Reactivity of (R)-4-phenyloxazolidine-2-thione chiral auxiliary: From deprotection to heterocyclic interconversion

Article abstract of DOI:10.3987/COM-08-11410

Using (R)-3-benzyl-4-phenyloxazolidin-2-thione (2) as model compound, a sequence of reactions has been established that allows the chiral auxiliary deprotection to furnish a primary amine. Treatment of 2 with ethyl triflate (3b) followed by ring opening with RbI (4b) and HI elimination with DBU, in a one pot process, gave S-ethyl-N-benzyl-N-1-phenylvinylcarbamothioate (5, 95% yield) which acid hydrolysis (9) and saponification liberated benzylamine. Through a mechanistic study, we showed that the activated chiral oxazolidin-2-thione 3b is a tunable intermediate towards the corresponding oxazolidin-2-one 7, thiazolidin-2-one 8 and thiazolidin-2-thione 10. All those reactions were chemoselective and preserved the chiral center. A structural analysis of this series of heterocycles, by NMR and X-ray diffraction, has been performed. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11410

HETEROCYCLES, Vol. 75, No. 10, 2008
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HETEROCYCLES, Vol. 75, No. 10, 2008, pp. 2459 - 2475. © The Japan Institute of Heterocyclic Chemistry
Received, 16th April, 2008, Accepted, 22nd May, 2008, Published online, 26th May, 2008. COM-08-11410
REACTIVITY OF (R)-4-PHENYLOXAZOLIDINE-2-THIONE CHIRAL
AUXILIARY: FROM DEPROTECTION TO HETEROCYCLIC
INTERCONVERSION
Jean-Christophe Monbaliu,a Bernard Tinant,b and Jacqueline Marchand-
Brynaert a,*
a Unité de Chimie Organique et Médicinale, Département de Chimie, Université
catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, B-1348
Louvain-la-Neuve, Belgium
b Unité de Chimie Structurale et des Mécanismes Réactionnels, Département de
Chimie, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis
Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Corresponding author: Tel: +32 10 472740; Fax: +32 10 474168;
E-mail: jacqueline.marchand@uclouvain.be
Abstract - Using (R)-3-benzyl-4-phenyloxazolidin-2-thione (2) as model
compound, a sequence of reactions has been established that allows the chiral
auxiliary deprotection to furnish a primary amine. Treatment of 2 with ethyl
triflate (3b) followed by ring opening with RbI (4b) and HI elimination with DBU,
in a one pot process, gave S-ethyl-N-benzyl-N-1-phenylvinylcarbamothioate (5,
95% yield) which acid hydrolysis (9) and saponification liberated benzylamine.
Through a mechanistic study, we showed that the activated chiral oxazolidin-2-
thione 3b is a tunable intermediate towards the corresponding oxazolidin-2-one 7,
thiazolidin-2-one 8 and thiazolidin-2-thione 10. All those reactions were
chemoselective and preserved the chiral center. A structural analysis of this series
of heterocycles, by NMR and X-ray diffraction, has been performed.
INTRODUCTION
Homochiral oxazolidin-2-(thi)ones and thiazolidin-2-(thi)ones1,2 have found synthetic applications mainly
as vehicle to transfer chirality, with predictable stereochemistry of the newly formed stereocenters.3
Contrary to chiral catalysts, chiral auxiliaries are used in stoichiometric amounts and their involvement in
organic chemistry is based on the “protecting group” concept: their attachment to the substrate has to be

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HETEROCYCLES, Vol. 75, No. 10, 2008
stable under the reaction conditions but their deprotection at the end of the synthesis has to be easy,
complete and smooth, to avoid degradation, isomerisation, … of the target-molecule. Ideal situation is
reached when the recycling of the chiral source is possible; this is the case when the Evan’s type chiral
auxiliaries are anchored on the substrate via an acyl function as illustrated in Figure 1 (exocyclic
hydrolysis).4-6 But occasionally, the heterocyclic nitrogen atom is designed to make part of the final
target-molecule and hence, the chiral auxiliaries have to be sacrified by a ring opening reaction (Figure 1,
endocyclic hydrolysis). This is also the situation if the nitrogen atom cannot be introduced via exocyclic
aminolysis because of the absence of acyl-anchoring function.3 Very few examples of endocyclic
cleavage have been illustrated in the literature and moreover they have been specifically applied to
oxazolidin-2-one (X = Y = O) chiral auxiliaries.7-9
X
X
O
R
O
O
exocyclic
hydrolysis
endocyclic
hydrolysis
Y
Z'
Y
H
N
R1
N
R1
+
N
Z
R1
H
R
R
X = O, S; Y = O, S
Z = OH, NH2, ...
Figure 1. Cleavage modes of chiral auxiliaries from the literature
We have previously developed a novel 1-amino-diene, N-protected with a chiral oxazolidin-2-thione
moiety.10 This reagent revealed very useful in [4+2] Diels-Alder reactions, giving cycloadducts with very
high diastereoselectivities, particularly in the case of phosphonodienophiles.3 This stimulates our interest
in the selective ″deprotection″ of oxazolidin-2-thione chiral auxiliaries. Our objective was to replace the
heterocycle with a free primary amine function, which nitrogen atom comes from the heterocycle.
In this paper, we illustrate an original deprotection method validated on the model compound 2 featuring
a masked benzylamine. A one-pot protocol involving four steps leads efficiently to the free amine. On
the way, novel chemo- and stereoselective heterocyclic rearrangements have been discovered. The
structural analysis of all heterocycles based on NMR and crystallographic data, is fully described.
RESULTS AND DISCUSSION
1. GENERAL STRATEGY. While oxazolidin-2-thione derivatives are commonly prepared by
condensation of carbon disulfide with β-aminoalcohols, we successfully made use of a less toxic reagent,
i.e. 1,1’-thiocarbonyldiimidazole for the condensation with 1 furnishing nearly quantitatively the model
compound 2.11

