Synthesis of chiral thiazoline ligands tethered to a sulfur function and first immobilization of a thiazoline-ligand

Article abstract of DOI:10.1002/hc.20603

A new family of thiazoline ligands tethered to a sulfanyl or a sulfinyl group has been prepared using short and efficient reaction sequences. Among the different structures, one sulfanyl-thiazoline homopolymer was synthesized as a first example of an immo

Full text of DOI:10.1002/hc.20603

Heteroatom Chemistry
Volume 21, Number 4, 2010
Synthesis of Chiral Thiazoline Ligands
Tethered to a Sulfur Function and First
Immobilization of a Thiazoline-Ligand
Isabelle Abrunhosa-Thomas, Alexander Betz, Mickael Denance´,
Isabelle Dez, Annie-Claude Gaumont, and Mihaela Gulea
Laboratoire de Chimie Mole´culaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038,
ENSICAEN, Universite´ de Caen Basse-Normandie, 6 Bd. Mare´chal Juin, 14050 Caen, France
Received 12 February 2010; revised 31 March 2010
siderably leading to the publication of some reviews
ABSTRACT: A new family of thiazoline ligands teth-
[1].
ered to a sulfanyl or a sulfinyl group has been pre-
Among the large variety of chiral ligands, the
pared using short and efficient reaction sequences.
thiazolines, which are sulfur-analogues of oxazo-
Among the different structures, one sulfanyl-thiazoline
lines, represent a young family of ligands [2]. They
homopolymer was synthesized as a first example of an
have proved to be useful sulfur-containing ligands
immobilized thiazoline ligand. The catalytic proper-
in various metal-catalyzed reactions and to behave
ties of these new ligands were evaluated in the Pd-
sometimes differently from oxazolines. Among the
ꢀ
C
catalyzed allylic substitution. 2010 Wiley Periodicals,
various structures of thiazoline-ligands including
Inc. Heteroatom Chem 21:242–249, 2010; Published on-
bis(thiazolines) [3a–f], phosphine-thiazolines [3d,e],
line in Wiley InterScience (www.interscience.wiley.com).
pyridyl-thiazolines [3d–f], oxazoline-thiazolines
DOI 10.1002/hc.20603
[3g,l], ferrocenyl-bis(thiazolines) [3h], hydroxyalkyl-
thiazolines [3j], and tris(thiazolines) [3k], only one
example of sulfanyl-thiazoline ligand has been
described [3i]. These ligands are of interest be-
cause they contain one S-coordinating and one
S-noncoordinating atom [1a].
This paper describes the preparation of a series
of sulfanyl- and sulfinyl-thiazolines, and the first ex-
ample of the immobilization of a thiazoline ligand.
The catalytic properties of these new ligands have
been evaluated in the well-known reaction test, the
Pd-catalyzed allylic substitution, and the results are
reported herein.
INTRODUCTION
Compared with the widely used nitrogen and
phosphorus-containing chiral ligands in asymmetric
metal-catalyzed reactions, the sulfur counterparts
have been less studied for this purpose. However, in
recent years, the number of studies dealing with the
chiral sulfur-containing ligands has increased con-
Correspondence to: Isabelle Dez; e-mail: isabelle.dez@ensicaen
.fr. Mihaela Gulea; e-mail: mihaela.gulea@ensicaen.fr.
Contract grant sponsor: Ministe`re de la Recherche et des
Nouvelles Technologies.
RESULTS AND DISCUSSION
Contract grant sponsor: “PUNCHOrga” (Poˆle Universitaire
Normand de Chimie Organique).
Contract grant sponsor: Re´gion Basse-Normandie.
Contract grant sponsor: CNRS (Centre National de la Recherche
Scientifique).
Four types of structures have been selected for this
study (Fig. 1). Some of them can be considered as the
sulfur analogues of sulfanyl-oxazoline N, S-ligands
described by Williams [4]. Ligands of type I and II
are thiazolines bearing, respectively, a sulfanyl or a
Contract grant sponsor: European Union (FEDER funding).
2010 Wiley Periodicals, Inc.
c
ꢀ
242

Synthesis of Chiral Thiazoline Ligands Tethered to a Sulfur Function and First Immobilization of a Thiazoline-Ligand 243
FIGURE 1 Selected structures of thiazoline ligands.
SCHEME 2
sulfinyl group in α-position. Ligands III possess a
sulfanyl group in β-position. In the case of ligands
IV, the sulfanyl group belongs to the substituent
placed in the 4-position of the thiazoline. Depending
on the position of the sulfur function on the thiazo-
line, the proposed bidentate thiazoline-ligands may
form five- or six-membered ring metal complexes
(five for I and II; six for III and IV).
