Chlorination reactions of ephedrines revisited. Stereochemistry and functional groups effect on the reaction mechanisms

Article abstract of DOI:10.1016/S0957-4166(98)00155-4

The stereochemistry of the chlorination reactions with SOCl₂ of free ephedrine and pseudoephedrine and their hydrochlorides, examides and sulfonamides was analyzed. Chlorination of free and hydrochloride erythro isomers occurs with 100% inversion of configuration at C-1 (S(N)2 mechanism). Chlorination of examides and sulfonamides of erythro isomers occurs with retention of the configuration at C-1, (S(N)i mechanism). Chlorination reactions in all three isomers and derivatives hydrochlorides, examides or sulfonamides gave the same ratio of erythro (40%) and three isomers (60%) (S(N)1 mechanism). Treatment of the isomeric mixture of the chlorodeoxyephedrine and chlorodeoxypseudoephedrine hydrochloride in DMSO with HCl changes the isomeric ratio, increasing the erythro isomer content (65%). Using the erythro ethanolamines it is possible to arrive stereoselectively at the erythro chloroamines if the compound is previously tosylated or converted to the amide, or to the three chloroamines if the compound is directly chlorinated with SOCl₂.

Full text of DOI:10.1016/S0957-4166(98)00155-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1661–1671
Chlorination reactions of ephedrines revisited. Stereochemistry
and functional groups effect on the reaction mechanisms†
Angelina Flores-Parra,a,∗ Patricia Suárez-Moreno,a Sonia A. Sánchez-Ruíz,a
Margarita Tlahuextl,a Javier Jaen-Gaspar,a Hugo Tlahuext,b Raúl Salas-Coronado,a
Alejandro Cruz,a Heinrich Nöth c and Rosalinda Contreras a,∗
aDepartamento de Química, Centro de Investigación y de Estudios Avanzados del IPN A.P. 14-740, 07000 México DF, México
bFacultad de Ciencias, Universidad A. del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa, Cuernavaca Morelos,
México
cInstitut für Anorganische Chemie, Universität München, Meiserstrasse 1, 80333 Munich, Germany
Received 2 February 1998; accepted 29 March 1998
Abstract
The stereochemistry of the chlorination reactions with SOCl2 of free ephedrine and pseudoephedrine and their
hydrochlorides, oxamides and sulfonamides was analyzed. Chlorination of free and hydrochloride erythro isomers
occurs with 100% inversion of configuration at C-1 (SN2 mechanism). Chlorination of oxamides and sulfonamides
of erythro isomers occurs with retention of the configuration at C-1, (SNi mechanism). Chlorination reactions in
all threo isomers and derivatives hydrochlorides, oxamides or sulfonamides gave the same ratio of erythro (40%)
and threo isomers (60%) (SN1 mechanism). Treatment of the isomeric mixture of the chlorodeoxyephedrine and
chlorodeoxypseudoephedrine hydrochloride in DMSO with HCl changes the isomeric ratio, increasing the erythro
isomer content (65%). Using the erythro ethanolamines it is possible to arrive stereoselectively at the erythro
chloroamines if the compound is previously tosylated or converted to the amide, or to the threo chloroamines if the
compound is directly chlorinated with SOCl2. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Ephedrines are very important substances in asymmetric synthesis; they are also widely used as
building elements for heterocycles and, as organometallic or metallic complexes, used as reagents or
catalytic agents in organic chemistry.1–3 We are currently studying the synthesis of ligands derived from
ephedrines which are used for the preparation of optically active boron or phosphorous derivatives.4–22
We are especially interested in the synthesis of ligands bearing amide groups, which have an acidic N–H
∗
†
Corresponding authors. E-mail: aflores@mail.cinvestav.mx
Dedicated to the memory of Professor Sir Derek H. R. Barton.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00155-4

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Fig. 1.
proton, easily substituted by hetero- or metallic atoms to give heterocycles.17,19,23 Herein, we describe
the stereochemistry of the synthesis of a series of chlorodeoxyephedrines, chlorodeoxysulfonamides and
bis-chlorodeoxyephedrine oxamides, which are versatile intermediates for many other optically active
ligands. During the preparation of these compounds, we discovered that chlorination reactions with
thionyl chloride gave different results depending on the isomer used, pseudoephedrine or ephedrine, and
on the nitrogen substitution.24–26 Herein, we discuss our results which attempt to give some explanation
of the mechanisms.
