A novel nucleophilic attack to N-enoyl oxazolidinethiones

Article abstract of DOI:10.1016/S0040-4039(03)01189-4

The oxazolidinethione synthon can act as a chiral auxiliary and nucleophile (S^-) carrier molecule simultaneously. Surprisingly, the thiolate attacks N-enoyl oxazolidinethiones producing a new heterocycle, as established by X-ray analysis.

Full text of DOI:10.1016/S0040-4039(03)01189-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5053–5055
A novel nucleophilic attack to N-enoyl oxazolidinethiones
Aurelio Ortiz,a,* Leticia Quintero,a Guadalupe Mendozaa and Sylvain Berne`sb
aCentro de investigacio´n de la Facultad de Ciencias Qu´ımicas, Puebla Pue. 72570, Mexico
bInstituto de Ciencias de la Beneme´rita Universidad Auto´noma de Puebla, Puebla Pue. 72570, Mexico
Received 28 March 2003; revised 29 April 2003; accepted 7 May 2003
Abstract—The oxazolidinethione synthon can act as a chiral auxiliary and nucleophile (S−) carrier molecule simultaneously.
Surprisingly, the thiolate attacks N-enoyl oxazolidinethiones producing a new heterocycle, as established by X-ray analysis.
© 2003 Elsevier Science Ltd. All rights reserved.
The oxazolidinethione structure has been widely used
as a chiral auxiliary in different types of synthetic
transformations. The asymmetric Diels–Alder reaction
of its corresponding N-enoyl1 and aldol reaction of
N-acyl derivatives with aldehydes,2,3 are important
applications of oxazolidinethiones in the total synthesis
of biologically important natural products.4
Chiral auxiliary 1 was prepared from the commercially
available (1R,2S) norephedrine under the reaction con-
ditions described previously,9 followed by deprotona-
tion with NaH and acylation with 0.5 equiv. of
trans-crotonyl chloride to afford 2 as a white crystalline
solid10 in 65% yield, mp 133–135°C, [h]2D5=+159.4, c=
0.96 CHCl3, and the corresponding oxazolidinone 3
(Scheme 1).
Currently the obtention of N-acyl or N-enoyl oxazo-
lidinethiones is realized by different methods, using acyl
chlorides and different bases like n-butyl lithium,2 pyri-
dine,5 triethylamine6 and sodium hydride2,7 but in no
methods have the characteristics that the base requires
to react with the amidic proton been described.
On the other hand cleavage of oxazolidinethiones
derivatives is easier than in N-acyl or N-enoyl oxazo-
lidinones. Furthermore it has been described recently
that N-enoyl oxazolidinethiones show
a
novel
Scheme 1. Reagents and conditions: (a) NaH (1.1 equiv.),
THF, 0°C, 45 min, trans-crotonyl chloride (0.5 equiv.), 0°C, 1
h.
intramolecular sulfur atom transfer reaction to a,b-
unsaturated systems promoted by Lewis acid to yield
b-mercapto carboxylic acid derivatives.8,9 This reaction
was undetected in the case of oxazolidinones
derivatives.
The new product 2 was prepared by in situ formation
of the corresponding N-enoyl derivative and subse-
quent thiolate addition (via SN2) of 1 at the C-5 posi-
tion of the N-enoyl oxazolidinethione, followed by a
cyclization assisted by the known intramolecular rear-
rangement,8,9 and hydrolysis (Scheme 2).
In this paper we describe an interesting side reaction
observed during the attempted attachment of thione-
type auxiliaries to trans-crotonyl chloride, where the
oxazolidinethiones act as chiral auxiliary and nucle-
ophile thiolate carrier molecules, simultaneously. This
was probed in the context of the illustrated reaction
with chiral auxiliary 1.
The absolute configurations at the newly formed stereo-
genic centers (C-6, C-8) are R and S, respectively, as
established by X-ray analysis11 of compound 2, derived
from norephedrine (Fig. 1). The X-ray structure of 2
shows the expected six-membered ring for the heterocy-
cle, in which all atoms are nearly planar except for C-6.
It should be mentioned that few X-ray characteriza-
* Corresponding author. Tel.: 222-2295500-7481; fax: 222-2295584;
e-mail: jaortizm@siu.buap.mx
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01189-4

5054
A. Ortiz et al. / Tetrahedron Letters 44 (2003) 5053–5055
trans-crotonyl chloride was realized so that the rest of
the oxazolidinethione 4 should react in situ by a
Michael addition at the beta position of the a,b-unsatu-
rated system to give the sulfide 5.
In order to establish if the new chiral auxiliary9
6
behaved like nucleophile (S−) carrier molecule, the reac-
tion was performed under the conditions described
above (Scheme 4).
Scheme 2.
Scheme 4. Reagents and conditions: (a) NaH (1.1 equiv.),
THF, 0°C, 45 min, trans-crotonyl chloride (0.5 equiv.), 0°C, 1
h, H2O.
In this case the reaction afforded the b-mercapto
adducts
7
in quantitative yield16 as
a
(80:20)
diastereomeric mixture (by 13C NMR) and unreacted
oxazolidinethione 6. The obtention of the adduct 7 can
be explained by in situ formation of the corresponding
N-enoyl oxazolidinethione, followed by intramolecular
sulfur atom transfer to the unsaturated system.8,9 The
Michael addition product was undetected due to the
fact that the intramolecular attack is favored over the
intermolecular one, probably because of steric
hindrance.
Figure 1. Molecular structure of heterocycle 2.
tions for thiouracil containing molecules have been
reported so far.12,13
In conclusion, we propose that the oxazolidinethione
structure besides acting as a chiral auxiliary, can behave
as a source of the nucleophile (S−), although this ability
can be affected by steric hindrance of its substituents in
C4 and C5. This novel reaction has potential applica-
tions in heterocyclic synthesis.
The conformational analysis of heterocycle 2 shows
that the N-methylene group has a preference to be in
the plane and its bond angle is C2-N3-C7, 114.5°. The
1H NMR spectrum of 2 at 323 K shows a doublet at l
1.44 ppm for CH3-16, which coalesces at 304 K (DG"=
15.6 Kcal mol−1), a dynamic behavior that may be
attributed to C-6 interconversion.14 In the solid state
one conformation is stabilized corresponding to a
screw-boat at C-6, as observed by X-ray diffraction.
Acknowledgements
The authors gratefully acknowledge financial support
from CONACyT (Project J35098-E).
Our next task involved the preparation of the achiral
oxazolidinethione 4 in quantitative yield.15 This was
deprotonated with NaH followed by acylation with 0.5
equiv. of trans-crotonyl chloride to afford 5 in 70%
yield as a white solid which decomposes at 286°C
(Scheme 3). The addition of a controlled quantity of
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Scheme 3. Reagents and conditions: (a) NaH (1.1 equiv.),
THF, 0°C, 45 min, trans-crotonyl chloride (0.5 equiv.), 0°C, 1
h.

A. Ortiz et al. / Tetrahedron Letters 44 (2003) 5053–5055
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