We first prepared α-sulfanyl-thiazolines 2a–c,
which are, respectively, substituted in the 4-position
with an ethyl, a tert-butyl, and a benzyl group. They
were prepared from the corresponding enantiop-
ure 2-isopropyl-thiazolines 1a–c [3b] by deprotona-
tion in α-position with tert-butyllithium and addi-
tion of diphenyl disulfide (Scheme 1). The expected
products were obtained in satisfactory yields (65–
75%). In a similar way, diastereomeric α-sulfinyl-
thiazolines (R, Rs)-3a and (R, Ss)-3b were synthe-
sized from thiazoline (R)-1a and the (R) or (S) tert-
butyl thiosulfinate [5] respectively.
β-Sulfanyl-thiazolines 5 were prepared by 1,4-
addition of a thiol to α,β-unsaturated thiazolines 4.
The synthesis of thiazolines of type 4 was previously
described by some of us and consists in a Horner–
Wadsworth–Emmons (HWE) reaction of the cor-
responding thiazoline-phosphonates with acetone
[6]. The two-methyl groups on the double bond
were placed to avoid the formation of a new stere-
ogenic center after the 1,4-addition. Thus, two α,β-
unsaturated thiazolines 4a and 4b, substituted in
the 4-position with a benzyl and with a phenyl
group, respectively, were reacted with thiophenol or
ethanethiol, in the presence of a catalytic amount of
triethylamine, to afford β-sulfanyl-thiazolines 5a–c
in moderate yields (52–68% yield; Scheme 2).
Compound 8 was chosen as an example of
sulfanyl-thiazoline ligand, in which the chain bear-
ing the sulfanyl group is placed in the 4-position
of the thiazoline. The synthesis was performed in
two steps (thioacylation and intramolecular cycliza-
tion) starting from phenyldithioic methyl ester [7]
and commercially available (S)-methioninol [8]. The
nonoptimized overall yield was 59% (Scheme 3).
All prepared ligands were tested in the
Pd-catalyzed allylic substitution using 1,3-
diphenylpropenyl acetate and dimethylmalonate,
in the presence of bis(trimethylsilyl)acetamide,
potassium acetate (KOAc), and [Pd(C3H5)Cl]2
(Scheme 4). The results are given in Table 1.
α-Sulfanyl-thiazolines 2a–c (Table 1, entries 1–
3) gave almost complete conversion after 24 h and
quite similar enantiomeric excess (37%, 43%, and
40% ee, respectively). Ligand (R)-2a favored the
formation of product (R), and ligands (S)-2b,c fa-
vored the (S) product. These results show that in
this series the steric hindrance of the substituent
in the 4-position of the thiazoline does not influ-
ence the asymmetric induction, which is probably
under electronic control (the trans effect of the sul-
fur atom). α-Sulfinyl-thiazolines 3a and 3b, which
SCHEME 3
SCHEME 4
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

244 Abrunhosa-Thomas et al.
TABLE 1 Pd-Catalyzed Asymmetric Allylic Substitution Us-
ing Ligands 2a–c, 3a-b, 5a–c, and 8
Conversion Enantiometric
% (time) Excess (ee) (%) Configuration
Product
Entry Ligand
1
2
3
4
5
6
7
8
9
(R)-2a >95 (24 h)
37
43
40
47
47
49
73
42
66
(R)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(R)
(S)-2b >95 (24 h)
(S)-2c >95 (48 h)
(R,RS)-3a 30 (168 h)
(R,SS)-3b 30 (168 h)
(S)-5a
(S)-5b
(S)-5c
50 (120 h)
60 (120 h)
80 (120 h)
(S)-8 >95 (24 h)
SCHEME 5
are diastereomers having the same thiazoline and
opposite configurations on the sulfur stereocenter,
gave a low conversion of 30% after 168 h (entries 4
and 5), probably due to the weaker coordination of
the metal by the sulfinyl ligand (compared to a sul-
fanyl group). Both of them afforded an enantiomeric
excess of 47% in favor of the (R) product, indicating
that the sense of the asymmetric induction is deter-
mined by the configuration of the carbon stereocen-
ter of the thiazoline (in this case R) and not by that
of the sulfinyl group. This result differs from the re-
sults obtained with some sulfinyl-oxazolines ligands,
for which the configuration at the sulfur center was
found to be important for the enantioselectivity [9].
