Diastereoselective synthesis of pyridyl substituted thiazolidin-4-ones. New ligands for the Cu(I) catalyzed asymmetric conjugate addition of diethylzinc to enones

Article abstract of DOI:10.1016/S0957-4166(97)00146-8

Several novel thiazolidin-cones have been synthesized from chiral nonracemic α-mercapto acids by a three component reaction in high yields and with diastereomeric excesses up to 91%. After recrystallization, the thiazolidinones were obtained diastereomeri

Full text of DOI:10.1016/S0957-4166(97)00146-8

Tetrahedron: Asymmetry, Vol 8, No 10, pp. 1539-1543, 1997
(~) 1997 Elsevier Science Ltd All rights reserved.
Printed in Great Britain
)
Pergamon
~
PII: S0957-4166(97)0~146-8
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Diastereoselective synthesis of pyridyl substituted thiazolidin-4-ones.
New ligands for the Cu(I) catalyzed asymmetric conjugate addition
of diethylzinc to enones
Andr6 H. M. de Vries, Robert E Hof, D a n n y Staai, Richard M. Kellogg* t and
Ben L. Feringa* *
Department of Organic and Molecular Inorganic Chemistry, Groningen Center for Catalysis and Synthesis,
University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Abstract: Several novel thiazolidin-4-ones have been synthesized from chiral non-
racemic o~-mercapto acids by a three component reaction in high yields and with
diastereomeric excesses up to 91%. After recrystallization, the thiazolidinones were
obtained diastereomerically pure and were employed as chiral ligands in the copper
catalyzed conjugate addition of diethylzinc to cyclohexenone and chalcone as model
substrates. Enantioselectivities up to 62% were achieved. (~ 1997 Elsevier Science Ltd
Introduction
Chiral non-racemic 13-amino alcohols are popular ligands in asymmetric catalysis.Z The use of the
corresponding 13-amino thiols, however, has been limited due to the lack, until recently, of simple
synthetic transformations to these interesting molecules. Building on the synthesis of enantiomerically
pure 13-amino thiols, -sulfides, and -disulfides2 and a recently improved synthesis of both enantiomers
of thiolactic acid, starting from a cheap building block, ethyl (S)-lactate,3 we describe herein the
synthesis and application of novel chiral thiazolidinones.
Sulfur containing compounds have been used as chiral ligands for stoichiometric4 and catalytic
enantioselective conjugate addition reactions of Grignard reagents to enones.5-7 Furthermore, enantio-
merically pure thiols and sulfides are successful catalysts in the enantioselective addition of diethylzinc
to benzaldehyde.8 Because sulfides and pyridines have a pronounced affinity for Cu(I)9 and chiral
copper catalysts have been used successfully in the enantioselective conjugate addition of dialkylzinc
to enones, l°'16b we envisioned that combination of these elements in the form of chiral thiazolidinones
also might lead to ligands suited for this asymmetric transformation.
Results and discussion
Synthesis of thiazolidin-4-ones 2
Although thiazolidinones have been the subject of extensive study and diverse biological activities
have been found to be associated with this class of heterocycles, II the elegant cyclocondensation
of a mercapto acid, an amine and an aldehyde under conditions of azeotropic removal of water to
give thiazolidin-4-ones is relatively unexplored.12 The 2-pyridyl-thiazolidin-4-ones 2 are obtained
in quantitative yield just by mixing o~-mercapto acid, aniline, and 2-pyridinecarboxaldehyde in
appropriate amounts (Scheme 1). A mixture of cis- and trans-diastereomers is produced; the former
predominates (vide infra). No racemization of the cx-mercapto acid was observed. In contrast to
reactions whereby chiral amines are used (no diastereoselectivity), 12b this synthesis using chiral cx-
mercapto acids proceeds with diastereomeric excesses (d.e., determined by I H NMR) varying from
*
t
Corresponding author. E-mail: Feringa@chem.rug.nl
Kellogg@chem.rug.nl
1
539

1540
A. H, M. DE VRIES et al.
2
4% 2c to 91% 2a. No attempts were undertaken to optimize the reactions conditions in order
to enhance the diastereomeric excess. Diastereomerically pure materials were obtained by simple
recrystallization. In analogy to cyclocondensations of et-hydroxy acids with aldehydes13 and other
studies,12a-c we expected that the major isomer should have a cis-geometry which allows both
substituents to remain in pseudo-equatorial positions. Indeed NOE experiments on 2a confirm an
interaction between hydrogens on the 2- and 5-position.