HETEROCYCLES, Vol. 75, No. 10, 2008
2461
H
O
5
1
H
O
2
i.
ii.
OH
NH2
S
N
N
6
4
99%
95 %
H
3
2
1
Reagents and conditions: i. Benzaldehyde (1 eq.), MgSO4, MeOH, rt, 5 h; then NaBH4, rt,
30 min.; ii.Thiocarbonyldiimidazole (1.5 eq. ), DCM, rt, 5 h.
Scheme 1. Synthesis of model compound 2
The precursor 1 was obtained by reductive amination12 of (R)-phenylglycinol (Scheme 1). It is well
known that this kind of heterocycle 2 is resistant to the cleavage by hydrogenolysis and the most popular
method for achieving ″deprotection″ employs sodium or lithium in liquid ammonia,13 experimental
conditions incompatible with a wide range of chemical functions. Accordingly, we decided to exploit the
thiocarbonyl reactivity in a first activation step (via a S-alkylation reaction), followed by an endocyclic
SN2-like opening step (chemoselective nucleophilic attack on C5); elimination providing an enamine-type
intermediate and hydrolysis were planned to achieve the release of the free amine (Figure 2).
Nu
NH2
O
O
O
R1
R1W
Nu-
R1
elimination
hydrolysis
S
S
N
S
N
N
W-
Figure 2. Strategy to cleave the chiral oxazolidin-2-thione moiety
Alkylation of thioamide-containing heterocycles is generally accomplished by using alkyl halides (R1W;
W = Cl, Br, I), while a lot of other alkylating reagents such as propiolactone, diazomethane, α-
chloroacetates, isonitriles and N-acetyl-chloroacetaldimine14-19 are able to react on the sulphur atom of
C=S bonds with enhanced nucleophilicity due to the presence of two vicinal heteroatoms. The resulting
alkyl thionium species generally undergo rapid dealkylation (W = halogen)19 or evolve towards
rearrangement products (W ≠ halogen; see Figure 2).14-19 Alkyl triflates are well known as efficient
-
alkylating agents20,21 they generate a non-nucleophilic counter-anion CF3SO3 , thus avoiding dealkylation.
Accordingly, we used methyl, ethyl and isopropyl triflates for the oxazolidin-2-thione activation step.
Reaction with 2 in anhydrous acetonitrile at room temperature furnished quantitatively the corresponding
alkylated heterocycles 3a, 3b and 3c, after 15 min, 30 min and 15 h respectively (Figure 3). We never
observed polymerization reactions under those conditions.22 Intermediates 3 could not be purified, but
the crude products were properly characterized by the usual spectroscopies (see Experimental Section).
According to the literature, this kind of activated heterocycles offers three sites for further reactions, with

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HETEROCYCLES, Vol. 75, No. 10, 2008
different hardness/softness properties, named A, B and C as shown in Figure 3. The A and B sp3 soft
sites have been respectively involved in polymerization reactions towards optically active polyurethanes22
and in the above mentioned dealkylation19 reactions. The C sp2 hard reactive center has been exploited in
a novel methodology for opening reactions of thiolactams.23 In agreement with the strategy outlined in
Figure 2, we decided to exploit the reactivity of the soft methylene center A by opposing metal iodides as
soft nucleophiles. In order to possibly control the competition with the reactive site B (dealkylation), we
considered substrates 3 with various steric hindrance of the SR1 substituent.
Soft site A
Hard site C
O
R1
S
R1OTf
N
2
Soft site B
-OTf
Figure 3. Possible reactions of intermediate 3
2. MECHANISTIC STUDY. The ring opening of 3 has been investigated through reactions with a
stoichiometric amount of alkaline earth metal iodides (MI; M = Rb, K and Li) in view of producing the
alkyl iodide derivative 4, precursor of the enamine compound 5 (Scheme 2). Surprisingly, after 15 h of
treatment with potassium iodide (KI), in acetonitrile at 0 °C or 20 °C, the starting material 3 was
recovered unchanged, independently of the nature of R1 (a, Me; b, Et; c, iPr). However, in refluxing
acetonitrile (MeCN), with a small excess of lithium iodide (LiI), (R)-3-benzyl-4-phenylthiazolidin-2-
thione (8) was quantitatively generated (Table 1, entries 1 and 2). Using a more polar solvent,
dimethylformamide (DMF), we recovered in all cases (3a-c with KI or LiI) a mixture of three products:
the desired iodide 4, the previously obtained heterocycle 8 and (R)-3-benzyl-4-phenyloxazolidin-2-one
(7).11 Their relative amounts were variable, depending on the nature of R1 and M. Interestingly, the
dealkylation product 2 was never observed. Therefore, we continued our mechanistic study with 3a and
3b, more easily accessible than 3c because the corresponding triflate reagents are commercially available.
The behaviour of 3a-b versus MI, in solution, appeared tunable and the relevant parameters were the
following, by order of importance: (a) M softness/hardness; (b) relative concentration [3]/[I-], dilution and
rate of addition; (e) solvent nature and dryness (7 results from hydrolysis of 3); (d) temperature; (e) R1
steric hindrance. As shown in Table 1, optimal formation of the target compound 4 was reached by slow
addition of rubidium iodide (RbI) in 0.19 M DMF solution to a 0.38 M solution of 3 at 0 °C, with R1 = Et
(4b, entry 8).

