz, C2–CH3). 13C NMR
[d, ppm, CDCl3]: 137.82 (Ci), 128.86 (Co), 126.83 (Cm), 128.37
(Cp), 79.78 (C1), 65.41 (C2), 59.77 (O–CH2), 30.75 (N–CH3), 15.52
(CH2–CH3), 9.81 (C2–CH3). z/e (%): 58 (100), 77 (11.2), 194 (6.2).
4.6.1. (1R,2R)-Isochlorodeoxypseudoephedrine hydrochloride
8a
1H NMR [d, ppm, DMSO-d6]: 9.35 (br, 2H, +NH2CH3), 7.5 (m, 5H,
Ph), 4.76 (dq, 1H, 8.5, 6.4 Hz, C2-H), 4.49 (d, 1H, 3J = 8.5 Hz, C1-H),
2.59 (s, 3H, N–CH3), 1.26 (d, 3H, 3J = 6.4 Hz, C2–CH3). 13C NMR [d,
ppm, DMSO-d6]: 132.61 (Ci), 130.34 (Cp), 130.00 (Co), 129.83
(Cm), 68.45 (C1), 58.07 (C2), 32.08 (N–CH3); 22.44 (C2–CH3).
4.10.1. Crystal data
Formula, C12H20NOCl; formula weight, 229.74; crystal system,
monoclinic; space group, P21 (No. 4); a, b, c [Å], 14.1041(19),
4.6.2. (1S,2S)-Isochlorodeoxynorpseudoephedrine
hydrochloride 8b
7.1403(10), 14.642(2); a, b, c
[°], 90, 113.044(2), 90; V [°3],
1356.9(3); Z, 4; D(calcd) [g/cm3], 1.125; Mu(MoKa) [mm ], 0.260;
F(0 0 0), 496; crystal size [mm], 0.35 ꢃ 0.30 ꢃ 0.20.
1H NMR [d, ppm, DMSO-d6]: 7.65–7.40 (m, 5H, Ph), 4.63 (dq, 1H,
J = 9.7, 6.6 Hz, C2-H), 4.47 (d, 1H, 3J = 9.7 Hz, C1-H), 1.26 (d, 3H,
3J = 6.6 Hz, C4–CH3). 13C NMR [d, ppm, DMSO-d6]: 137.29 (Ci),
129.82 (Cp), 129.48 (Co), 127.96 (Cm), 60.91 (C1), 59.41 (C2),
22.35 (C2–CH3).
4.10.2. Data collection
Temperature (K), 293; radiation [Å], MoKa 0.71073; Theta Min–
Max [Deg], 1.5–25.0; dataset: ꢁ16:16; ꢁ8:8; ꢁ17:17; Tot., Uniq.

A. Cruz et al. / Tetrahedron: Asymmetry 21 (2010) 909–913
913
Mao, J.; Wan, B.; Wu, F.; Lu, S. Tetrahedron Lett. 2005, 46, 7341–7344; (w)
Unaleroglu, C.; Aydin, A. E.; Demir, A. S. Tetrahedron: Asymmetry 2006, 17, 742–
749; (x) Reyes, E.; Vicario, J. L.; Carrillo, L.; Badia, D.; Iza, A.; Uria, U. Org. Lett.
2006, 8, 2535–2538; (y) Guille, S.; Cabello, S.; Kizirian, J.-C.; Alexakis, A.
Tetrahedron: Asymmetry 2006, 17, 1045–1047; (z) Biswas, K.; Woodward, S.
Tetrahedron: Asymmetry 2008, 19, 1702–1708; (aa) Parrot, R. W., II; Dore, D. D.;
Chandrashekar, S. P.; Bentley, J. T.; Morgan, B. S.; Hitchcock, S. R. Tetrahedron:
Asymmetry 2008, 19, 607–611.
Data, R(int), 13286, 4798, 0.070; Observed data [I >2.0 sigma(I)],
3086; refinement: Nref, Npar, 4798, 271; R, wR2, S: 0.0654,
0.1320, 1.02; w = 1/[s2(Fo2) + (0.0422P)2] where P = (Fo2+2Fc2)/3;
Max. and Av. Shift/Error, 0.00, 0.00; Flack x, 0.10(10): Min. and
Max. Resd. Dens. [e/Ang3], ꢁ0.18, 0.20.
2. (a) Cruz, A.; Flores-Parra, A.; Tlahuext, H.; Contreras, R. Tetrahedron: Asymmetry
1995, 6, 1933–1940; (b) Cruz, A.; Macías-Mendoza, D.; Barragán Rodríguez, E.;
Tlahuext, H.; Nôth, H.; Contreras, R. Tetrahedron: Asymmetry 1998, 8, 3903–
3911; (c) Cruz, A.; Geníz, E.; Contreras, R. Tetrahedron: Asymmetry 1998, 9,
3391–3396; (d) Cruz, A.; Vásquez-Badillo, A.; Ramos-García, I.; Contreras, R.
Tetrahedron: Asymmetry 2001, 12, 711–717; Cruz, A.; Gayosso, M.; Contreras, R.
Heteroatom Chem. 2001, 12, 586–593; (e) Cruz, A.; Contreras, R.; Padilla-
Martinez, I. I.; Juárez-Juárez, M. Tetrahedron: Asymmetry 2006, 17, 1499–1505;
(f) Cruz, A.; Padilla-Martinez, I. I.; García-Báez, E. V.; Contreras, R. Tetrahedron:
Asymmetry 2007, 18, 123–130.