SH
- 2 H20
N
R ( ~ C O 2H
+
PhNH2
+
R
b e n z e n e ;
R3
R~
(
R)-I
a
b
R I = M e
R1 = kPr
a RI=Me,R 2=R 3=H
b
e
d
R1 = Me, R2 = Me, R3 = H
R1 = Me, RuR 3 = (CH=CH)2
R ~ = k P r , R 2 = R 3 = H
Scheme 1. Synthesis of thiazolidin-4-ones 2.
Thiolactic acid, required for the synthesis of 2a-c, was obtained as described. 3 Previously we
have shown that optically active Ix-mercapto acids are also accessible from naturally occurring amino
acids, 14 and this protocol was used for the synthesis of 2-mercapto-3-methyl-butanoic acid lb from S-
valine, leading to thiazolidin-4-one 2d (d.e. 85%). Overall, this makes these stable class of compounds
easily accessible.
Application of compound 2 as chiral ligand in the copper catalyzed addition of diethylzinc to enones
First, the substituted thiazolidin-4-ones 2a-d were examined in the CuOTf catalysed addition of
diethylzinc to cyclohexenone (Table 1). With ligand 2a (11 mol%) and 5 mol% of CuOTf a highly
selective reaction to afford the 1,4-product (>95% yield, GC analysis) was found. Isolation, purification,
and derivatization of the 1,4-product 415 revealed an e.e. of 47% (entry ! ). Sterically demanding groups
on both the pyridyl group 2b and 2c or the ix-position 2d had an influence on the enantioselectivity. A
methyl substituent at the 6-position of the pyridine ring reduces the e.e. (2b, 39%, entry 2), probably
by inducing the formation of another aggregate of the copper complex in solution. Use of quinoline
derivative 2e, instead of pyridine, had a minor influence, whereas a sterically demanding group at the
Ix-position in ligand 2d gave the best results. After 2 h quantitative conversion to the 1,4-product was
achieved and an enantiomeric excess of 62% was observed. This is the first example of successful
copper catalyzed enantioselective conjugate addition of dialkylzinc reagents using sulfur containing
ligands and the e.e. values of 4 are comparable with those found using cbiral phosphorus amidites. 10,16
When chalcone was used as substrate these new ligands showed excellent conversions to the 1,4-
product and complete regioselectivity was observed. However, enantioselectivity was low (up to 11%
for 2e). Although this class of ligands has scarcely been explored in asymmetric synthesis the results
look most promising, in particular as variations in the ligand structure can easily be achieved. At this
moment the optimization of the structure of this type of sulfur containing ligands is in progress. Also
extension in other asymmetric transformations will be investigated.
Experimental section
General
See Ref.18 Elemental analyses were performed in the Microanalytical Department of this laboratory.