It has been reported that chlorination reactions of aliphatic alcohols with SOCl2 in the presence of a
base afford the corresponding chlorides with inversion of configuration, this fact has been explained by
an SN2 mechanism,27 whereas in the absence of base, the configuration of the carbon atom is retained,
and an SNi mechanism has been proposed.27 Chlorination reactions with SOCl2 of the ephedrines are
reported,24–26,28 but a clear picture of the behavior of these isomers in the reaction has not yet emerged.
Therefore, we decided to investigate the behavior of the ephedrine isomers and the nitrogen substitution
effect under comparable conditions.
2. Results and discussion
We have reacted free norephedrine 1, its hydrochloride 1a (1S,2R), ephedrine 2 and its hydrochloride
2a21 (1S,2R) with SOCl2 in the absence of solvent and base: the corresponding chlorodeoxynorpseudo-
ephedrine 3a (1R,2R) or chlorodeoxypseudoephedrine 4a (1R,2R) hydrochlorides were formed with
100% inversion at C-1 (Fig. 1). The X-ray diffraction structures of 3a and 4a21 confirmed the stereo-
chemistry (Fig. 2). Compounds 3a and 4a were tosylated to give 5 and 6, respectively; their structures
were determined by X-ray methods (Fig. 3).
In the molecular structure of compound 3a, we have found that the molecule adopts the staggered
conformation and the dihedral angle H1–C1–C2–H2 is 177.9°. The chlorine and nitrogen atoms are
present in a gauche position due to hydrogen bonding between the N–H and the chlorine atom, Cl1–H
distance is 2.54 Å. In the lattice there are intermolecular hydrogen bonds between the N–H atoms and
the chloride as shown in Fig. 2b.
Compound 5 presents a staggered conformation, the chlorine and the nitrogen atoms are in gauche
positions and the dihedral angle H1–C1–C2–H2 is 64.6° (Fig. 3a). This conformation is stabilized
by five hydrogen bonds in five-membered rings (H17–C17–C12–C1–Cl1, H17–Cl1 distance is 2.47
Å; Cl1–C1–C2–N4–H4, Cl1–H4 distance is 2.89 Å; H2–C2–N4–S1–O1, H2–O1 distance is 2.59 Å;
O1–S1–C5–C10–H10, O1–H10 distance is 2.61 Å; O2–S1–C5–C6–H6, O2–H6 distance is 2.66 Å).
Compound 6 was crystallized from chloroform and its structure was determined by X-ray diffraction.

A. Flores-Parra et al. / Tetrahedron: Asymmetry 9 (1998) 1661–1671
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Fig. 2. (a) Molecular structure of 3a; (b) intermolecular hydrogen bonds of 3a
Fig. 3. Molecular structure of (a) compound 5; (b) compound 6
It is present in the lattice as a staggered conformer with a gauche conformation of Cl1–C1–C2–N4.
The dihedral angles are Cl–C1–C2–N4 54.79° and H1–C1–C2–H2 179.76°. There are four hydrogen
bond interactions: H2–C2–N4–S5–O1, H2–O1 distance is 2.49 Å; O1–S5–C6–C7–H7, O1–H7 distance
is 2.50 Å; O2–S5–N4–C4–H4, O2–C4 distance is 2.58 Å; O2–S5–C6–C12–H12, O2–H12 distance is
2.83 Å (Fig. 3).
Chlorination of pseudoephedrine 7 and pseudoephedrine hydrochloride 7a (1S,2S) with SOCl2 af-
forded an isomeric mixture: 40% of the chlorodeoxyephedrine hydrochloride 8a (1R,2S) and 60% of
chlorodeoxypseudoephedrine hydrochloride 4a (1S,2S) (Fig. 4). If this mixture of 4a and 8a is acidified
(50 mg of the ephedrine mixture in 0.5 ml of DMSO-d6 and 1 ml of concentrated HCl), after five hours
the isomer ratio has changed to 65:35 of 8a:4a respectively, and no additional change was noted after one
week.
We have looked for an explanation of these apparently contradictory results and, therefore, we have

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Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
analyzed the conformers of the chlorosulfite ester intermediates resulting from the reaction of the
ephedrines and SOCl2. It has been found that for the ephedrine isomer the conformer that has the
ammonium group anti to the sulfite is the more stable one with only two gauche interactions. In this
conformer, the ammonium protons give assistance to the chloride approach in an SN2 mechanism leading
to a total inversion at C-1. An aziridine intermediate can be ruled out because it is not a basic medium,
and we have not observed the isomeric mixture which could come from the chloride attack on C-1 or
C-2 carbon atoms of the aziridine.28 In the pseudoephedrine family the conformer with the nitrogen atom
anti to the sulfite is not the most stable and an SN2 mechanism is therefore not favored (Fig. 5).
