Novel synthesis of 2-thiazolines

Article abstract of DOI:10.1016/S0040-4039(00)00419-6

The synthesis of a series of 2-thiazolines was carried out under mild conditions from the corresponding thiazolidines, by a Ru-catalyzed/TBHP oxidation reaction conditions. The reaction was chemoselective towards the amine-imine oxidation and was also regioselective, affording the unsaturation at the 2-position of the heterocycle, even with thiazolidine substrates bearing ester groups at the 4-position. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00419-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3381–3384
Novel synthesis of 2-thiazolines
Xavier Fernandez, Roland Fellous and Elisabet Duñach ∗
Laboratoire Arômes, Synthèse et Interactions, Université de Nice-Sophia Antipolis, 06108 Nice Cedex 2, France
Received 10 February 2000; accepted 10 March 2000
Abstract
The synthesis of a series of 2-thiazolines was carried out under mild conditions from the corresponding
thiazolidines, by a Ru-catalyzed/TBHP oxidation reaction conditions. The reaction was chemoselective towards the
amine-imine oxidation and was also regioselective, affording the unsaturation at the 2-position of the heterocycle,
even with thiazolidine substrates bearing ester groups at the 4-position. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: thiazolines; thiazolidines; oxidation; ruthenium-catalyzed; TBHP.
Thiazolines constitute a family of compounds known for their application in flavor chemistry.1 More
than 30 thiazoline structures have been up to now identified from natural sources,2 in particular in
cooked meat,1 and in certain exotic fruits such as litchis.3 The biosynthesis of thiazolines (in fruits
and vegetables) seems to involve the enzymatic oxidation of thiazolidine intermediates, formed from
the coupling reaction of cysteine or cysteamine with aldehydes.4 Thiazolines have also been studied
for their pharmacological properties. Thus, some thiazoline derivatives present interesting anti-HIV5 or
anti-cancer6,7 activities and can inhibit cell division.8
The chemical preparation of 2-thiazolines is generally carried out by the condensation of 2-aminothiols
such as cysteine (or a cysteine derivative) with either a nitrile,9 a carboxylic acid10 or an ester.11 2-
Thiazolines can also be obtained from the dehydration of β-hydroxythioamides under the Mitsunobu
conditions12,13 or with the Burgess reagent.14 A multistep synthesis from oxazolidines or oxazolines has
also been reported.15 However, these reactions generally require drastic reaction conditions, such as the
use of triisobutyl aluminum.
We present here our results concerning a new strategy, parallel to the biosynthetic route, in which
thiazolidines are catalytically and selectively oxidized to 2-thiazolines.
Thiazolidines, 1, are easily obtained in 60–90% yields by the condensation of a 2-aminothiol (or its
ammonium salt) and an aldehyde derivative under slightly basic conditions.16,17 The use of (L)-cysteine
esters afforded 1f–h as a mixture of (2R,4R) and (2S,4R) diastereomers. 2D-NOESY NMR experiments
indicated the preferential formation of the cis isomer in cis/trans ratios of about 65/35. Epimerization
∗
Corresponding author. Fax: 33(0)492076151; e-mail: dunach@unice.fr (E. Duñach)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00419-6
tetl 16699

3382
of thiazolidines with ring opening involving C-2 has been reported.18 Under strong acidic or basic
conditions, or at high temperature, 1,3-thiazolidines undergo epimerization followed by decomposition.19
The selectivity in the oxidation of thiazolidines has not been thoroughly studied. These substrates
present several sites of reactivity: a nitrogen-centered oxidation can afford either N-oxides or 2- or 3-
thiazolines, and further oxidation to thiazoles. Oxidation can also occur at sulfur, to afford sulfoxide or
sulfone derivatives.
In particular, for the desired oxidation of thiazolidines to 2-thiazolines, the related oxidations of amines
to imines include the use of oxidants such as the di-t-butyliminoxyl radical,20 the bis(trifluoroacetate)
of diphenylselenium21 and iodosyl benzene22 or t-butylhydroperoxide23 in the presence of a ruthenium
catalyst. However, these methods have only been applied to simple and acyclic amines, generally benzylic
(to afford the conjugated imines or nitriles) and without other oxidable functional groups present.
We examined the Ru-catalyzed oxidation of thiazolidines (Scheme 1) under different reaction condi-
tions, and the main results are presented in Table 1.
Scheme 1.
In a typical experiment the RuCl2(PPh3)3-catalyzed (10 mol%) oxidation of 2-isopropyl-1,3-
thiazolidine, 1c, in the presence of 1 equiv. of TBHP in CH2Cl2 at room temperature, afforded a 67%
isolated yield of 2-isopropyl 2-thiazoline, 2c (after column purification), in a selective reaction, with a
conversion of 90% (entry 1). No reaction occurred under the same conditions in the absence of the Ru
catalyst. The selectivity of 2c among the other possible oxidation compounds was of 98%.
This Ru-catalyzed procedure was applied to the oxidation of several substrates 1 with isolated yields of
2-thiazolines in the range of 36 to 86%. The formation of N-oxide, sulfoxide or sulfone was not observed,
and the isomeric 3-thiazoline was obtained in only 1–4% yield.
Several ligands on RuCl2 or RuCl3 complexes were tested; phosphine ligands such as PPh3 and amine
ligands such as TMEDA or cyclam (1,4,8,11-tetraazacyclotetradecane). The comparison between the
catalytic activities of the three systems was evaluated in the oxidations of 1c and 1f (entries 1, 3–6).
Ru/PPh3 and Ru/TMEDA systems were more active and afforded better yields of 2 than the Ru/cyclam
system.
The influence of several factors was examined. The use of toluene instead of CH2Cl2 led to emulsion
problems upon isolation (entry 2). However, good results were obtained in acetonitrile (entries 3, 5, 6 10,
12). The use of two equiv. of TBHP led to further decomposition of the thiazoline with RuCl2(PPh3)2,
and to an increase of the corresponding thiazole with the use of RuCl3/TMEDA or RuCl3/cyclam. No
reaction occurred when using molecular oxygen or PHIO as the oxidants.
The oxidation to 2-thiazolines was very selective. It afforded better yields and selectivities in the
case of 4-unsubstituted thiazolidines, 1a–e (95–100%) as compared to the 4-substituted analogs, 1f–h
(80–96%).

