1,3-Heterazolidines-2-heterounsaturated compounds derived from ephedrines

Article abstract of DOI:10.1016/j.tetasy.2006.05.009

Herein, a direct and easy method for preparing 2-oxo-, 2-thione- or 2-imine-1,3-heterazolidines derived from ephedrines and norephedrines are reported. The method is based on solvent free heating of ephedrines with oxocyanate or thiocyanate salts (180-200 °C). In the reactions with potassium oxocyanate in refluxing ethanol, it was possible to isolate ureidic derivatives. The structure and stereochemistry of the compounds were determined by ¹H, ¹³C NMR, IR spectroscopies and mass spectrometry. Ureidic derivatives, cis-1,5-dimethyl-4-phenyl-imidazolidine-2-thione and trans-4-methyl-5-phenyl-thiazolidine-2-one are new compounds. Ephedrineurea, cis-1,5-dimethyl-4-phenyl-imidazolidine-2-thione and trans-4-methyl-5-phenyl-thiazolidine-2-one were also studied by X-ray diffraction.

Full text of DOI:10.1016/j.tetasy.2006.05.009

Tetrahedron: Asymmetry 17 (2006) 1499–1505
1,3-Heterazolidines-2-heterounsaturated compounds
derived from ephedrines
b
a
Alejandro Cruz,a, Rosalinda Contreras, Itzia I. Padilla-Martınez
*
´
a
´
´
and Minerva Juarez-Juarez
aDepartamento de Quı´mica de la Unidad Profesional Interdisciplinaria de Biotecnologı´a del IPN Me´xico, DF 07340, Mexico
bDepartamento de Quı´mica del Centro de Investigacio´n y de Estudios Avanzados del IPN. A. P. 14-740, Me´xico, DF 07000, Mexico
Received 16 March 2006; accepted 11 May 2006
Abstract—Herein, a direct and easy method for preparing 2-oxo-, 2-thione- or 2-imine-1,3-heterazolidines derived from ephedrines and
norephedrines are reported. The method is based on solvent free heating of ephedrines with oxocyanate or thiocyanate salts (180–
200 ꢀC). In the reactions with potassium oxocyanate in refluxing ethanol, it was possible to isolate ureidic derivatives. The structure
and stereochemistry of the compounds were determined by 1H, 13C NMR, IR spectroscopies and mass spectrometry. Ureidic derivatives,
cis-1,5-dimethyl-4-phenyl-imidazolidine-2-thione and trans-4-methyl-5-phenyl-thiazolidine-2-one are new compounds. Ephedrineurea,
cis-1,5-dimethyl-4-phenyl-imidazolidine-2-thione and trans-4-methyl-5-phenyl-thiazolidine-2-one were also studied by X-ray diffraction.
ꢁ 2006 Elsevier Ltd. All rights reserved.
O
180-200 ºC
NH2
NH4+NCO-
-H2O
1. Introduction
H2N
H
N
Ph
There are several reports in the literature concerning the syn-
thesis of 1,3-heterocycles with 2-one, 2-thione and 2-imine
functional groups derived from b-aminoalcohols, b-amino-
thiols and ethylendiamines, by the use of dialkylcarbonates,1
phosgene,2 urea,3 thiophosgene and thiourea,4 carbon disul-
fide5 and cyanogen bromide.6 In a previous work we have
reported the synthesis of 1,3-thiazolidine-2-thiones,7 1,3-
thiazolidine-2-imines,8 1,3-heterazaborolidines,7–9 thiazol-
idines10 and2-imino-benzothiazolylheterazolidines11 derived
from ephedrines, which were recently reviewed.12
O
O
O
H3C
N
CH3
Ph
OH
Ph
OH
O
HS NH2
180-200 ºC
6a-(t)
_
+
H3C
N
NH2
H3C
NH2Cl
CH3
O
Ph
-NH3
CH
2a-(e)
3
1a-(e)
H3C
N
CH3
10a-(c)
Scheme 1. Dehydration of ephedrine 1a-(e) with urea according to Close.3
In 1950, Close3 reported the solvent free dehydration of
ephedrine hydrochloride 1a-(e) in the presence of urea at
180–200 ꢀC to afford imidazolidinone 6a-(t) and oxazolidi-
none 10a-(c) (Scheme 1). In that report it was assumed that
at 180–200 ꢀC, the urea was transformed into ammonium
oxocyanate, which, in the presence of hydrochloride, trans-
formed into ammonium chloride and oxocyanic acid. It
was proposed that this reacts with free ephedrine to give
ureidic intermediate 2a-(e) (not isolated), which upon cycli-
zation and dehydration, afforded the trans-imidazolidone
6a-(t). In addition, nucleophilic attack of the oxygen atom
of the ephedrine to the ureidic carbonyl and ammonia elim-
ination, produced oxazolidone heterocycle 10a-(c).