The constant isomeric ratio found in the chlorination reactions of different pseudoephedrine derivatives
(vide infra) indicates that dissociation into a carbonium ion and the sulfite anion occurs prior to the
chloride attack. Under these conditions, the chloride can attack either of the two faces of the benzylic
carbonium group affording the two isomers 4a and 8a (Fig. 6).
2.1. Chlorination of amides derived from ephedrine
An interesting fact is that the chlorination reaction by SOCl2 of the tosylamide derived from the (+)-
norephedrine 9 (1S,2R) or (−)-ephedrine 10 (1R,2S) produces the corresponding chlorides 11 and 12
respectively with 100% retention of configuration. The SN2 mechanism does not work here because
there is no assistance to the chloride approach, but an SNi chlorination is possible (Fig. 7).

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Fig. 8. Molecular structure of (a) compound 9; (b) compound 11
Fig. 9.
Figure 8a presents the molecular structure of the erythro compound 9. The conformer in this structure
has the O1 and N4 and phenyl and methyl groups in gauche positions, respectively. The dihedral angles
O1–C2–C3–N4 and H3–C3–C2–H2 are 57.5° and 58.0°. The structure is stabilized by six hydrogen
bonds in five-membered rings O1–C2–C3–N4–H4, O1–H4 distance is 2.71 Å; O1–C2–C14–C19–H19,
O1–H19 distance is 2.44 Å; O1–C2–C3–C13–H13, O1–H13 distance is 2.62 Å; O2–S5–N4–C3–H3,
O2–H3 distance is 2.64 Å; O2–S5–C6–C7–H7, O2–H7 distance is 2.40 Å; O3–S5–C6–C11–H11,
O3–H11 distance is 2.76 Å.
Compound 11 was crystallized from MeOH and its structure was determined by X-ray diffrac-
tion (Fig. 8b). Compound 11 in the solid state shows a different conformation to compound 9. The
staggered conformer has the chloride and the nitrogen atoms in anti-positions, the torsion angle for
Cl–C1–C2–N4 is 175.2° and for C3–C2–C1–C14 is 174.9°. The structure has four hydrogen bonds
H12–C12–C7–S6–O6b, H12–O6b distance is 2.60 Å; H8–C8–C7–S6–O6a, H8–O6a distance is 2.55
Å; Cl1–C1–C14–C19–H19, Cl1–H19 distance is 2.34 Å and Cl1–C1–C2–C3–H3, Cl1–H3 distance is
2.78 Å.
The same stereochemical behavior of the chlorination with SOCl2 in CH2Cl2 at rt, was found in the
bis-ephedrine oxamide 13 derived from norephedrine which gave the bis-chloro derivative 14 with total
retention of configuration at C-1 (Fig. 9).
2.2. Chlorination of amides derived from pseudoephedrine
Pseudoephedrine 7 (1S,2S) has been tosylated to give compound 15. The chlorination reaction of
pseudoephedrine N-tosylate 15 (1S,2S) with SOCl2 in the absence of base, gave 40% of the same isomeric
ratio of the corresponding chloro isomers: chlorodeoxypseudoephedrine 6 (1S,2S, 60%) and compound
16 (1R,2S, 40%) (Fig. 10).
Figure 11 presents the molecular structure of compound 15. The staggered conformation has O1 and N
atoms in gauche positions and the dihedral angles are O1–C1–C2–N4 75.63° and H1–C1–C2–H2 50.83°.
This molecule is also stabilized by hydrogen bonds, there is one hydrogen bond in a six-membered ring
O1–C1–C2–N4–C5–H5, bond distance O1–H5 is 2.25 Å, and five hydrogen bonds in five-membered

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Fig. 10.
Fig. 11. Perspective representation of compound 15
Fig. 12.
rings: O1–C1–C14–C15–H15, distance O1–H15 is 2.39 Å; O6b–S6–N4–C2–H2, distance is 2.35 Å;
O6b–S6–C7–C12–H12, distance O6b–H12 is 2.53 Å; O6a–S6–N4–C5–H5 distance O6a–H5 is 3.09 Å;
O6a–S6–C7–C8–H8, distance O6a–H8 is 2.69 Å.