Acknowledgment
Alejandro Cruz thanks Secretaría de Investigación y Posgrado
del IPN, Grant SIP-20080690, for the financial support.
References
1. (a) Kagan, H. B.. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press,
1985; Vol. 5, (b) Frump, J. A. Chem. Rev. 1971, 71, 485; (c) Mûller, D.; Umbricht,
G.; Wever, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232; (d) Pfaltz, A. Acc. Chem.
Res. 1993, 26, 339; (e) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835–876; (f) Lin, P.; Hong-Bin, Y. Chem. Rev. 2001, 101, 757–824; (g) Andrus, M.
B.; Meredith, E. L.; Simmons, B. L.; Sekhar, B. B. V. S.; Hicken, E. J. Org. Lett. 2002,
4, 3549–3552; (h) Thorey, C.; Bouquillon, S.; Helimi, A.; Henin, F.; Muzart, J. Eur.
J. Org. Chem. 2002, 13, 2151–2159; (i) Smitrovich, J. H.; Boice, G. N.; Qu, C.;
DiMichele, L.; Nelson, T. D.; Huffman, M. A.; Murry, J.; McNamara, J.; Reider, P. J.
Org. Lett. 2002, 4, 1963–1966; (j) Chen, Y. C.; Li, X. Q.; Tu Yong, Q.; Deng, J.-G.
Tetrahedron: Asymmetry 2003, 14, 2481–2485; (k) Rivero, M. R.; De la Rosa, J. C.;
Carretero, J. C. J. Am. Chem. Soc. 2003, 125, 14992–14993; (l) Garcia Ruano, J. L.;
Alemparte, C.; Teresa Aranda, M.; Zarzuelo, M. M. Org. Lett. 2003, 5, 75–78; (m)
Guo, R.; Lough, A. J.; Morris, R. H.; Song, D. Organometallics 2004, 23, 5524–
5529; (n) Krebs, A.; Ludwig, V.; Pfizer, J.; Duerner, G.; Goebel, M. W. Chem. Eur.
J. 2004, 10, 544–553; (o) Mao, J.; Wan, B.; Wan, R.; Wu, F.; Lu, S. J. Org. Chem.
2004, 69, 9123–9127; (p) Sibi, M. P.; Stanley, L. M. Tetrahedron: Asymmetry
2004, 15, 3353, 3356; (q) Hitchcock, S. R.; Casper, D. M.; Vaughn, J. F.; Finefield,
J. M.; Ferrence, G. M.; Esken, J. M. J. Org. Chem. 2004, 69, 714–718; (r) Hein, J. E.;
Zimmerman, J.; Sibi, M. P.; Hultin, P. G. Org. Lett. 2005, 7, 2755–2758; (s)
Rodriguez, M.; Vicario, J. L.; Badia, D.; Carrillo, L. Org. Biomol. Chem. 2005, 3,
2026–2030; (t) Cheung, F. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. D.; Wills,
M. J. Org. Chem. 2005, 70, 3188–3197; (u) Blay, G.; Fernández, I.; Marco-
Aleixandre, A.; Pedro, J. R. Tetrahedron: Asymmetry 2005, 16, 1207–1213; (v)
3. Flores-Parra, A.; Suárez-Moreno, P.; Sánchez-Ruíz, S. A.; Tlahuextl, M.; Jaen-
Gaspar, J.; Tlahuext, H.; Salas Coronado, R.; Cruz, A.; Nôth, H.; Contreras, R.
Tetrahedron: Asymmetry 1998, 9, 1661–1671.
4. (a) Dieter, R. K.; Deo, N.; Lagu, B.; Dieter, J. W. J. Org. Chem. 1992, 57, 1663–
1671; (b) Poelert, M. A.; Hulshof, L. A.; Kellogg, R. M. Recl. Trav. Chim. Pays-Bas
´
1994, 113, 335–364; (c) De Sousa, S. E.; OBrien, P.; Poumellec, P. J. Chem. Soc.,
Perkin Trans. I 1998, 1483, 1492.
5. (a) Boris, S. J.; Beardsley, G. P. Tetrahedron Lett. 1966, 5113; (b) Boris, S. J. J. Org.
Chem. 1962, 27, 3532.
6. Okada, I.; Ichimura, K.; Sudo, R. Bull. Soc. Chem. Jpn. 1970, 43, 1185.
7. Pfister, J. R. Synthesis 1984, 969.
8. Poelert, M. A.; Hof, R. P.; Peper, N. C. M. W.; Kellogg, R. M. Heterocycles 1994, 37,
461.
9. Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1994, 59, 3210.
10. Galindo, A.; Orea-F, L.; Gnecco, D.; Enríquez, R. G.; Toscano, R. F.; Reynolds, W.
F. Tetrahedron: Asymmetry 1997, 8, 2877–2879.
11. Enraf-Nonius. CAD-4 EXPRESS. Version 5.1. Enraf-Nonius, Delft, The
Netherlands, 1995.
ˇ
12. Petricek, V.; Dušek, M. JANA98. Institute of Physics, Czech Academy of Sciences,
Cukravarnicka 10, 162 53, Prague, Czech Republic, 1998.
13. Sheldrick, G. M. SHELXS97 and SHELXL97. University of Göttingen: Germany, 1997.
14. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.