HETEROCYCLES, Vol. 75, No. 10, 2008
2463
Table 1. Reactions of 3 with MI
Entry Solvent
T (°C)
Reagent
3a-c
3a-c
3a
MI (eq.) [I] (M) 4 (%) (a) 7 (%) (a) 8 (%) (a)
(b)
1
2
3
4
5
6
7
8
MeCN
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
0-20
KI (1)
LiI (1,5)
LiI (1)
KI (1)
/
/
0
0
0
> 99
53
45
22
65
49
6
(b)
reflux
0
0
0
0
0
0
0
0
0.19 (c)
0.19 (c)
0.19 (c)
0.19 (c)
0.19 (c)
0.19 (c)
24
36
58
29
36
62
14
18
20
6
3a
3a
RbI (1)
LiI (1)
KI (1)
3b
3b
15
31
3b
RbI (1)
(a) Determined from 1H NMR (500 MHz) analysis of the crude mixtures; (b) Addition of neat MI in
one portion; (c) Slow addition (5 mL/h) of freshly prepared DMF solution (0.19 M) to a 0.38 M
solution of 3.
Formation of 8 remains intriguing under those mild reaction conditions, although isomerization of O-
alkyl thiocarbamates into S-alkylthiolcarbamates in acyclic series24 and in cyclic series, under Lewis acid
activation of the thiocarbonyl moiety, has been previously reported.25 Formation of 7 implies the reaction
of the hard site C with residual water (addition-elimination process). This side reaction could be
prevented by working with drastically dried solvents and reagents and in the presence of molecular sieve
(see Experimental Section).
The behavior of S-alkyl-3-benzyl-4-phenyloxazolidin-2-thionium triflates (3) towards MI implies most
probably the soft heterocyclic methylene site A. The first supposed step is the desired ring opening
leading to 4 which existence could be transitory in the presence of MI. Iodide-dependent dealkylation of
4 led to the transient species 6 (resonance form 6’) susceptible to undergo (a) the 5-exo-tet ring closure
into 8 in the presence of hard counter-cation and less polar solvent or (b) the realkylation into 4 in the
presence of stabilizating factors, namely soft counter-cation and highly polar solvent.26 As a matter of
fact, treatment of 3b with 1.5 equivalents of LiI in refluxing MeCN furnished 8 in quantitative yield,
while the slow addition of 1 equivalent of RbI to 3b in diluted DMF solution, produced mainly 4b.
Moreover, treatment of 4b with LiI in MeCN at room temperature led to 8 after a few days, consistently
to the proposed mechanism of Scheme 2.

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HETEROCYCLES, Vol. 75, No. 10, 2008
O
S
N
2
O
O
S
R1
ii.
S
N
O
O
N
N
-
CF3SO3
7
8
3
M+I-
i.
-
CF3SO3 M+
fast if M = Li+
(MeCN)
5-exo-tet
I
I
S
O
O
R1
O-M+
iii.
N
N
S
N
S
6'
4
M+I-
fast if M =
Rb+ (DMF)
5
M+I-
fast if R1 = Me
I
R1I
O
N
S-M+
RI
6
Reagents and conditions: i. MI (1 eq.), DMF, 0°C, 2.5 h; ii. residual water; iii. DBU (1.5 eq.), 0°C to rt, overnight.
Scheme 2. Proposed mechanism leading to 4, 5, 7 and 8
Practically, the optimal conditions for preparing 4b required the slow addition of a diluted DMF solution
of dried RbI to a cold solution of 3b, in the presence of 4Ǻ molecular sieve (MS) and 1 equivalent of
LiSO3CF3, added to bring the reaction to completion within 1 hour. After column chromatography, pure
4b could be isolated in 65% yield. However, this compound was poorly stable and the elimination
reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) producing 5 (Scheme 2) had to be performed
immediately. When the complete sequence was realized in a one-pot process, without intermediate
purification of 4b, S-ethyl-N-benzyl-N-1-phenylvinylcarbamothioate (5) was obtained in 95% yield. This
enamine 5 was found to be quite reluctant to hydrolysis. The compound was stable in hot 6N HCl, but
fortunately, could be hydrolyzed by treatment with a MeCN/AcOH/H2O mixture at 80 °C: acetophenone
and S-ethyl-N-benzylcarbamothioate (9)27 were quantitatively formed (Scheme 3). In fact, isolation of 9
was not necessary; acid treatment of 5 as above followed by raising the pH with aqueous LiOH, directly
produced benzylamine, thus achieving the complete deprotection of the oxazolidin-2-thione auxiliary.

HETEROCYCLES, Vol. 75, No. 10, 2008
2465
O
O
ii.
i.
+
5
NH2
HN
S
9
Reagents and conditions: i. MeCN/AcOH/H2O (2/2/1), 80 °C,17 h; ii. LiOH, H2O, 70 °C, 17 h.
Scheme 3. Hydrolysis of 5
In view to valorize the versatility of S-alkyl oxazolidin-2-thionium triflates (such as 3b), each of the
observed heterocyclic rearrangements was optimized for proposing efficient heterocyclic interconversion
pathways. As depicted in Scheme 4, conversion of (R)-S-ethyl-3-benzyl-4-phenyloxazolidin-2-thionium
triflate (3b) was chemo- and stereo-selective, and almost quantitative: treatment of 3b with LiI in MeCN
at 60 °C led to 8; addition of LiOH monohydrate to a MeCN solution of 3b at 60 °C led to 7. This
reaction provides an interesting ″formal oxidation″ process under mild conditions of oxazolidin-2-thiones
to oxazolidin-2-ones.24,28,29 Finally, thionation of 8 with Lawesson’s reagent30-33 in toluene at 85 °C
furnished (R)-3-benzyl-4-phenylthiazolidin-2-thione (10) with 90 % yield.
O
O
N
7
ii.
O
O
S
Et
i.
iii.
S
S
O
N
N
N
-
CF3SO3
3b
2
8
iii. + iv.
S
S
N
10
Reagents and conditions: i. EtSO3CF3 (1.1 eq.), MeCN, rt, 30 min (quant.);
ii. LiOH.H2O (1 eq.), MeCN, 60 °C, overnight (quant.);
iii. LiI (1.5 eq.), MeCN, 60 °C, overnight (quant.);
iv. Lawesson's reagent (1 eq.), toluene, 85 °C, overnight (90 %).
Scheme 4. Heterocyclic interconversion pathways
3. STRUCTURAL ANALYSIS. Our mechanistic proposal for the reaction of MI with oxazolidin-2-
thione 2 relies upon the unambiguous identification of all the formed heterocycles. Compounds 2, 7 and