The same stereochemical behavior of the chlorination as in pseudoephedrine was observed for bis-
pseudoephedrine oxamide 17 with SOCl2 in CH2Cl2 at rt which gave a mixture of three compounds: 14,
18 and 19. Under these reaction conditions the inversion at C-1 was about 40% (Fig. 12).
Compound 18 was crystallized from methanol–acetone, yielding crystals suitable for an X-ray diffrac-
tion study, Fig. 13. The structure found shows the threo configuration for the ethylenic chain fragment.
The oxamide group has a planar arrangement as is deduced from the dihedral angle of O16–C5–C7–O8,
−179°. There are hydrogen bonds between H4–O8 (2.35 Å), H9–O6 (2.28 Å), H3–O6 (2.41 Å) and
H10–O8 (2.46 Å). The chain has an alternating conformation. The chlorine atoms are not forming a
hydrogen bond with the acidic N–H proton as was found for ephedrine,19 the dihedral angles between
the chlorine and nitrogen atoms are Cl1–C2–C3–N4 53.9°, Cl12–C11–C10–N9 57.8°.

A. Flores-Parra et al. / Tetrahedron: Asymmetry 9 (1998) 1661–1671
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Fig. 13. (a) Molecular structure of compound 18; (b) view of intermolecular hydrogen bonds in 18. Each molecule presents four
intermolecular hydrogen bonds between N–H and the carbonyl groups, the bond distances marked are around 2.14 Å
3. Conclusions
By analyzing the stereochemistry of the chlorination products important conclusions are evident.
If chlorination is performed in the erythro ephedrine series by SOCl2 in the absence of pyridine, a
100% stereoselective formation of the chlorodeoxypseudoephedrine occurs. But if the sulfonamide of
the erythro ephedrine is chlorinated configuration at C-1 is retained. When the stereoisomer employed is
the pseudoephedrine, the reactions are not selective but it is possible to obtain the chlorodeoxyephedrine
as the predominant compound if the chlorinated compounds mixture is treated with HCl.
The X-ray diffraction structures of compounds 3a, 5, 6, 9, 11, 15, and 18 present several hydrogen
bonds between the heteroatoms with lone pairs and nonacidic hydrogen atoms which determine the
conformer in the lattice. The O–S–O angle in compounds 5 (119.9), 6 (119.3), 9 (119.5), 11 (119.9),
15 (119.2) is very open, and the oxygen atoms approach the phenyl plane favoring hydrogen bonding
with ortho aromatic protons.
4. Experimental section
1H and 13C NMR spectra were recorded on a JEOL GXS-270 spectrometer in DMSO-d6 and CDCl3
solution with TMS as an internal reference. The IR spectra were taken as KBr discs using a Perkin–Elmer
16 F PC IR spectrometer. Mass spectra were obtained on an HP 5989A. Elemental analyses were
performed by Oneida Research Services. The optical rotation were obtained on a Perkin–Elmer 241
polarimeter. Melting points were measured on a Gallenkamp apparatus and are uncorrected. Solvents
were dried according to literature procedures. The X-ray diffraction experimental data has been deposited
at the Cambridge Crystallographic Database.

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4.1. Chlorination reactions
4.1.1. (−)-1R,2R-1-Chloro-1-phenyl-2-aminepropane hydrochloride 3a
To the (+)-1S,2R-norephedrine 1 (1 g, 6.61 mmol), SOCl2 (1.43 ml, 19.8 mmol) was added. After
stirring for 5 h at rt the excess of SOCl2 was removed under vacuum. The white solid obtained was
washed with acetone, filtered and recrystallized from CH3OH (0.76 g, 74%). Mp 205–207°C. IR (KBr,
ν cm−1): 3420, 3058, 2996, 2974, 2958, 716, 692. [α]D33=−10.4 (H2O, c=0.1). 13C NMR (CDCl3):
δ=16.1 (C-3), 52.4 (C-2), 64.1 (C-1), 126.1 (Cm), 127.5 (Cp), 128.3 (Co), 137.3 (Ci). 1H NMR (CDCl3):
δ=1.13 (d, J 6.20, 3H, H-3), 3.91 (qd, J 6.2 and 6.6, 1H, H-2), 5.45 (d, J 6.6, 1H, H-1), 7.47 (m, 5H).
Calcd for C9H13NCl2, C (52.47), N (6.79), H (6.31); found: C (53.12), N (7.55), H (6.49).