Pyridyl substituted thiazolidin-4-ones
1541
Table 1. Enantioselective 1,4-addition of diethylzinc to cyclohexenone catalysed by CuOTf and 2a
0
2 (cat,)
0
[
~
+
E t2 Zn
Ct uol OuenTef(c a t' ) "
-1 0 °C
~ *
3
4
entry
ligand
e.e. of 4 (%)~
abs. conf.¢
1
2
3
4
2a
2b
2¢
2d
47
39
49
62
R
R
R
R
aReactions at I mmol scale at - 10°C in 5 ml of toluene Reaction time 2 6 h. Conversion to the 1.4-product >95% (based on
GC analysis). Isolated yields >70%. bEnantiomefic excess of 4 was determined by derivatization with enantiomerically pure
1,2-diphenylethylene diamine.15 CComparison of the specific rotation of4 with known data gave the absolute configuration.17
General procedure for the synthesis of thiazolidinones 2
A mixture of the (R)-(x-mercapto acid (10 mmol), the aldehyde (10 mmol) and aniline (0.93 g,
1
0 mmol) was azeotropically refluxed in 100 ml benzene in a Dean-Stark apparatus overnight. After
cooling, the solution was evaporated to dryness to give a quantitative yield of crude 2 as a mixture
of diastereomers. The diastereomeric excess of crude 2 was determined by 200 MHz IH - N M R (the
absorptions of the thioacetal proton were used to determine the ratio). Diastereomerically pure material
(
cis) was obtained after recrystallization as indicated.
(
2S,5R)-5-Methyl-3-phenyl-2-pyridin-2-yl-thiazolidin-4-one cis-2a
From la, aniline and 2-pyridinecarboxaldehyde crude 2a (d.e. 91%) was obtained. This material
was recrystallized from EtOH to give diastereomerically pure cis-2a (1.84 g, 6.81 mmol, 68%) as
glistening needles; mp 204.8-205.2°C; [O[]D +287.0 (c 1.03, CHC13); IH NMR ~i 1.65 (d, J=7. 0 Hz,
3
H), 4.31 (q, J=7. 0 Hz, 1H), 6.03 (s, 1H), 7.12-7.31 (m, 8H), 7.59-7.68 (m, 1H), 8.56 (d, J=4. 4
Hz, 1H); 13C NMR 8 18.22 (q), 41.28 (d), 63.95 (d), 120.08 (d), 123.21 (d), 124.52 (d), 126.61 (d),
1
1
29.03 (d), 137.15 (d), 149.97 (d), 159.31 (s); Anal. Calcd. for CIsH14N2OS: C, 66.64; H, 5.22; N,
0.36; S, 11.86. Found: C, 66.64; H, 5.14; N, 10.21; S, 11.71.
(
2S,5R)-5-Methyl-3-phenyl-2-( 6-methyl-pyridin-2- yl )-thiazolidin-4-one cis-2b
From la, aniline and 6-methyl-2-pyridinecarboxaldehyde crude 2b (d.e. 51%) was obtained. This
material was recrystallized from ether/hexane to give diastereomerically pure cis-2b ( 1.54 g, 5.4 mmol,
4%); mp 110.5-112.3°C; [aiD +161.5 (c 1.20, CHCI3); ]H NMR 8 1.64 (d, J=7.1 Hz, 3H), 2.53
s, 3H), 4.30 (q, J=7.1 Hz, 1H), 5.98 (s, IH), 6.97-7.55 (m, 8H); 13C NMR ~i 17.99 (q), 24.21 (q),
5
(
4
5
(
1.13 (d), 63.97 (d), 116.67 (d), 122.80 (d), 124.43 (d), 126.50 (d), 128.99 (d), 137.31 (d), 138.13 (s),
1
58.87 (s); Anal. Calcd. for CI6HI6N2OS: C, 67.58; H, 5.67; N, 9.85; S, 1.27. Found: C, 67.36; H,
.69; N, 9.81; S, 11.18.
2S,5R)-5-Methyl-3-phenyl- 2-quinolin-2-yl-thiazolidin-4-one cis-2c
From la, aniline and 2-quinolinecarboxaldehyde crude 2e (d.e. 24%) was obtained. This material
was recrystallized four times from EtOH to give cis-2c (697 .mg, 2.17 mmol, 22%, d.e. 94%) as
glistening plates; mp 179.8-180.5°C; [(X]D +327.9 (c 1.20, CHC13); IH NMR 6 1.70 (d, ./=7.1 Hz,
3
H), 4.33 (dq, J=7.1 Hz and J = l . 2 Hz, 1H), 6.25 (d, J = l . 2 Hz, 1H), 7.08-8.17 (m, 11H); 13C NMR
8.59 (q), 41.44 (d), 64.46 (d), 117.66 (d), 124.62 (d), 126.67 (d), 126.93 (d), 127.57 (d), 129.05
d), 129.30 (d), 130.01 (d), 137.82 (d), 137.98 (s), 147.43 (s), 159.33 (s), 174.03 (s).