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HETEROCYCLES, Vol. 75, No. 10, 2008
8 (unfortunately not 10) smoothly crystallized in hexane affording crystallographic structural data. The
ORTEP34 views of the crystal structures for heterocycles 2, 7 and 8 are pictured in Figures 4, 5 and 6
respectively. Absolute configuration at C4 was unambiguously determined by X-ray diffraction for
compounds 2 and 8. The antipodal compound (S)-2 has been synthesized from (S)-phenylglycinol by
using the same protocol as described above, and further engaged in all the described reactions. [α]D
measurements were consistent with stereoselective transformations in both R and S series (see
Experimental Section).
Figure 4. View and atom labelling of (R)-3-benzyl-4-phenyloxazolidine-2-thione (2)
Figure 5. View and atom labelling of (R)-3-benzyl-4-phenyloxazolidin-2-one (7)
Figure 6. View and atom labelling of (R)-3-benzyl-4-phenylthiazolidin-2-one (8)
For the three structures, the conformation of the 5-membered heterocycle showed slight modifications:
the observed conformation of 2 is half-chair, with two-fold axis passing through the thiocarbonyl
function; compound 7 shows a heterocycle conformation as an envelope with the mirror plane passing
through the C4 chiral atom, whereas 8 features an intermediate conformation between those two limits.

HETEROCYCLES, Vol. 75, No. 10, 2008
2467
We have calculated the asymmetry parameter from a perfect half-chair conformation using the procedure
of Duax et al.35; it was in the range 0.7-7 ° indicating only small deformations from the perfect
conformation (Table 2).
Table 2. Comparison of the torsion angles (degrees; σ = 1°).
Torsion angle
N3-C2-O1-C5
C2-O1-C5-C4
O1-C5-C4-N3
C5-C4-N3-C2
C4-N3-C2-O1
∆Cs(C4)
2
3
7
8
-3
-6
-9
10
-9
4
11
14
13
-7
22
-31
29
-13
6.5
7
2.9
0.7
∆C2(C2)
1H NMR analysis of compounds 2, 7, 8 and 10 showed typical features for 5-membered heterocycles.
Generally in such heterocycles, cis coupling constants (3JH) are higher than the corresponding trans. For
compounds 2, 7, 8 and 10, the cis 3JH values are indeed higher than the corresponding trans, by a range of
1.7 to 3.6 Hz.36 Representative chemical shifts are collected in Table 3. Protons cis to the phenyl group
showed signals at δ 3.13-4.63, whereas protons trans to the phenyl group showed signals at δ 3.54-4.75.
An additional observation was that the proton on C4 appears systematicaly at lower field when Y = S than
for Y = O.
Table 3. Typical 500 MHz 1H NMR features for compounds 2, 7, 8 and 10.
δ
J
2
H-C5
trans
4.4
H-C5
cis
3J
trans
5.8
3J
2JH-H(C5) JH-H(C7)
H-C4
H-C7
cis
9.4
9.2
8.2
8.9
gem
8.2
gem
14.7
14.7
14.7
14.7
2
7
4.7
4.5
4.6
5.0
4.7
4.6
3.5
3.6
3.8-5.5
3.6-4.9
3.5-5.1
3.8-5.9
4.1
5.8
7.5
8
3.1
6.5
11.3
11.2
10
3.1
5.3
CONCLUSION
Through this work, we have emphasized the importance of S-alkyl oxazolidin-2-thionium triflate (3),
obtained quantitatively by alkylation of an oxazolidin-2-thione precursor with alkyl
2

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HETEROCYCLES, Vol. 75, No. 10, 2008
trifluoromethanesulfonate, as key intermediate both for N-deprotection purpose and controlled heteroatom
permutations in heterocyclic chemistry. Compound 3 is an activated oxazolidine-2-thione 2 in which the
C5 methylene electrophilicity has been greatly enhanced (125 MHz 13C: δ 80.38 (3b) versus 73.6 (2)) and
behaves as a tunable intermediate, contrary to the 2:LA (Lewis Acid) complex previously described.25
Exploitation of the reactivity of 3b towards iodide associated with a stabilizating soft counter-cation led
us to disclose the first example of oxazolidin-2-thione moiety deprotection into free amine. During our
study of deprotection optimization, we highlighted a useful rearrangement. Treatment of 3b with iodide
associated with a hard counter-cation supplied (R)-phenylthiazolidin-2-one 8 through 5-exo-tet
recyclisation. This protocol allows a clean preparation of thiazolidin-2-ones working without aminothiols
intermediates.24 Although thiazolidin-2-ones are not usually exploited as chiral auxiliaries, they are
precursors for the preparation of chiral thiazolidin-2-thiones (10) by efficient thionation using Lawesson’s
reagent. Those heterocycles are useful compounds as chiral auxiliaries, as well as bactericides, fungicides
and catalysts for photopolymerisation.37 Finally, simple hydrolysis of 3b offers under mild conditions a
formal oxidation process of 2, leading to oxazolidin-2-one 7, for which several validated endocyclic
deprotection techniques are described.7-9
Beyond the chemistry of chiral auxiliary deprotection, our work has demonstrated interesting heterocyclic
conversion pathways linking the four members of the (thia)oxazolidin-2-(thi)one family. Since such
motifs are present on several biologically active molecules,37-40 our research provides a chemo- and
stereoselective methodology for bioisosteric modifications.
EXPERIMENTAL
1. Methods. X-Ray intensity data were collected at low temperature for 7 and 8 (120K) and at room
temperature for 2 with a MAR345 image plate detector using MoKα (λ= 0.71069Å) monochromatized
radiation. The crystal data and the data collection parameters are summarized in the synthesis section.
The unit cell parameters were refined using all the collected spots after the integration process. Figures 4-
6 are drawn in the ORTEP style.34 All the structures were solved by direct methods with SHELXS97 and
refined by full-matrix least-squares on F2 using SHELXL97.41 All the non hydrogen atoms were refined
with anisotropic temperature factors. The hydrogen atoms were located from Fourier difference or
calculated with AFIX and included in the refinement with a common isotropic temperature factor. The
structures 2, 7 and 8 have been deposited within the Cambridge Crystallographic data Centre, n° CCDC
661559, 661560 and 661561, respectively. NMR spectra were measured at room temperature on a Bruker
Avance 500 or on a Bruker Avance II 300 spectrometer; J values are given in Hz. IR spectra were
recorded on Shimadzu FTIR-8400S spectrometer; values are reported in cm-1. Mass spectra were
performed on a LCQ Finnigan MAT spectrometer at the UCL mass spectrometry service, in APCI mode