4.1.2. (+)-1S,2S-1-Chloro-1-phenyl-2-(N-methyl)aminepropane hydrochloride 4a
The same general procedure of chlorination was used for (−)-1R,2S-ephedrine 2 (3.0 g, 18.1 mmol).
The white solid obtained was washed with acetone, filtered and recrystallized from CH3OH (3.7 g, 94%).
Mp 198–200°C. [α]D30=+10.5 (CH3OH, c=0.1). 13C NMR (DMSO-d6): δ=13.37 (C-3), 29.68 (CH3–Ts),
1
58.78 (C-2), 62.78 (C-1), 128.44 (Cm), 129.46 (Cp), 129.74 (Co), 137.70 (Ci). H NMR (DMSO-d6):
δ=1.04 (d, J 6.2, 3H, H-3), 2.59 (s, 3H, CH3–Ts), 3.95 (quint, J 6.2 and 9.5, 1H, H-2), 5.46 (d, J 9.5, 1H,
H-1), 7.5–7.4 (m, 5H), 9.51 (s, br, NH).
4.1.3. N[(+)-1R,2R-1-Chloro-1-phenyl-2-propyl]-p-toluensulfonamide 11
The same procedure of chlorination was used for 9 (0.6 g, 1.96 mmol). The brown solid obtained was
recrystallized from THF/ethanol (0.61 g, 96%). Mp 135–136°C. [α]D33=+51.0 (THF, c=0.1). 13C NMR
(CDCl3): δ=15.29 (C-3), 21.62 (CH3–Ts), 55.44 (C-2), 68.04 (C-1), 127.05, 127.36, 128.41, 128.56,
129.90, 137.64 (Ci), 137.94 (Cp–Ts), 143.68 (Ci–Ts). 1H NMR (CDCl3): δ=1.0 (d, J 6.5, 3H, H-3), 2.39
(s, 3H, CH3–Ts), 3.71 (dq, J 6.5 and 3.4, 1H, H-2), 7.27 (s, 7H, arom.) 7.75 (d, J 8.6, 2H, Ts).
4.1.4. N[(−)-1R,2S-1-Chloro-1-phenyl-2-propyl]-N-methyl-p-toluensulfonamide 12
The same procedure of chlorination was used for 10 (1.0 g, 3.3 mmol). A brown viscous liquid was
obtained (1.1 g, 100%). Mp 119–120°C. [α]D33=−56.6 (THF, c=0.1). 13C NMR (CDCl3): δ=135.02
(C-3), 21.53 (CH3–Ts), 29.67 (NCH3), 58.17 (C-2), 67.42 (C-1), 127.16 (Cm–Ts), 127.55 (Co), 128.46
1
(Cp), 128.59 (Cm), 129.72 (Cp–Ts), 137.19 (Ci), 139.05 (Cp–Ts), 143.41 (Ci–Ts). H NMR (CDCl3):
δ=1.12 (d, J 6.7, 3H, H-3), 2.33 (s, 3H, CH3–Ts), 2.66 (s, 3H, NCH3), 4.45 (quint, J 6.7, 1H, H-2), 4.97
(d, J 6.7, 1H, H-1), 7.1–7.5 (m, 9H, arom).
4.1.5. N[1R,2S-1-Chloro-1-phenyl-2-propyl]-N-methyl-p-toluensulfonamide 16
The same procedure of chlorination was used for 15 (1.0 g, 3.13 mmol). To the reaction mixture,
acetone was added and the mixture was precipitated and filtered. The solution was evaporated and a
brown viscous liquid was obtained [0.67 g, 6 (60%) and 16 (40%)]. Data for compound 16: 13C NMR
(CDCl3): δ=12.91 (C-3), 21.54 (CH3–Ts), 58.13 (C-2), 67.47 (C-1). 1H NMR (CDCl3): δ=1.50 (d, J 7.3,
3H, H-3), 2.38 (s, 3H, CH3–Ts), 4.08 (dd, J 7.3 and 6.6, 1H, H-2), 5.02 (d, J 6.6, 1H, H-1).

A. Flores-Parra et al. / Tetrahedron: Asymmetry 9 (1998) 1661–1671
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4.2. Synthesis of oxamides
4.2.1. N,N0-Bis[1S,2R-norephedrine]oxamide 13
A mixture of (+)-1S,2R-norephedrine (9.8 g, 64.8 mmol) and diethyl oxalate (4.4 ml, 32.4 mmol) was
refluxed in 60 ml of toluene for 3 hours. A white solid was formed which was separated by filtration
(11.4 g, 98%). [α]D=−39.7 (DMSO, c 1.4).