1
(

1
542
A . H . M . DE VRIES et al.
(2S,5R)-5-1sopropyl-3-phenyl-2-pyridin-2-yl-thiazolidin-4-one
cis-2d
Starting from 9.5 mmol (R)-2-mercapto-3-methylbutanoic acid lb, 14 aniline and 2-pyridine-
carboxaldehyde crude 2d (d.e. 85%) was obtained. This material was recrystallized from EtOH to
give diastereomerically pure cis-2d (1.09 g, 3.66 mmol, 39%) as a white powder; mp 119.6-120.9°C;
[
1
5
(
0~]D +292.2 (c 0.51, CHC13); IH-NMR 8 1.08 (dd, J=7.0 and J=6.6 Hz, 6H), 2.62 (m, IH), 4.30 (s,
H), 6.09 (s, 1H), 7.12-7.27 (m, 7H), 7.61 (m, 1H), 8.50 (m, IH); 13C-NMR ~ 20.96 (q), 30.99 (d),
5.09 (d), 64.83 (d), 120.62 (d), 123.13 (d), 124.81 (d), 126.61 (d), 128.91 (d), 137.03 (d), 149.52
d), CO and quartenary C not observed.
Conjugate addition of diethylzinc to cyclohexenone 3 and chalcone using catalytic amounts of
(CuOTf)2. benzene and chiral thiazolidinones 2
This procedure is typical for all conjugate addition reactions. A solution of (CuOTf)2.benzene (5
mol%) and of chiral thiazolidinone (11 tool%) in 5 ml of toluene and 2 ml of CH2Ci2 was stirred at
ambient temperature for 1 h under argon. A clear solution was formed. Substrate was added (1.0-2.0
mmol), the mixture was cooled to -20°C and diethylzinc in toluene (1.1 M, 1.5 equivalent) was
added. Stirring was continued at -10°C for 2-6 h. An aliquot of the solution (0.1 ml) was taken and
quenched with 1 ml of aqueous 1 N HC1. After extraction with 1 ml of diethyl ether the conversion was
determined by GC analysis.18 In all cases complete conversion was achieved with regioselectivities for
the 1A-product of >95%. The mixture was poured into 25 ml of aqueous 1 N HC1 and extracted with
diethyl ether (3x20 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4),
filtered and evaporated to give the crude 1,4-product. After purification by column chromatography
(SIO2, hexane:diethyl ether 5:1) the e.e.'s were determined. 18
References
1. a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993. b) Brunner,
H.; Zettlmeier, W. Handbook of Enantioselective Catalysis; VCH Publishers: New York, 1993. c)
Noyori, R. Asymmetric Catalysis in Organic Chemistry; Wiley: New York, 1994. See for example
also de Vries, A.H.M.; Feringa, B.L. Tetrahedron: Asymmetry 1997, 8, 1377 and Ref. 18.
. Poelert, M.A.; Hof, R.P.; Peper, N.C.M.W.; Kellogg, R.M. Heterocycles 1994, 37, 461.
2
3. Hof, R.P.; Kellogg, R.M.J. Chem. Soc., Perkin Trans. I 1995, 1247.
4
. a) Leyendecker, E; Laucher, D. Tetrahedron Lett. 1983, 24, 3517. b) Leyendecker, F.; Laucher,
D. Nouv. J. Chim. 1985, 9, 13.
5
. a) Lambert, E; Knotter, D.M.; Janssen, M.D.; van Klaveren, M.; Boersma, J.; van Koten, G.