HETEROCYCLES, Vol. 75, No. 10, 2008
2469
(Atmospheric Pressure Chemical Ionosation) or ESI mode (Electron Spray Ionization). HRMS were
measured at the University of Mons-Hainaut (Belgium) in the service of Prof. R. Flammang. Elemental
analyses were measured at the analytical service of Imperial College of London, UK. [α]D values are
given in deg.cm³.dm-1.g-1 and concentrations are given in g/100 cm³. Mps are uncorrected.
2. Synthesis. The reagents were purchased from commercial sources (Aldrich and Fluka) and used
without further purification. LiI, RbI and LiSO3CF3 were washed with THF and dried under high vacuum.
The solvents (anhydrous grade; H2O < 0.001 %) were purchased from Fluka and stored under argon
atmosphere over molecular sieve. The vessel was flamed and dried under high vacuum, and then cooled
under argon atmosphere. TLC analyses were performed on aluminium plates coated with silica gel 60
F254 from Merck and visualized with UV (254 nm) or KMnO4 solution (3 g KMnO4, 20 g K2CO3, 5 cm³
AcOH 5% and 300 cm³ water). Column chromatographies were performed on silica gel Merck 60 (40-63
µm). i-Propyl trifluoromethanesulfonate was synthesized as described in the literature.20
Preparation of (R)-2-(benzylamino)-2-phenylethanol (1):11 A solution of (R)-phenylglycinol (5 g, 36.5
mmol) in dry MeOH (150 cm³) was treated under magnetic stirring by freshly distilled benzaldehyde
(3.37 cm³, 33.18 mmol) at rt. The reaction was monitored by TLC. Upon complete addition, the mixture
was then carefully treated with sodium borohydride (1.38 g, 36.5 mmol) over 10 min. After complete
addition, the mixture was left under stirring over 30 min, before dilution by 1N NaOH and Et2O
extraction (3x). Combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered
and concentrated to dryness. The crude product was purified by crystallization in hexane with 10 %
20
1
EtOAc to give 1 as white crystals (99 %): mp 91-92 °C; [α]D -65.4 (c 1.07 in CHCl3); H NMR (300
MHz, CDCl3) δ: 7.23 to 7.37 (m, 10 H), 3.82 (dd, J=4.8 Hz and J=4.8 Hz, 1H), 3.75 (d, J=10.6 Hz, 1H),
3.7 (dd, J=10.6 Hz and J=4.8 Hz, 1H), 3.59 (dd, J=8.5 Hz and J=1.9 Hz, 1H), 3.55 (d, 1H), 2.88 (broad s,
13
2H); C NMR (75 MHz, CDCl3) δ: 140.47, 140.04, 128.87, 128.59, 128.39, 127.87, 127.44, 127.27,
66.95, 63.97, 51.38; IR (NaCl, ν, cm-1) 3330, 3060, 3027, 2926, 2837, 1602, 1494, 1454, 1201, 1116,
1049, 1027; ESI MS m/z for C15H18NO [M+H+]: 228.1.
(S)-1: same procedure and structural assignment: [α]D20 +65.2 (c 1.23 in CHCl3).
Preparation of (R)-3-benzyl-4-phenyloxazolidine-2-thione (2):11 To a stirred solution of 1 (6.79 g,
29.86 mmol) in dry CH2Cl2 (150 cm³) was added 1,1′-thiocarbonyldiimidazole (8.4 g, 44.79 mmol) in one
portion. The reaction mixture was stirred for 5 h at rt. The organic layer was washed with water, dried
over MgSO4 and finally concentrated under vacuum. The resulting crude material was purified by
column chromatography [silica gel: hexane/Et2O (1/1)] to give 2 as a white solid (95 %): Rf [hexane/
Et2O (1/1)] = 0.35; mp 114-115 °C; [α]D20 +12.0 (c 1.59 in CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.19
to 7.42 (m, 10H), 5.51 (d, J=14.7 Hz, 1H), 4.75 (dd, J=8.2 Hz and J=9.4 Hz, 1H), 4.70 (dd, J=5.8 Hz and
13
J=9.4 Hz, 1H), 4.36 (dd, J=8.2 Hz and J=5.8 Hz, 1H), 3.81 (d, J=14.7 Hz, 1H); C NMR (125 MHz,