4.2.2. N,N0-Bis[1R,2R-norpseudoephedrine]oxamide 17
[α]D=−47.8 (DMSO, c 1.6).
4.2.3. N,N0-Bis[1-chloro-1-phenylpropyl]oxamide 14
A solution of 13 (5 g, 14 mmol) and SOCl2 (3.1 ml, 42 mmol) in CH2Cl2 (70 ml) was stirred for 48 h.
The reaction afforded a white solid which was washed with acetone/hexane (5 g, 91%). Mp 215–216°C.
[α]D=+67.6 (DMSO, c 1.4). IR (KBr, ν cm−1): 3442, 3308, 3192, 2936, 1656, 1508, 1208, 1130, 742,
698, 668. 13C NMR (DMSO-d6, 50°C): 65.1 (C-1), 50.2 (C-2), 158.2 (C-3), 17.0 (CH3), 138.3 (Ci), 127.9
(Co), 127.2 (Cm), 128.0 (Cp), 1H NMR (DMSO-d6, rt): 5.06 (d, 2H, J 8.3, H-1), 4.30 (m, 2H, H-2), 1.27
(d, 6H, J 6.2, CH3), 8.56 (d, 2H, J 9.0, NH), 7.30 (m, 10H, C6H5). M+ (%): 357.20 (1), 91.15 (28),
117.25 (44), 125.15 (36), 231.25 (22), 267.25 (65), 44.0 (100). Calcd for C20H22O2N2Cl2, C (61.08), N
(7.12), H (5.63); found: C (60.85), N (6.98), H (5.59).
4.2.4. N,N-Bis-[1-chloro-1-phenylpropyl]oxamides 14, 18, 19
Oxamide 17 (2 g, 5.6 mmol) was mixed with SOCl2 (1.2 ml, 16.8 mmol) and stirred for 15 h, acetone
was added (20 ml) and the mixture was stirred for 15 minutes, then the solvent was evaporated under
vacuum. The reaction product was a mixture of diastereoisomers 14 18%, 18 33% and 19 49%, their
ratio was calculated from the NMR spectra (2.2 g, 100%). After 7 h standing with NaOH (0.3 g), the
reaction mixture gave crystals of compound 18, which were recrystallized from methanol acetone to give
suitable crystals for an X-ray diffraction structure.
Compound 18: Mp 211–213°C. IR (KBr, ν cm−1): 3408, 3306, 2940, 1664, 1512, 1456, 736, 700,
676, 1210, 1144, 1242. [α]D=−174.6 (DMSO, c=11.7). 13C NMR (DMSO-d6): 65.9 (C-1), 51.1 (C-2),
159.2 (C-3), 18.0 (CH3), 138.9 (Ci), 128.7 (Co), 127.5 (Cm), 128.6 (Cp). 1H NMR (DMSO-d6): 5.26 (d,
2H, J 9.2, H-1), 4.44 (m, 2H, H-2), 0.96 (d, 6H, J 6.6, CH3), 8.92 (d, 2H, J 9.2, NH) 7.41 (s, C6H5) M+
(%): 357.25 (2), 44.15 (100), 91.20 (24), 117.30 (41), 125.20 (33), 231.25 (25), 267.20 (92), 269.20 (34).
Calcd for C20H22O2N2·1/8H2O, C (60.74), N (7.08), H (5.60); found: C (60.71), N (7.03), H (5.58).
Compound 19: 13C NMR (DMSO-d6): 65.6 (C-1), 50.9 (C-2), 158.8 (C-3), 17.8 (CH3–C-2), 138.8
(Ci), 65.3 (C-10), 50.3 (C-20), 158.5 (C-30), 17.4 (CH3–C-20), 138.7 (Ci). 1H NMR (DMSO-d6): 5.18 (d,
1H, J 8.6, H-1), 4.43 (m, 1H, H-2), 0.89 (d, 3H, J 7.3, CH3), 8.76 (d, 1H, J 9.2, NH), 5.12 (d, 1H, J 9.3,
H-10), 4.3 (m, 1H, H-20), 1.36 (d, 3H, J 6.6, CH3-20), 8.73 (d, 1H, J 9.24, NH-20), 7.33 (C6H5).