With β-sulfanyl-thiazoline ligands 5a–c, conversions
were still incomplete after 120 h (entries 6–8). The
three ligands of (R) configuration afforded the (R)
stereoisomer as the main product. Phenylsulfanyl-
thiazoline 5b (with R1, R2 = Ph) gave the best enan-
tiomeric excess (73% ee). Upon replacing the phenyl
by benzyl in ligand 5a (R1 = Bn, R2 = Ph), or the
phenylsulfanyl by an ethylsulfanyl in ligand 5c, the
enantioselectivity decreased (from 73% to 49% and
42%, respectively). For this type of ligand, both steric
and electronic effects seem to be involved in the
asymmetric induction. Sulfanyl-thiazoline 8 derived
from (S)-methioninol afforded a total conversion af-
ter 24 h and an enantiomeric excess of 66% in favor
of the (R) product.
polymer on the activity and selectivity of the catalyst
and then to attempt its recycling.
From a structural point of view, the chosen lig-
and was the polymeric analogue of the sulfanyl-
thiazoline 8 described above, which gave a satis-
factory ee of 66% and seemed to be easy to tether
to a polymer through the 2-position of the thi-
azoline. Thus, monomer M-12a was synthesized
from the commercially available 1-(chloromethyl)-4-
vinylbenzene 9, in four steps, according to Scheme 5.
First, we prepared the styrene-dithioester 11 using a
general method described previously to access aro-
matic dithioesters [13]. The overall yield via sulfone
10 was 68%. Starting from dithioester 11, sulfanyl-
thiazoline M-12a was prepared in 58% yield by a
two-steps sequence (thioacylation with methioninol
and cyclization). Finally, the radical polymerization
of M-12a was performed using AIBN as initiator,
in THF at 80◦C. The polymer P-12a was obtained
in a moderate yield of 43%. Unfunctionalized thi-
azoline M-12b was prepared similarly, as the pre-
cursor of the homopolymer monodentate ligand P-
12b, to compare it to the former polymeric biden-
tate thiazoline ligand P-12a. The synthesis of P-12b
was similar, just replacing the (S)-methioninol with
(R)-2-amino-1-butanol. The overall yield for M-12b
starting from 11 was 59%, and the polymer P-12b
was obtained in a 51% yield.
Immobilized chiral ligands for asymmetric
metal-catalyzed reactions have been widely stud-
ied and reviewed because of their major advan-
tages: easy recoverability and possibility of the cata-
lyst recycling [10]. If immobilized oxazolines have
been well studied [11], to the best of our knowl-
edge, no example with thiazolines has ever been
reported. Therefore, we decided to immobilize a
thiazoline-ligand by polymerization of a chiral thi-
azoline monomer [12], to examine the effect of the
Tested in the selected Pd-catalyzed allylic substi-
tution, the polymeric ligand P-12a showed the same
catalytic activity as the corresponding monomeric
ligand 8 (full conversion after 24 h) and also favored
the (R) product, albeit with a lower enantiomeric ex-
cess (36% ee). Both monomeric and polymeric mon-
odentate ligands M-12b and P-12b were found to
be totally inactive in the test reaction. This result
seems to indicate that two nearby thiazolines in the
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Chiral Thiazoline Ligands Tethered to a Sulfur Function and First Immobilization of a Thiazoline-Ligand 245
HRMS on a Waters QTOF micro spectrometer. IR
spectra were recorded with a Perkin Elmer 16 PC
FT-IR instrument. Analytical data were obtained us-
ing a THERMOQUEST NA 2500 instrument. Op-
tical rotations were measured on a Perkin–Elmer
241 polarimeter. THF was purified with a PURE-
SOLV apparatus developed by Innovative Technol-
ogy Inc. Reaction progress was monitored by thin-
layer chromatography (TLC) using Merck silica gel
60 aluminum sheets (F254). The plates were visual-
ized by either UV light (254 nm), or by a solution
of potassium permanganate. Column chromatogra-
phy was performed using Merck silica gel Si 60 (40–
63 μm).
polymer do not behave as a bidentate ligand and that
the sulfanyl-thiazoline moiety in P-12a clearly acts
as a bidentate ligand. We then attempted to reuse
the catalyst with P-12a as ligand. After the first run,
the catalyst was recovered by precipitation in diethyl
ether and filtration and used in a second catalytic cy-
cle. After 48 h, the conversion poorly reached 15%
(probably due to metal leaching during the precipi-
tation. Black precipitate of Pd(0) could be observed
in the reaction mixture.) and the enantiomeric ex-
cess decreased from 36% to 8%. Although this result
is rather disappointing, supplementary experiments
should be done to improve the treatment at the end
of the catalytic cycle (change of the solvent), but also
by changing the polymer structure by copolymeriza-
tion of M-12a with styrene or divinylstyrene.