With the aim of studying the mechanistic transformation of
the Close’s reaction, it was revisited by the use of K+NCOꢀ
instead of urea, and the study was extended for thiocyan-
ates and pseudoephedrine 1a-(th), norephedrine 1b-(e)
and norpseudoephedrine 1b-(th), as chiral aminoalcohols
to afford a series of optically active 1,3-heteroazolidine-2-
heterounsaturated compounds 4–10 (Scheme 2), which
are relevant because of their potential use as chiral induc-
tors, specially those with the N–H functionality.13
*
Corresponding author. Tel.: +55 572 96000; fax: +55 572 56325; e-mail:
acruz@acei.upibi.ipn.mx
0957-4166/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.009

1500
A. Cruz et al. / Tetrahedron: Asymmetry 17 (2006) 1499–1505
oxygen atom to form a seven membered ring was observed.
1a-(e), (1R,2S)-(-)-ephedrine
X
Y
˚
1a-(th), (1R,2R)-(-)-pseudoephedrine
1b-(e), (1S,2R)-(+)-norephedrine
1b-(th), (1R,2R-(-)-norpseudoephedrine
The O1H1ꢁ ꢁ ꢁO6 distance of 1.820(24) A [angle of 166.72ꢀ
4
5
6
7
8
9
S
NH2+NCS-
(2.25)] is within the range for a strong interaction.14 The
hydrogen bond formed is strong enough that it forces the
NH2 group to adopt a syn-conformation to the N-Me
group [C8N4C5N7 angle of ꢀ6.00 (0.26)ꢀ], in spite of the
steric hindance. On the other hand, both nitrogen atoms
are conjugated with the carbonyl group since both N–CO
NH
NH
S
S
O
S
O
S
O
S
O
M = K, NH4
Z = O, S
Ph
H3C
OH
+
Ph
M+NCZ-
X
Y
_
180-200 ºC
H3C
N
R
NH2Cl
R
a
b
10 O
4-10
1
R = CH3, H
bond distances are of intermediate value between a single
15
˚
˚
(1.469 A) and a double (1.279) N–C bond (1.35 A mean).
Scheme 2. 1,3-Heterazolidines-2-heterounsaturated from ephedrines.
The formation of an equimolar mixture of imidazolidone
6a-(c) and oxazolidone 10a-(c) from intermediate 2a-(e)
was demonstrated when this last compound was free of sol-
vent, heated at 180–200 ꢀC for 1 h (Scheme 4). Imidazolid-
inone 6a-(c) was precipitated from a CHCl3 solution and
was purified by recrystallization from ethanol. The analysis
2. Results
2.1. Reactions with oxocyanate
Urea derivative 2a-(e), which in principle is formed in the
Close’s reaction, was isolated when ephedrine hydrochlo-
ride 1a-(e) was reacted with K+NCOꢀ for 72 h in refluxing
ethanol (78% yield). The reaction is quite general, it was
also performed with pseudoephedrine 1a-(th), norephe-
drine 1b-(e) and norpseudoephedrine 1b-(th) to give, quan-
titatively, the ureidic derivatives 2a-(th), 2b-(e) and 2b-(th)
in 83%, 80% and 86% isolated yield, respectively (Scheme
3). On the other hand, reaction of 1a,b-(e,th) with
Na+NCSꢀ only exchanged the chloride with a thiocyanate
anion to give the corresponding hydrothiocyanates 3a,b-
(e,th) (Scheme 3).
1
of H and 13C NMR spectra showed the formation of the
cis (c) isomer instead of the expected trans (t) isomer and
this was confirmed by X-ray diffraction.9 Retention of the
C1 configuration was in disagreement with the Close’s
mechanistic proposal. A mechanism based on an aziridine
intermediacy could explain the formation of the cis-imidaz-
olidone 6a. It is known that aziridines are involved in a
double inversion of the benzylic carbon atom to produce
heterocycles with retention of configuration.16 Thus, aziri-
dine I and later on isocyanate II intermediate products
would give the observed configuration for 6a-(c) (Scheme
4). On the other hand, competitive attack of the hydroxy
group onto the carbonyl oxygen atom with ammonia elim-
ination explained the formation of the oxazolidone 10a-(c),
according to the Close’s idea (Scheme 4). The results are in
agreement with several reports in the literature, where the
in situ generation of amide derivatives from amino alcohols
are involved in oxazolidine formation.1–3
NH4+NCS-
Ethanol
Ph
OH
+
K+NCO-
Ph
OH
+
Ph
OH
O
_
_
Ethanol
Reflux
H3C
NH2Cl
CH3
H3C
NH2SCN
CH3
H3C
N
CH3
2a,b-(e,th)
NH2
Reflux
1a,b-(e,th)
3a,b-(e,th)
Scheme 3. Reaction of ephedrines 1a,b-(e,th) with K+NCOꢀ and
NHþ4 NCSꢀ in refluxing ethanol.