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HETEROCYCLES, Vol. 75, No. 10, 2008
CDCl3) δ: 187.97, 136.28, 134.32, 129.39, 128.67, 128.46, 128.16, 127.14, 73.62, 62.15, 49.27; IR (NaCl,
ν, cm-1) 3029, 2915, 1494, 1479, 1453, 1295, 1237; APCI MS m/z for C16H16NOS [M+H+]: 270.1; Anal.
Calcd for C16H15NOS: C, 71.34; H, 5.61; N, 5.20. Found: C, 71.34; H, 5.75; N, 5.19; XR: C16H15NOS,
Mr = 269.35, orthorhombic, P212121 (Nr 19) a = 7.119(3), b = 12.207(5), c = 16.274(6) Å, V = 1414(1)
Å3 , Z = 4, Dx = 1.26 g.cm-3, T= 293K. A total of 8650 reflections were collected; 1470 independent
reflections (Rint = 0.084), 2Θmax = 41.6°. R = 0.037 for 1366 observed reflections and WR2 = 0.092 all
data. Flack absolute structure parameter 0.14 (14). Selected bond lengths (Å): O(1)-C(2) = 1.348(4),
C(2)-S(6) = 1.649(4), C(2)-N(3) = 1.329(4), N(3)-C(4) = 1.472(4), C(4)-C(5) = 1.531(5), O(1)-C(5) =
1.445(4), N(3)-C(7) = 1.448(4), C(4)-C(14) = 1.497(4).
(S)-2: same procedure and structural assignment: [α]D20 -12.2 (c 2.1 in CHCl3).
General procedure for alkylation of (R)-3-benzyl-4-phenyloxazolidin-2-thione (2) by alkyl triflates:
A stirred solution of 2 (5 g, 18.56 mmol) in anhydrous MeCN (100 cm³) was treated dropwise by alkyl
triflate (20.42 mmol) at rt. The reaction was monitored by TLC. After completion, the residue was
concentrated under vacuum to dryness. The crude material was used further without any purification.
1
(R)-S-methyl-3-benzyl-4-phenyloxazolidin-2-thionium triflate (3a): H NMR (500 MHz, CDCl3) δ:
7.12 to 7.45 (m, 10H), 5.68 (dd, J=10.4 Hz and J=9.3 Hz, 1H), 5.55 (dd, J=8.4 Hz and J=10.4 Hz, 1H),
4.95 (dd, J=9.3 Hz and J=8.4 Hz, 1H), 4.78 (d, J=15.2 Hz, 1H), 4.44 (d, J=15.2 Hz, 1H), 2.93 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ: 180, 132.21, 130.71, 129.84, 129.49, 129.16, 129.07, 128.28, 126.85, 80.4,
67.15, 50.71, 15.25; ESI(+) MS m/z for C17H18NOS [M+]: 284.01; ESI(-) MS m/z for CF3SO3 [M-]: 149;
IR (NaCl, ν, cm-1) 1550, 1240, 705.
(R)-S-ethyl-3-benzyl-4-phenyloxazolidin-2-thionium triflate (3b): 1H NMR (500 MHz, CDCl3) δ: 7.12
to 7.45 (m, 10H), 5.7 (dd, J=10.4 Hz and J=9.3 Hz, 1H), 5.55 (dd, J=8.4 Hz and J=10.4 Hz, 1H), 4.95 (dd,
J=9.3 Hz and J=8.4 Hz, 1H), 4.75 (d, J=15.2 Hz, 1H), 4.46 (d, J=15.2 Hz, 1H), 3.53 (m, 2H), 1.55 (t,
3H); 13C NMR (125 MHz, CDCl3) δ: 179.87, 133.81, 131.65, 130.56, 129.9, 129.76, 129.5, 129.32,
129.04, 128.16, 126.85, 80.38, 66.94, 50.83, 28.42, 14.08; ESI (+) MS m/z for C18H20NOS [M+]: 298.13;
ESI(-) MS m/z for CF3SO3 [M-]: 149; IR (NaCl, ν, cm-1) 1558, 1259, 702; ESI HRMS m/z for C18H20NOS
[M+]: calcd 298.1266. Found 298.1259.
1
(R)-S-isopropyl-3-benzyl-4-phenyloxazolidin-2-thionium triflate (3c): H NMR (300 MHz, CDCl3) δ:
7.03 to 7.42 (m, 10H), 5.57 (dd, J=10.5 Hz and J=9.6 Hz, 1H), 5.42 (dd, J=8.6 Hz and J=10.5 Hz, 1H),
4.95 (dd, J=9.6 Hz and J=8.6 Hz, 1H), 4.68 (d, J=15.3 Hz, 1H), 4.31 (d, J=15.3 Hz, 1H), 4.23 (m, 1H),
1.59 (d, 3H), 1.57 (d, 3H); 13C NMR (75 MHz, CDCl3) δ: 179.53, 130.78 to 128.37, 128.85, 80.67, 66.71,
50.67, 42.63, 23.72; ESI(+) MS m/z for C19H22NOS [M+]: 312.09; ESI(-) MS m/z for CF3SO3 [M-]: 149;
IR (NaCl, ν, cm-1) 1550, 1262, 704.