3383
Table 1
Ru-catalyzed oxidation of thiazolidines, 1, to 2-thiazolines, 2, by TBHPa
Among the 2-thiazolines prepared, some of them such as 2e and 2a constitute interesting compounds
from the point of view of their flavor and perfume properties. Thus, 2-acetyl-2-thiazoline, 2e, presents
some popcorn aroma properties,24,25 and 2a the flavor of cooked beef.5
In conclusion, the selective synthesis of 2-thiazolines has been achieved via the easy preparation of
thiazolidines followed by their mild Ru/PPh3 or Ru/TMEDA-catalyzed oxidation with TBHP. This new
access to 2-thiazolines is parallel to the biosynthetic way for these compounds in plants.

3384
References
1. MacLeod, G.; Ames, J. J. Food Sci., 1987, 52, 42–46.
2. MacLeod, G.; Ames, J. Flavour Fragr. J. 1986, 1, 91–107.
3. Ong, P.; Acree, T. J. Agric. Food Chem. 1998, 46, 2282–2286.
4. Vernin, G.; Metzger, J. J. Bull. Soc. Chim. Belg. 1981, 30, 553–588.
5. Pattenden, G.; Mulqueen, B.; Falck, J. Tetrahedron Lett. 1994, 35, 5705–5708.
6. Wipf, P.; Fritch, P. Tetrahedron Lett. 1994, 35, 5377–5400.
7. Pattenden, G.; Boden, C.; Ye, T. Synlett 1995, 417–419.
8. Lai, J.-H.; Yu, J.; Makennen, B.; Falck, J. Tetrahedron Lett. 1996, 37, 7167–7170.
9. Mulqueen, G.; Pattenden, G.; Whiting, D. Tetrahedron 1993, 49, 5359–5364.
10. Vorbrügen, H.; Krolikiewick, K. Tetrahedron 1993, 49, 9353–9372.
11. Busacca, C.; Dong, Y.; Spinelli, E. Tetrahedron Lett. 1996, 37, 2935–2938.
12. Galéotti, N.; Montagne, C.; Pioncet, J.; Join, P. Tetrahedron Lett. 1992, 33, 2807–2810.
13. Wipf, P.; Miller, C. Tetrahedron Lett. 1992, 33, 6267–6270.
14. Wipf, P.; Fritc, P. Tetrahedron Lett. 1994, 35, 5397–5400.
15. Wipf, P.; Miller, C.; Venketremen, S.; Fritc, P. Tetrahedron Lett. 1995, 36, 6395–6398.
16. Chiarno, D.; Ferrario, F.; Pellacini, F.; Sala, A. J. Heterocycl. Chem. 1989, 26, 589–593.
17. Szilágyi, L.; Györgudeákz, Z. J. Am. Chem. Soc. 1979, 101, 427–432.
18. Hamri, A.; Péra, M. H.; Fillion, H. J. Heterocycl. Chem. 1987, 24, 1629–1633.
19. Pesek, J.; Frost, J. Tetrahedron 1975, 31, 907–913.
20. Cornejo, J.; Larsen, K.; Mendenhall, G. J. Org. Chem. 1985, 103, 5382–5383.
21. Marino, J.; Larsen, R. J. Am. Chem. Soc. 1987, 103, 4643–4645.
22. Muller, P.; Gilabert, D. Helv. Chim. Acta 1988, 7171–7175.
23. Murahashi, S.; Naota, T.; Tahi, H. J. Chem. Soc., Chem. Commun. 1985, 613–615.
24. Bultery, R.; Stean, D.; Ling, L. J. Agric. Food Chem. 1994, 42, 791–795.
25. Hartman, G.; Jin, Q. Z.; Collins, G.; Lee, K.; Ho, C. T.; Chang, S. J. Agric. Food Chem. 1983, 31, 1030–1033.