On the basis of these previous findings, the solvent free
reaction of ephedrines 1a,b-(e,th) were performed either
with sodium or ammonium thiocyanates.
When a racemic mixture of ephedrine hydrochloride 1a-(e)
was reacted with K+NCOꢀ, the ureidic intermediate 2a-(e)
was crystallized from ethanol and its structure studied by
X-ray diffraction (Fig. 1).
2.2. Reactions with thiocyanate
The reaction of 1a-(e) with one equimolar amount of
Na+NCSꢀ was carried out at 180–200 ꢀC for 0.5 h without
solvent. After CHCl3/H2O partition, the ephedrine hydro-
thiocyanate 3a-(e) was isolated from the aqueous phase,
whereas trans-thiazolidine-2-imino hydrothio-cyanate 4a-
(t) precipitated from the chloroform phase (10% yield)
(Scheme 5).
Ph
OH
+
_
S
Ph
1Na+NCS-
+
+
NH2SCN
_
180-200 ºC
0.5 h
H3C
N
CH3
H3C
NH2SCN
CH3
Ph
OH
4a-(t)
3a-(e)
Ph
H3C
_
+
H3C
NH2Cl
CH3
O
Figure 1. Molecular structure of ephedrineurea 2a-(e).
2Na+NCS-
180-200 ºC
4 h
1a-(e)
An intramolecular hydrogen bonding interaction between
the hydrogen atom of the hydroxyl group and the ureidic
Scheme 5. Reaction of ephedrine 1a-(e) with NaSCN.

A. Cruz et al. / Tetrahedron: Asymmetry 17 (2006) 1499–1505
1501
+
Ph
Ph
OH
H2O
Ph
OCN-
H3C
Ph
NCO
H
O
180-200 ºC
- H+NCO-
-H2O
N+
CH3
H3C
N
CH3
NH2
H3C
N
CH3
H
H3C
NH
CH3
2a-(e)
1a-(e)
I
II
H
O
Ph
H
N
O
N
Ph
H3C
10a-(c)
NH2
-NH3
Ph
O
O
H3C
N
CH3
O
H3C
N
CH3
CH3
6a-(t)
2a-(e)
Scheme 4. Competitive mechanistic proposal for the cyclization of ephedrineurea 2a-(e).
In order to improve the yield, the reaction time was
increased to 4 h. Under these conditions, deamination of
ephedrine hydrothiocyanate proceeded to give the forma-
tion of ethylphenylketone via enolate formation. The result
was the same when using one or 2 M equiv of sodium thio-
cyanate (Scheme 5). Ethylphenylketone was identified from
1H and 13C NMR data [d13C in 200 ppm (C@O)], a triple
and a quadruple signals in 1.2 and 2.98 ppm (CH3CH2)]
and by mass spectrometry [(z/e) = 134 (18%), M+].
Pseudoephedrine 1a-(th), norephedrine 1 b-(e) and nor-
pseudoephedrine 1b-(th) were each reacted with 2 M equiv
of NHþ4 NCSꢀ as described above for ephedrine 1a-(e). The
corresponding resulting mixtures were separated by col-
1
umn chromatography and the fractions analyzed by H
and 13C NMR and by mass spectrometry. The identified
compounds are listed in Table 1.
The reaction mixture of pseudoephedrine hydrochloride
1a-(th) was extracted with a 50:50 ratio of a CHCl3/H2O
mixture. The chloroform phase was separated by column
chromatography, using chloroform as eluent. From the
second fraction, the imidazolidine-2-thione 5a-(c) was sep-
arated in 40% yield. Three remaining fractions were ana-
lyzed by mass spectrometry and imidazolidones 6a-(c)
and 6a-(t), thiazolidinethione 7a-(c), thiazolidinones 8a-
(c) and 8a-(t) were identified in small quantities. A solid
was obtained after evaporation of the aqueous phase, from
which thiazolidine-2-imino hydrothiocyanate 4a-(c), oxa-
zolidinones 10a-(c) and 10a-(t) were identified by mass
spectrometry.