HETEROCYCLES, Vol. 75, No. 10, 2008
2471
Preparation of S-ethyl-N-benzyl-N-(R)-2-iodo-1-phenylethylcarbamathioate (4b): To a stirred
solution of 3b (0.83 g, 1.86 mmol) in anhydrous DMF (10 cm³) at 0 °C containing MS 4Ǻ was added
anhydrous lithium triflate (0.23 g, 1.86 mmol) under argon flux in one portion, and the reaction mixture
was stirred for 30 min. Afterwards, the reaction mixture was treated dropwise for 1 h with a freshly
prepared 0.19 M DMF solution of anhydrous rubidium iodide (1.86 mmol). After completion, the
organic layer was diluted with Et2O, washed with brine, dried over MgSO4 and concentrated under
vacuum. The resulting dark, highly moisture sensitive, residue was purified by column chromatography
[silica gel: cyclohexane/EtOAc (5/1)] to give 4b as a yellow oil (65 %): Rf [cyclohexane/EtOAc (5/1)] =
0.79; 1H NMR (500 MHz, CDCl3) δ: 7.27 (m, 10H), 5.59 (broad t, 1H), 4.59 (broad s, 1H), 4.18 (broad s,
13
1H), 3.67 (broad s, 1H), 3.4 (t, 1H), 3.03 (q, 2H), 1.37 (t, 3H); C NMR (125 MHz, CDCl3) δ: 169.34,
136.88, 136.28, 128.46, 128.29, 127.39, 62.38, 49.43, 25.22, 15.07, 4.19; APCI MS m/z for C18H21INOS
[M+H+]: 425.78.
Preparation of S-ethyl-N-benzyl-N-1-phenylvinylcarbamothioate (5): To a stirred solution of 3b
(0.83 g, 1.86 mmol) in anhydrous DMF (5 cm³) at 0 °C containing MS 4Ǻ was added anhydrous lithium
triflate (0.23 g, 1.86 mmol) under argon flux in one portion. After 30 min, the reaction mixture was
treated dropwise for 1 h with a freshly prepared 0.19 M DMF solution of anhydrous RbI (1.86 mmol) at
0 °C. The solution was stirred for additional 30 min and then treated with a freshly prepared DMF
solution (2.5 cm³) of DBU (0.42 cm³, 2.79 mmol) at 0 °C. The mixture was allowed to slowly warm up
to rt and was then stirred overnight. The organic layer was diluted with ethyl acetate, washed with water
and then brine, dried over MgSO4, filtered and finally concentrated under vacuum. The oily residue was
purified by column chromatography [silica gel: hexane/Et2O (2/1)] to give 5 as a pale yellow oil (95 %):
Rf [hexane/Et2O (2/1)] = 0.81; 1H NMR (300 MHz, CDCl3) δ: 7.22 to 7.39 (m, 10H), 5.68 (s, 1H), 5.1 (s,
1H), 4.64 (broad s, 2H), 2.89 (q, 2H), 1.27 (t, 3H); 13C NMR (75 MHz, CDCl3) δ: 169.78, 144.91, 137.55,
135.46, 129.48, 129.24, 128.82, 127.91, 126.74, 118.09, 51.54, 25.59, 15.54; APCI MS m/z for
C18H20NOS [M+H+]: 297.92; IR (NaCl, ν, cm-1) 1645, 1625, 1265, 968; ESI HRMS m/z C18H20NOS
[M+H]: calcd 298.1266. Found 298.1265.
Preparation
of
S-ethyl-N-benzylcarbamothioate
(9):27 S-ethyl-N-benzyl-N-1-phenylvinyl-
carbamothioate (5) (0.18 g, 0.6 mmol) was diluted in a mixture MeCN/AcOH/H2O (2/2/1, 5 cm³) and
vigorously stirred at 80 °C overnight. To the reaction mixture was then carefully added K2CO3 portion-
wise to neutral pH and then 3N KOH to pH = 9. The mixture was extracted several times with CH2Cl2.
Organic layers were washed with water, dried over MgSO4, filtered and concentrated under high vacuum
in order to evaporate acetophenone. This left 9 as yellow needles (99%): Rf [hexane/Et2O (2/1)] = 0.4;
mp 62-63 °C; 1H NMR (300 MHz, CDCl3) δ: 7.24 to 7.31 (m, 5H), 5.55 (broad s, 1H), 4.46 (br d, J=5.7
Hz, 2H), 2.94 (q, 2H), 1.3 (t, 3H); 13C NMR (75 MHz, CDCl3) δ: 172.5, 137.52, 133.53, 128.80, 128.04,