Tetrahedron: Asymmetry 1991, 2, 1097. b) van Klaveren, M.; Lambert, F.; Eijkelkamp, D.J.EM.;
Grove, D.M.; van Koten, G. Tetrahedron Lett. 1994, 35, 6135. c) Zhou, Q.-L.; Pfaltz, A. Tetrahedron
Lett. 1993, 34, 7725. d) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467. e) Spescha, M.; Rihs,
G. Helv. Chim. Acta 1993, 76, 1219.
6
7
. For a recent review on catalytic enantioselective conjugate addition reactions, see: Feringa, B.L.; de
Vries, A.H.M. in Advances in Catalytic Processes. Vol 1: Asymmetric Chemical Transformations;
Doyle, M.P., Ed.; JAI Press, Connecticut, 1995, p. 151.
. The use of a chirai bidentate phoshine as ligand in a CuI catalyzed addition of Grignard reagents
to cyclic enones (e.e. up to 92%) has been reported recently: M. Kanai, K. Tomioka, Tetrahedron
Lett. 1995, 36, 4275.
8. a) Hof, R.P.; Poelert, M.A.; Peper, N.C.M.W.; Kellogg, R.M. Tetrahedron: Asymmetry 1994, 5,
31. b) Fitzpatrick, K.; Hulst, R.; Kellogg, R.M. Tetrahedron: Asymmetry 1995, 6, 1861.
9
. Hathaway, B.J. In Comprehensive Coordination Chemistry; Wilkinson, G.; Gillard, R.D.; McLe-
verty, J.A., Eds.; Pergamon: Oxford, 1987, Vol. 5, Chapter 53.
1
1
1
0. de Vries, A.H.M.; Meetsma, A.; Feringa, B.L. Angew. Chem., Int. Ed. Engl. 1996, 35, 2374.
1. Singh, S.P.; Parmar, S.S.; Raman, K.; Stenberg, V.I. Chem. Rev. 1981, 81,175-203.
2. a) Johnson, M.R.; Fazio, M.J.; Ward, D.L.; Sousa, L.R.J. Org. Chem. 1983, 48, 495, and references
therein, b) Botteghi, C.; Schionato, A.; Chelucci, G.; Brunner, H.; Ktirzinger, A.; Obermann, U.

Pyridyl substituted thiazolidin-4-ones
1543
J. Organomet. Chem. 1989, 370, 17. c) Tanabe, Y.; Yamamoto, H.; Murakami, M.; Yanagi, K.;
Kubota, Y.; Okumura, H.; Sanmitsu, Y.; Suzukamo, G. J. Chem. Soc., Perkin Trans l 1995, 935.
1
1
1
3. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313.
4. Strijtveen, B.M.; Kellogg, R.M.J. Org. Chem. 1986, 51, 3664.
5. Alexakis, A.; Frutos, J.C.; Mangeney, P. Tetrahedron: Asymmetry 1993, 4, 2431.
1
6. a) Very recently a [~-amino disulfide, derived from proline, has been used as chiral ligand in the
nickel catalyzed conjugate addition of diethylzinc to chalcone (e.e. <50%); no results with other
enones, for example cyclohexenone, are described: Gibson, C.L. Tetrahedron: Asymmetry 1996,
7, 3357. b) Except for our own results (reference 10), only one other example of enantioselectivity
in a copper catalyzed addition of diethylzinc to cyclohexenone has been reported (e.e. 30%), see:
Alexakis, A.; Frutos, J.; Mangeney, E Tetrahedron: Asymmeto, 1993, 4, 2427.
17. Posner, G.H.; Frye, L.L. Isr. J. Chem. 1984, 24, 88.
18. See de Vries, A.H.M.; Imbos, R.; Feringa, B.L. Tetrahedron: Asymmeto, 1997, 8, 1467.
(Received in UK 19 February 1997; accepted 25 March 1997)