The reaction with 2 equiv of ammonium thiocyanate
for 4 h resulted in the formation of thiazolidine-2-imino
hydrothiocyanate 4a-(t) in 50% yield, which precipitates
from a chloroform solution of the reaction mixture. The
change from sodium to ammonium thiocyanate salt,
avoided deamination, probably due to its lower melting
point (153 ꢀC). Compound 4a-(t) was identified by compar-
1
ing H and 13C NMR data with the previously reported
data confirmed from an X-ray authenticated structure, ob-
tained from chlorodeoxypseudoephedrine derivative.8 The
remaining chloroform mixture was eluted in a chromato-
graphic column using chloroform as eluent. The analysis
of the fractions by mass spectrometry showed the presence
of the heterocycles as summarized in Table 1.
Compound 5a-(c) was purified and recrystallized from
ethyl acetate (40% yield). NMR spectra shows a broad
Table 1. Carbonyl carbon chemical shift in parts per million, proportion (%) and mass spectrometry data [M+ (%)] of heterocycles 4–10
Heterocycle
4
5
6
7
8
9
10
Ephedrine
X
Y
S
NH
S
NH
O
S
S
S
O
O
S
O
O
NH2SCN
1a-(e)
c
t
184(2)
183(7)
163(3)
[190(27)]
162(7)
196(7)
[223(100)]
195(2)
172(4)
171(7)
160(2)
[191(19)]
191(23)
168(50)
[206(98)]
[223(100)]
1a-(th)
c
t
169(15)
[206(15)]
184(40)
[206(100)]
163(5)
[190(27)]
162(2)
196(6)
[223(100)]
Traces
172
[207(64)]
171
160(5)
[191(19)]
159(20)
[191(23)]
[223(100)]
[207(41)]
1b-(e)
c
t
Traces
[192(100)]
Traces
200(5)
[209(100)]
199(2)
176(5)
189(2)
[193(35)]
160(40)
[177(8)]
[193(16)]
175(40)
[193(25)]
[209(100)]
1b-(th)
c
t
173(40)
[192(62)]
172(10)
183(10)
[192(100)]
200(15)
[209(100)]
175(10)
[193(16)]
174(5)
160(3)
159(3)

1502
A. Cruz et al. / Tetrahedron: Asymmetry 17 (2006) 1499–1505
signal at 6.32 ppm (1H) and at 183 ppm (13C) characteristic
of the N–H and thiocarbonyl groups, respectively. The
molecular ion [z/e = 206 (100%), M+] supported the struc-
ture. The X-ray diffraction analysis confirmed the stereo-
chemistry of 5a-(c) (Fig. 2). The bond distances C2–N1
as eluents and each fraction analyzed by mass spectro-
metry. Thiazoline-2-amine hydrothiocyanate 4b-(c) was
isolated from the fourth fraction.
The cis or trans configuration of the heterocycles was estab-
lished by the 1H NMR chemical shifts of the C–CH3 signal.
The cis isomers showed a low frequency shift of the C–CH3
group, which appears in the range between 0.9 and
0.7 ppm, due to the shielding effect exerted by the phenyl
group. In contrast, the C–CH3 chemical shift of the trans
isomers is shifted to high frequency, appearing between
1.1 and 1.4 ppm.
˚
˚
[1.345(14) A] and C2–N3 [1.332(13) A] show an intermedi-
15
˚
ate value between a single (1.469 A) and a double (1.279)
N–C bond, thus extensive conjugation through the N1–
C2–N3 fragment is demonstrated.
3. Discussion
According to our results, at least four competitive mecha-
nisms were proposed to explain the formation of hetero-
cycles 4–10a,b in the reaction of ephedrines 1a-(e,th) and
norephedrines 1b-(e,th) with ammonium thiocyanate
(Scheme 6). With the exception of norephedrine 1b-(e), in
these reactions, an SN2 dehydration mechanism occurs
due to the thiocyanate ꢀ isothiocyanate anions acting as
nucleophiles and subsequent cyclization of the ephedri-
nethiocyanate (IV) and ephedrineisothiocyanate (III) inter-
mediates to give the corresponding thiazolidine-2-imino
hydrothiocyanates 4a,b and imidazolidinethiones 5a,b.