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HETEROCYCLES, Vol. 75, No. 10, 2008
45.61, 24.82, 16.13; APCI MS m/z for C10H14NOS [M+H+]: 196; IR (NaCl, ν, cm-1) 3309, 1645, 698; ESI
HRMS m/z C10H13NONaS [M+Na+]: calcd 218.0616. Found 218.0616.
Preparation of (R)-3-benzyl-4-phenyloxazolidin-2-one (7):11 To a stirred solution of 3b (8.3 g, 18.56
mmol) in MeCN (100 cm³) was added in one portion LiOH monohydrate (1.17 g, 27.84 mmol) at rt.
After 15h, the reaction mixture was filtered through celite and concentrated under vacuum. The yellow
oily residue was purified by column chromatography [silica gel: hexane/Et2O (1/1)] and was then
crystallized from hexane to give 7 as colourless crystals (95 %): Rf [hexane/Et2O (1/1)] = 0.33; mp 72-
20
1
73 °C; [α]D -46.2 (c 2.2 in CHCl3); H NMR (500 MHz, CDCl3) δ: 7.13 to 7.41 (m, 10H), 4.86 (d,
J=14.7 Hz, 1H), 4.55 (dd, J=7.5 Hz, and J=9.2 Hz, 1H), 4.52 (dd, J=9.2 Hz and J=5.8 Hz, 1H), 4.12 (dd,
13
J=7.5 Hz and J=5.8 Hz, 1H), 3.64 (d, J=14.7 Hz, 1H); C NMR (125 MHz, CDCl3) δ: 158.2, 137.29,
135.28, 129.2, 128.62, 128.60, 128.56, 127.84, 127.13, 69.78, 58.61, 45.7; APCI MS m/z for C16H16NO2
[M+H+]: 270; IR (NaCl, ν, cm-1) 1751, 1458, 1413, 1259, 1172, 1035; Anal. Calcd for C16H15NO2: C,
75.87; H, 5.97; N, 5.53. Found: C, 75.87; H, 6.02; N, 5.52; XR: C16H15NO2, Mr = 253.29, orthorhombic,
P212121 (Nr 19) a = 9.011(3), b = 10.095(4), c = 14.298(5) Å, V = 1300.6(8) Å3 , Z = 4, Dx = 1.29 gcm-3,
T= 120K. A total of 8796 reflections were collected using; 2105 independent reflections (Rint = 0.078),
2Θmax = 49°. R = 0.043 for 1935 observed reflections and WR2 = 0.113 all data. Selected bond lengths
(Å): O(1)-C(2) = 1.362(3), C(2)-O(6) = 1.209(3), C(2)-N(3) = 1.340(3), N(3)-C(4) = 1.463(3), C(4)-C(5)
= 1.536(4), O(1)-C(5) = 1.445(3), N(3)-C(7) = 1.452(3), C(4)-C(14) = 1.508(3).
(S)-7: same procedure and structural assignment: [α]D20 +46.0 (c 1.7 in CHCl3).
Preparation of (R)-3-benzyl-4-phenylthiazolidin-2-one (8): To a stirred solution of 3b (0.83 g, 1.86
mmol) in MeCN (2 cm³) was added in one portion anhydrous LiI (0.37 g, 2.77 mmol). After 15h at 60 °C,
the reaction mixture was filtered through celite and concentrated under vacuum. The dark oily residue
was purified by column chromatography [silica gel: hexane/Et2O (1/1)] and then crystallized from hexane
to give 8 as colourless crystals (99 %): Rf [hexane/Et2O (1/1)] = 0.56; mp 128-129 °C; [α]D20 +93.2 (c 1.4
in CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7 to 7.5 (m, 10H), 5.08 (d, J=14.7 Hz, 1H), 4.58 (dd, J=6.5 Hz
and J=8.2 Hz, 1H), 3.55 (dd, J=11.3 Hz and J=8.2 Hz, 1H), 3.54 (d, J=14.7 Hz, 1H), 3.14 (dd, J=6.5 Hz
13
and J=11.3 Hz, 1H); C NMR (125 MHz, CDCl3) δ: 172.28, 138.59, 135.57, 129.04, 128.75, 128.51,
128.34, 127.64, 126.8, 62.08, 46.62, 36.65; APCI MS m/z for C16H16NOS [M+H+]: 270.05; IR (NaCl, ν,
cm-1) 2387, 1670, 1492, 1396, 1195; Anal. Calcd for C16H15NOS: C, 71.34; H, 5.66; N, 5.20. Found: C,
71.05; H, 5.61; N, 5.12; XR: C16H15NOS, Mr = 269.35, orthorhombic, P212121 (Nr 19) a = 10.071(4), b =
10.294(4), c = 13.296(5) Å, V = 1378.4(9) Å3 , Z = 4, Dx = 1.30 gcm-3, T= 120K. A total of 12086
reflections were collected; 2520 independent reflections (Rint = 0.060), 2Θmax = 50.7°. R = 0.032 for
2421 observed reflections and WR2 = 0.083 all data. Flack absolute structure parameter 0.04 (8).

HETEROCYCLES, Vol. 75, No. 10, 2008
2473
Selected bond lengths (Å): S(1)-C(2) = 1.777(2), C(2)-O(6) = 1.217(3), C(2)-N(3) = 1.358(3), N(3)-C(4)
= 1.463(3), C(4)-C(5) = 1.542(3), S(1)-C(5) = 1.813(2), N(3)-C(7) = 1.464(2), C(4)-C(14) = 1.509(3).
(S)-8: same procedure and structural assignment: [α]D20 -93.0 (c 1.5 in CHCl3).
Preparation of (R)-3-benzyl-4-phenylthiazolidin-2-thione (10): To a stirred solution of 8 (0.27 g, 1
mmol) in toluene (5 cm³) was added in one portion Lawesson’s reagent (0.2 g, 0.5 mmol). The reaction
mixture was stirred at 90 °C for 2 h, before a supplementary portion of Lawesson’s reagent was added
(0.2 g, 0.5 mmol). After 7 h at 90 °C, the reaction mixture was concentrated under vacuum and purified
by column chromatography [silica gel: EtOAc/cyclohexane (7/3)] and then precipitated from hexane to
20
give 9 as a colourless powder (90 %): Rf [EtOAc/cyclohexane (7/3)] = 0.81; ; mp 136-137 °C; [α]D
+57.8 (c 1.9 in CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.17 to 7.42 (m, 10H), 5.93 (d, J=14.7 Hz, 1H),
5.04 (dd, J=5.3 Hz and J=8.9 Hz, 1H), 3.75 (d, J=14.7 Hz, 1H), 3.65 (dd, J=8.9 Hz and J=11.2 Hz, 1H),
3.13 (dd, J=5.3 Hz and J=11.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 197.93, 137.99, 135.21, 129.59,
129.42, 129.00, 128.56, 128.31, 127.41, 70.23, 50.52, 35.46; ESI MS m/z for C16H16NS2 [M+H+]: 286.26;
IR (NaCl, ν, cm-1) 1495, 1446, 1419, 1224, 1171, 1080, 1031, 906; Anal. Calcd for C16H15NS2: C, 67.33;
H, 5.30; N, 4.91. Found: C, 67.33; H, 5.29; N, 4.87.
(S)-10: same procedure and structural assignment: [α]D20 -57.5 (c 1.1 in CHCl3).
ACKNOWLEDGMENTS
This work was supported by the UCL (Université catholique de Louvain, Belgium), the FRS-FNRS
(Fonds National de la Recherche Scientifique, Belgium), the FRIA (Fonds pour la Formation à la
Recherche dans l’Industrie et dans l’Agriculture, Belgium). Dr R. Touillaux is acknowledged for
contribution in NMR analyses. J. M-B is senior research associate of FRS-FNRS and J.-C. M is FRIA
fellow.
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