4.3. Tosylation reactions
4.3.1. N[(−)-1R,2R-1-Chloro-1-phenyl-2-propyl]-p-toluensulfonamide 5
General procedure: A solution of 3a (0.5 g, 2.44 mmol) and Na2CO3 (0.61 g) in a mixture of
CHCl3/ethanol (70/30, 10 ml) tosyl chloride (0.46 g, 2.43 mmol) was added. The reaction mixture
was stirred for 5 h. Then, 10 ml of H2O was added and the product extracted with CHCl3 (50 ml).
The combined extracts were dried with Na2SO4 and concentrated under vacuum. The yelow solid was
recrystallized from a mixture of CHCl3/hexane (25/75) (0.76 g, 90%). Mp 119–121°C. [α]D33=−40.3

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(THF, c=0.1). IR (KBr, ν cm−1): 3236, 3056, 2978, 2934, 2872, 1334, 668. 13C NMR (CDCl3): δ=18.2
(C-3), 21.5 (CH3–Ts), 55.4 (C-2), 65.9 (C-1), 128.0 (Co) 127.0 (Cm), 126.1 (Cp), 137.0 (Cp–Ts), 137.6
(Ci), 143.3 (Ci–Ts). 1H NMR (CDCl3): δ=1.82 (d, J 6.7, 3H, H-3), 2.39 (s, 3H, CH3–Ts), 3.76 (qd, J 6.7
and 4.9, 1H, H-2), 4.90 (d, J 4.9, 1H, H-1), 7.26 (m, 5H, Ar), 7.86 (d, J 8.4, 4H, Ts). M+ (%): 324 (1),
288 (1), 198 (100), 155 (58), 125 (16), 91 (55). Calcd for C16H19SO2N, C (59.40), N (4.32), H (5.56), S
(9.98); found: C (62.27), N (5.13), H (5.66), S (9.66).
4.3.2. N[(+)-1R,2R-1-Chloro-1-phenyl-2-propyl]-N-methyl-p-toluensulfonamide 6
The same tosylation procedure was used for 4a (2 g, 9.1 mmol). The solution was filtered and the
solvent was evaporated. The white solid was obtained from a mixture of CHCl3/hexane (25/75) (3
g, 98%). Mp 118–120°C. [α]D30=+69.1 (CHCl3, c=0.1). IR (KBr, ν cm−1): 3236, 3056, 2978, 2934,
2872, 1334, 668. 13C NMR (CDCl3): δ=14.69 (C-3), 21.44 (CH3–Ts), 58.47 (C-2), 63.97 (C-1), 127.41
(Cm–Ts), 128.26 (Cm), 128.53 (Cp), 129.22 (Co), 130.18 (Co–Ts), 136.96 (Ci), 139.43 (Cp–Ts), (Ci–Ts).
1H NMR (CDCl3): δ=0.58 (d, J 6.9, 3H, H-3), 2.35 (s, 3H, CH3–Ts), 4.41 (qd, J 6.9 and 9.9, 1H, H-2),
5.16 (d, J 9.9, 1H, H-1), (m, 5H, Ar), (d, J 8.4, 4H, Ts).
4.3.3. (+)-1R,2S-1-Chloro-1-phenyl-2-(N-methyl)aminepropane hydrochloride 8a
The same tosylation procedure was used for 7a. The reaction afforded a mixture of compounds 4a
(60%) and 8a (40%), which was analyzed by NMR. Data for 8a: 13C NMR (DMSO-d6): δ=10.41 (C-3),
59.47 (C-2), 63.25 (C-1), 31.06 (N–CH3). 1H NMR (CDCl3): δ=1.13 (d, J 6.6, 3H, H-3), 3.50 (N–CH3),
3.71 (qd, J 6.6 and 2.6, 1H, H-2), 5.98 (d, J 2.6, 1H, H-1).
4.3.4. N[(+)-1S,2R-1-Hydroxy-1-phenyl-2-propyl]-p-toluensulfonamide 9
General procedure: To a solution of (+)-1S,2R-norephedrine 1 (1.0 g, 6.6 mmol) and triethylamine
(1.0 ml, 6.7 mmol) in THF (10 ml), tosyl chloride (1.26 g, 6.63 mmol) was added. The reaction mixture
was stirred for 12 h. Then, 10 ml of H2O was added and the product was extracted with CHCl3 (50 ml).