For ephedrine 1a-(e), the product from thiocyanate anion
predominates and for pseudoephedrine 1a-(th), the product
from isothiocyanate gives the major product. It is notewor-
thy that, recently, an alkyl ephedrinethiocyanate analogue
to IV has been isolated.17
Figure 2. Molecular structure of cis-imidazolidinethione 5a-(c).
From the reaction mixture of norephedrine hydrochloride
1b-(e), four fractions were separated by column chroma-
tography using chloroform and then ethanol as eluents,
each fraction was analyzed by mass spectrometry. From
the second fraction, compounds 8b-(c) and 8b-(t) were
In the reaction with norephedrine 1b-(e), it is proposed that
the H2S generated by hydrolysis of thiocyanate, acts as the
main nucleophile via competitive SN2 and SN1 mechanisms
to form the intermediates VI-(e,th), which subsequently
cyclize with deamination to give thiazolidinethiones 7b-(c,t).
Desulfurization by hydrolysis of the corresponding thione
derivatives 7b-(c,t), gave the thiazolidinones 8b-(c,t). Simul-
taneously a mechanism through thioureidic intermediate V
operates, which is cyclized to get the oxazolidinethione 9b-
(c), the subsequent desulfurization led to the oxazolidinone
10b-(c). The desulfurization was demonstrated when the
reaction time was decreased from 4 h to 2 h, in which case
the proportion of oxazolidinethione 9b-(c) increased from
10% to 40% and cis-oxazolidinone 10b-(c) decreased by
the same proportion.
1
identified in a 1:8 ratio by H and 13C NMR. In a second
column, using CHCl3 as eluent, compound 8b-(t) (40%
yield) was separated from 8b-(c). The molecular ion [z/e =
193 (25%), M+] supported the structures. Compound
8b-(t) was crystallized from ethanol (40% yield) and the
trans configuration was confirmed by X-ray diffraction
˚
(Fig. 3). The bond distances C2–N [1.332(3) A] and C2–S
˚
[1.775(2) A] are shorter than the single bonds C4–N
˚
˚
[1.332(3) A] and C5–S [1.821(2) A], respectively, indicating
an extensive conjugation through the N–C2–S fragment.
The presence of oxazolidinone 10a-(t) (20%) in the reaction
of pseudoephedrine 1a-(th), occurred via the desulfuriza-
tion of oxazolidinethione 9a-(t) formed by the cyclization
of thioureidic intermediate V. As described in Scheme 6,
this mechanism is favoured when 1 M equiv of
NHþ4 NCSꢀ is used. In this case, oxazolidinone 10a-(t)
(40%) and imidazolidinethione 5a-(c) (20%) were observed
as the main products. Similar results were also obtained in
the reaction of norpseudoephedrine 1b-(th). When the
molar equivalents of NHþ4 NCSꢀ were changed from two
to one, thiazoline-2-amine hydrothiocyanates 4b-(c)
decreased from 40% to 15% yield, while oxazolidinone
10b-(t) increased from 3% to 45% yield.
Figure 3. Molecular structure of trans-thiazolidinone 8b-(t).
The reaction mixture of norpseudoephedrine hydrochlo-
ride 1b-(th) was separated into four fractions by a chro-
matographic column with chloroform and then ethanol

A. Cruz et al. / Tetrahedron: Asymmetry 17 (2006) 1499–1505
1503
+
+
+
Hydrolysis
+
NH4SCN
H2S
NH4NCO
NH4NCS
Oxocyanate
Thiocyanate
Isothiocyanate
Ph
SH
NH2
S
S
S
Ph
H3C
8a,b
Ph
Ph
OH
+
-NH3
H2O
-H2S
O
S
_
H3C
N
R
H3C
N
R
N
R
H3C
NH2Cl
R
VI
7a,b
1a,b
Nu = H2S
_
+
Ph
Ph
SCN
_
H
S
Ph
NH4NCS
+
+
NH2SCN
_
SN1
+
H3C
Nu
_
N
R
Nu
H3C
H3C
NH2SCN
+
_
NH2SCN
R
Ph
OH
4a,b
+
R
IV
III
NH4NCS
_
+
H3C
NH2SCN
R
H
N
Ph
NCS
Ph
H
SN2
_
Ph
3a,b
+
S
_
Nu
H3C
OH2
+
H3C
N
R
_
H3C
NH2SCN
R
_
NH2SCN
R
5a,b
Nu = NCS, SCN
R = CH3(a), H(b)
-H2SH2O
H
H
O
Ph
O
Ph
H3C
10a,b
NH2
O
Ph
H2O
-H2S
-NH3
N
Ph
O
S
O
H3C
N
R
S
N
R
H3C
N
R
H3C
N
R
V
9a,b
6a,b
Scheme 6. Proposed mechanisms to explain the formation of heterocycles 4–10.
4. Conclusions
tion numbers CCDC: 8b-(t), (601398); 2a-(e), (601399)
and 5a-(c), (601400). X-ray diffraction cell refinement and
data collection: CAD-4 EXPRESS;18 data reduction: JANA98;19
programs used to solve structure: SHELXS-97;20 software
used to prepare material for publication: WinGX.21 Mass
spectrometer HP 5989A, 5890 serie II.
In conclusion, from the reaction of ephedrines with potas-
sium oxocyanate, the ureidic intermediates 2a,b-(e,t) were
quantitatively isolated. Compound 2a-(e) was studied by
X-ray diffraction. Two mechanisms are involved in the
cyclization of ureaephedrine derivative 2a-(e), one of which
proceeds through the aziridine intermediate and the other
by nucleophilic attack of the hydroxy group to the ureidic
carbonyl. In both cases the heterocyclic products retain the
configuration of the parent compounds. Moreover, we
have described a solventless method to obtain heterazoli-
dines-2-heterounsaturated compounds 4–10 from ephed-
rines 1a,b-(e,t) and ammonium thiocyanate. Each
reaction stereoselectively produced one heterocycle in 40–
50% yield. Several interrelated mechanisms take place,
although the proportion of the products can be manipu-
lated by changing the reaction conditions such as stoichio-
metry and reaction time.
5.2. Preparation of ephedrineureas 2a,b-(e,t), general method
5.2.1. (1R,2S)-(ꢀ)-1-(2-Hydroxy-1-methyl-2-phenyl-ethyl)-
1-methyl-urea 2a-(e). Ephedrine chlorhydrate 1a-(e)
(1.0 g, 4.96 mmol), K+NCOꢀ (0.402 g, 4.96 mmol) and
50 mL of ethanol were added into a 100 mL flask and the
mixture refluxed for 72 h (96 h for ephedrine). The result-
ing suspension was cooled in an ice bath, until all the NaCl
was precipitated, it was filtered and the ethanol eliminated
1
in vacuo to obtain 0.8 g (78% yield) of white crystals: H
NMR, d (ppm), DMSO-d6: 7.15–7.30 (m, 5H, Ph), 5.64
(s, 2H, NH2), 5.46 (d, 1H, 3J = 4.7 Hz, OH), 4.55 (dd,
1H, 3J = 5.43 Hz, C1–H), 4.23 (dq, 1H, C2–H); 2.6 (s,
3H, N–CH3); 1.03 (d, 3H, 3J = 6.75, C2–CH3). 13C
NMR: 158.9 (C@O), 144.1 (Ci), 127.7 (Co), 126.8 (Cp),
126.4 (Cm), 75.4 (C1), 55.0 (C2), 30.0 (N–CH3); 12.9
(C2–CH3), mp = 122–124 ꢀC. mIR (cmꢀ1, KBr): (C@O).
[a]D =ꢀ8.1 (c 1.6 · 10ꢀ3 g/mL, 8.9 · 10ꢀ3 M, ethanol).
5. Experimental
5.1. General
Melting points were measured on an Electrothermal IA
apparatus and are uncorrected. IR spectrum were recorded
in a film on ZnSe using a Perkin–Elmer 16F PC IR spectro-
5.2.2. (1R,2R)-(ꢀ)-1-(2-Hydroxy-1-methyl-2-phenyl-ethyl)-
1-methyl-urea 2a-(t). Following the same procedure for
2a-(e), pseudoephedrine chlorhydrate 1a-(t) (1.0 g,
4.96 mmol) and K+NCOꢀ (0.402 g, 4.96 mmol) were used
photometer. H and 13C NMR spectra were recorded on a
1
Varian Mercury 300 MHz (1H, 300.08; 13C, 75.46 MHz).