The combined extracts were dried with Na2SO4 and concentrated under vacuum. The white solid was
recrystallized from CHCl3/MeOH (25/75) (1.94 g, 96%). Mp 103–105°C. [α]D33=+21.9 (THF, c=0.1).
IR (KBr, ν cm−1): 3440, 3306, 3040, 3022, 2926, 2856, 1398. 13C NMR (CDCl3): δ=14.2 (C-3), 21.4
(CH3–Ts), 55.0 (C-2), 75.5 (C-1), 125.9 (Co) 126.9 (Cm), 127.3 (Cp), 129.7 (Co–Ts), 128.1 (Cm–Ts),
137.7 (Ci), 140.4 (Cp–Ts), 143.3 (Ci–Ts). 1H NMR (CDCl3): δ=0.8 (d, J 7.3, 3H, H-3), 2.38 (s, 3H, CH3
Ts), 3.50 (qd, J 3.3 and 7.3, 1H, H-2), 4.78 (d, J 3.3, 1H, H-1), 7.23 (m, 5H), 7.75 (d, J 8.6, 4H, H–Ts).
M+ (%): 288 (5), 198 (100), 155 (72), 107 (38), 91 (92), 44 (23). Calcd for C16H19NSO2, C (62.94), N
(4.58), H (6.26), S (10.49), O (17.72); found: C (62.56), N (4.58), H (6.33), S (9.98).
4.3.5. N[(−)-1R,2S-1-Hydroxy-1-phenyl-2-propyl]-N-methyl-p-toluensulfonamide 10
The same tosylation procedure was used for (−)-1R,2S-ephedrine 2 (5 g, 30.2 mmol). The white solid
was recrystallized from a mixture of CHCl3 (8.6 g, 90%). Mp 60–61°C. [α]D30=−63.9 (THF, c=0.1).
13C NMR (CDCl3): δ=11.00 (C-3), 21.56 (CH3–Ts), 30.54 (NCH3), 57.98 (C-2), 77.17 (C-1), 126.31
(Cm–Ts), 127.10 (Co), 127.71 (Cp), 128.36 (Cm), 129.73 (Co–Ts), 136.33 (Ci), 141.69 (Cp–Ts), 143.26
(Ci–Ts). 1H NMR (CDCl3): δ=0.85 (d, J 7.2, 3H, H-3), 2.37 (s, 3H, CH3 Ts), 2.66 (s, 3H, NCH3), 4.13
(qd, J 7.2 and 4.2, 1H, H-2), 4.79 (t, J 4.2, 1H, H-1), 7.21 (d, J 7.22, 2H, Ts), 7.2–7.4 (m, 5H, arom),
7.54 (d, J 7.22, 2H, Ts).

A. Flores-Parra et al. / Tetrahedron: Asymmetry 9 (1998) 1661–1671
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4.3.6. N[(+)-1S,2S-1-Hydroxy-1-phenyl-2-propyl]-N-methyl-p-toluensulfonamide 15
The same tosylation procedure was used for (+)-1S,2S-pseudoephedrine 7 (2 g, 9.13 mmol). The white
solid was recrystallized from CHCl3 (g, 87%). Mp 70–71°C. [α]D33=+30.3 (THF, c=10−2). IR (KBr, ν
cm−1): 3440, 3306, 3040, 3022, 2926, 2856, 1398. 13C NMR (CDCl3): δ=12.8 (C-3), 21.3 (CH3–Ts),
28.6 (NCH3), 59.1 (C-2), 74.9 (C-1), 127.2 (Co), 127.3 (Cm), 128.2 (Cp), 129.8 (Co–Ts), 128.5 (Cm–Ts),
1
136.1 (Ci), 140.8 (Cp–Ts), 143.6 (Ci–Ts). H NMR (CDCl3): δ=0.50 (d, J 6.9, 3H, H-3), 2.32 (s, 3H,
CH3–Ts), 2.69 (NCH3), 3.99 (qd, J 6.9 and 8.9, 1H, H-2), 4.34 (d, J 8.9, 1H, H-1), 7.25 (m, 7H), 7.60
(d, J 8.2, 2H, Ho–Ts). M+ (%): 288 (5), 198 (100), 155 (72), 107 (38), 91 (92), 44 (23).
Acknowledgements
P.S.M, M.T., J.J.G., R.S.C. and A.C. are grateful for a scholarship from CONACYT-Mexico. Financial
suport was provided by CONACYT-Mexico. We thank Ing. Marco Antonio Leyva Ramírez for the X-ray
determination of the structures 6 and 13.
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