The spectra were measured with tetramethylsilane as the
internal reference following standard techniques. Crystallo-
graphic data (excluding structure factors) for the structures
in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
1
to obtain 0.85 g (82.5% yield) of white crystals: H NMR
[d, ppm, DMSO-d6]: 7.2–7.4 (m, 5H, Ph), 5.7 (s, 2H, NH2),
5.4 (d, 1H, 3J = 3.8 Hz, OH), 4.5 (dd, 1H, 3J = 7.9 Hz,
C1–H), 4.2 (dq, 1H, C2–H), 2.6 (s, 3H, N–CH3), 1.0 (d,
3H, 3J = 6.8 Hz, C2–CH3). 13C NMR [d, ppm, DMSO-d6]:

1504
A. Cruz et al. / Tetrahedron: Asymmetry 17 (2006) 1499–1505
158.9 (C@O), 144.1 (Ci), 127.7 (Co), 126.8 (Cp), 126.4 (Cm),
75.4 (C1), 55.0 (C2), 30.0 (N–CH3), 12.9 C2–CH3, mp =
144–147 ꢀC. mIR (cmꢀ1, KBr): 1650 (C@O). [a]D = ꢀ15.0
(c 1.53 · 10ꢀ3 g/mL, 8.5 · 10ꢀ3 M, ethanol).
form solution, over an ice bath, the solid was filtered off
and compound 4a-(t) was recrystallized from ethanol to
get 0.66 g of 4a-(t) (50% yield): 1H NMR [d, ppm,
DMSO-d6]: 9.0 (broad, 2H, +NH2), 7.30–7.45 (m, 5H,
3
Ph), 4.9 (d, 1H J = 5.0 Hz, C5–H), 4.4 (dq, 1H, C4–H);
5.2.3.
(1S,2R)-(+)-(2-Hydroxy-1-methyl-2-phenyl-ethyl)-
3.2 (s, 3H, N–CH3), 1.4 (d, 3H, 3J = 6.2 Hz, C4–CH3).
13C NMR [d, ppm, DMSO-d6]: 167.3 (C2@N), 138.3 (Ci),
128.95 (Co), 128.55 (Cp), 127.4 (Cm), 69.7 (C4), 53.2
(C5), 32.5 (N–CH3); 16.5 C4–CH3.
urea 2b-(e). Following the same procedure for 2a-(e), nor-
ephedrine hydrochloride 1b-(e) (1.0 g, 5.33 mmol) and
K+NCOꢀ (0.43 g, 5.33 mmol) were used to obtain 0.82 g
1
(80% yield) of white crystals: H NMR [d ppm, DMSO-
d6]: 7.18–7.30 (m, 5H, Ph), 5.93 (d, 1H, 3J = 8.5 Hz,
NH), 5.53 (d, 1H, 3J = 4.7 Hz, OH), 5.5 (s, 2H, NH2),
4.61 (t, 1H, 3J = 4.0 Hz, C1–H); 3.78 (dq, 1H, C2–H);
5.4.2. (4S,5R)-(+)-1,5-Dimethyl-4-phenyl-imidazolidine-2-
thione 5a-(c). ꢀPseudoephedrine 1a-(t) (1.0 g, 4.96 mmol)
and NHþ4 NCS (0.754 g, 9.92 mmol) were used. The chlo-
roform solution was extracted with water three times, dried
over Na2SO4, filtered and purified on a silica gel chromato-
graphic column (60, 70–230 mesh ASTM), which was
eluted with a 50:50 solution of CHCl3/AcOEt. The second
fraction was recrystallized from ethylacetate to give 0.41 g
(40% yield) of cis-imidazolidinethione 5a-(c) suitable for
X-ray analysis: 1H NMR [d, ppm, CDCl3]: 7.2–7.4 (m,
3
0.81 (d, 3H, J = 6.75 Hz, C2–CH3). 13C NMR [d ppm,
DMSO-d6]: 159.14 (C@O), 144.32 (Ci), 128.44 (Co),
127.22 (Cp), 126.72 (Cm), 75.47 (C1), 51.27 (C2), 14.92
(C2–CH3), mp = 122–124 ꢀC. mIR (cmꢀ1, KBr): 1656
(C@O). [a]D = +3.0 (c 1.68 · 10ꢀ3 g/mL, 8.66 · 10ꢀ3 M,
ethanol).
3
5.2.4.
(1R,2R)-(ꢀ)-(2-Hydroxy-1-methyl-2-phenyl-ethyl)-
5H, Ph), 6.3 (broad, 1H, NH), 5.0 (d, 1H, J = 9.4 Hz,
urea 2b-(t). Following the same procedure for 2a-(e) nor-
pseudoephedrine chlorhydrate 1b-(t) (1.0 g, 5.33 mmol)
and K+NCOꢀ (0.43 g, 5.33 mmol) were used to obtain
0.89 g (86% yield) of a viscous liquid: H NMR [d, ppm,
DMSO-d6]: 7.2–7.3 (m, 5H, Ph), 5.8 (d, 1H, J = 8.2 Hz,
C4–H), 4.2 (dq, 1H, C5–H), 3.1 (s, 3H, N–CH3); 0.8
3
(d, 3H, J = 6.45, C5–CH3). 13C NMR [d, ppm, CDCl3]:
183.7 (C2@S), 136.7 (Ci), 128.85 (Co), 128.6 (Cp), 127.3
(Cm); 64.9 (C4), 61.7 (C5), 32.0 (N–CH3); 14.3
(C5–CH3). z/e = 206 (100%). m (cmꢀ1, film): 3204.1
(NH), 1751.7 (C@S), mp = 138–140 ꢀC, [a]D = +34.3 (c
1.43 · 10ꢀ3 g/mL, 7.7 · 10ꢀ3 M, CHCl3).
1
3
NH), 5.6 (broad, 1H, OH), 5.5 (s, 2H, NH2), 4.5 (d, 1H,
3J = 3.8 Hz, C1–H); 3.75 (dq, 1H, C2–H); 0.95 (d, 3H,
3J = 6.75 Hz, C2–CH3). 13C NMR [d, ppm, DMSO-d6]:
159.25 (C@O), 144.0 (Ci), 127.3 (Co), 127.3 (Cp), 128.2
(Cm), 75.45 (C1), 51.1 (C2), 18.5 (C2–CH3), mIR (cmꢀ1
,
5.4.3.
(4R,5R)-(+)-4-Methyl-5-phenyl-thiazolidin-2-one
KBr): 1650 (C@O). [a]D = ꢀ6.1 (c 1.64 · 10ꢀ3 g/mL,
8b-(t). Norephedrine 1b-(e) (1.0 g, 5.33 mmol) and
NHþ4 NCSꢀ (0.81 g, 10.66 mmol) were used. The chloro-
form mixture was eluted on a silica gel chromatographic
column (60, 70–230 mesh ASTM) using chloroform as elu-
ent. From the second fraction, trans-thiazolidone 8b-(t)
together with its cis isomer 8b-(c) were separated in a 80/20
proportion, respectively. In a second column, compound
8b-(t) was separated from its cis isomer, using CHCl3 as
eluent: The trans-thiazolidinone 8b-(t) was recrystallized
from ethanol to obtain 0.41 g of pure product (40% yield):
1H NMR [d, ppm, CDCl3]: 7.30–7.5 (m, 5H, Ph), 7.0
(broad, 1H, NH), 4.55 (d, 1H, 3J = 8.3 Hz, C5–H), 4.0
8.45 · 10ꢀ3 M, ethanol).
5.3. Preparation of ephedrine hydrothiocyanates 3a,b-(e,t),
general method
The same procedure and quantities used for the syntheses
of ephedrineureas 2a,b-(e,t) were used to obtain 3a,b-(e,t)
1
in quantitative yields. The H and 13C NMR data were
similar as for the corresponding 2a,b-(e,t). All compounds
showed the same characteristic IR signals: mIR (cmꢀ1
,
KBr): 3328 (+NH2), 2043 (ꢀSCN). Mp for 3a-(e) is: 126–
128 ꢀC.
3
(dq, 1H, C4–H), 1.3 (d, 3H, J = 6.2 Hz, C4–CH3). 13C
NMR [d, ppm, CDCl3]: 175.0 (C2@O), 138.2 (Ci); 129.4
(Co), 128.9 (Cp), 128.5 (Cm), 58.1 (C5); 60.0 (C4); 19.5
(C4–CH3). z/e = 193 (25.6%). mIR (cmꢀ1, KBr): 3233.6
(NH), 1678.1 (C@O), [a]D = +33.0 (c 2.03 · 10ꢀ3 mg/mL,
CHCl3), mp = 90–91 ꢀC.
5.4. Heating of ephedrines 1a,b-(e,t) wih ammonium thio-
cyanate, general method
Ephedrine hydrochlorides 1a,b-(e,t) (1.0 g) and 2 M equiv
of NHþ4 NCSꢀ were poured into a 100 mL flask. The mix-
ture was heated at 180 ꢀC without a solvent for 3 h, and
then at 200 ꢀC for 1 h. The reaction mixture was cooled
and 50 mL of ethanol added. The solution was put into
an ice bath for one more hour, after which the NaCl was
filtered off and the ethanol evaporated. The remaining
solid was dissolved in chloroform and worked up as
described.
Acknowledgements
´
The authors thank Conacyt-Mexico (Grant 32190-E) and
´
´
Coordinacion General de Posgrado e Investigacion-IPN
for financial support.
5.4.1.
(1S,2S)-trans-3,4-Dimethyl-5-phenyl-thiazolidin-2-
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