Synthesis of α-Sulfanyl Thiazolines (2) and of
α-Sulfinyl Thiazolines (3)
CONCLUSION
General Procedure. t-BuLi (1.1 equiv) was
added dropwise to a solution of thiazoline 1 (1 equiv)
in dry THF (c = 0.4 M) at −78◦C. The yellow solu-
tion was stirred for 2 h at this temperature before the
corresponding sulfur electrophile (2 equiv dissolved
in dry THF) was added. The mixture was allowed to
reach room temperature within 1 h and was stirred
overnight. Water was added, and the product was
extracted with Et2O. The organic layers were dried
over MgSO4, filtered, and solvents were removed in
vacuum to yield the crude product, which was puri-
fied by column chromatography.
In conclusion, a new family of thiazoline ligands,
which are tethered to a sulfanyl or a sulfinyl
group through their 2- or 4-position, was synthe-
sized. A first example of an immobilized thiazo-
line ligand prepared in five steps starting from
1-(chloromethyl)-4-vinylbenzene is also described.
The methods used for the syntheses should allow
easy modulation of the ligand structure by modi-
fying the substituents on the thiazoline or on the
sulfur atom, or the spacer between the thiazoline
and the sulfanyl function. In the case of the im-
mobilized sulfanyl-thiazoline, the structure of the
polymeric support could also be changed. All the
newly synthesized ligands were examined for their
ability to introduce asymmetric induction in the
Pd-catalyzed allylic substitution, but none of them
gave a high-enantiomeric excess in this reaction.
Thiazoline-polymer P-12a gave total conversion af-
ter 24 h (the same as its monomeric analogous 8), but
lower ee (36% vs 66% ee). The polymer structure did
not allow the recycling of the catalyst. Further stud-
ies concerning the described sulfanyl- and sulfinyl-
thiazolines in other metal-catalyzed reactions will be
undertaken to expand the application of these new
thiazoline ligands in asymmetric catalysis.
(R)-4-Ethyl-2-(1-phenylsulfanyl-1-methylethyl)-
thiazoline (2a): Prepared by the general proce-
dure from 1a and diphenyl disulfide, purified by
chromatography on silica gel (eluent: pentane/Et2O
85:15), yellow oil, 71% yield, [α]2D0 +52 (c 0.95,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 0.89
3
(t, JHH = 7.4 Hz, 3H, CH2CH3), 1.43–1.73 (m,
2H, CH2CH3), 1.55 (s, 3H, C(CH3)2), 1.57 (s, 3H,
2
3
C(CH3)2), 2.95 (dd, JHH = 10.8 Hz, JHH = 7.5 Hz,
1H, SCHH), 3.35 (dd, 2 JHH = 10.8 Hz, 3 JHH = 8.3 Hz,
1H, SCHH), 4.25–4.32 (m, 1H, CHEt), 7.26–7.35,
and 7.51–7.55 (m, 5H, C6H5). 13C NMR (CDCl3,
101 MHz): δ = 10.9 (CH2CH3), 27.7 (CH2CH3), 28.4,
and 28.5 (C(CH3)2), 38.0 (SCH2), 51.9 (C(CH3)2), 78.7
(CHEt), 128.6 (C6H5), 129.1 (C6H5), 131.9 (Cipso),
136.2 (C6H5), 175.3 (SCN). IR (cm−1): 2964, 2827,
1610, 1438, 1128, 1026, 879, 749, 692.
EXPERIMENTAL
General
(S)-4-Tert-Butyl-2-(1-phenylsulfanyl-1-methy-
lethyl)thiazoline (2b): Prepared by the general pro-
cedure from 1b and diphenyl disulfide, purified by
chromatography on silica gel (eluent: pentane/Et2O
85:15), yellow oil, 75% yield, [α]2D0 −48 (c 1.05,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 0.88
(s, 9H, C(CH3)3), 1.566 (s, 3H, C(CH3)2), 1.568
(s, 3H, C(CH3)2), 3.05 (“t”, 1H, SCHH), 3.20
NMR spectra were recorded on a Bruker DRX 400
or a DPX 250 spectrometer. Chemical shifts (δ) are
reported in ppm (s = singlet, d = doublet, t = triplet,
m = multiplet, br = broad) and are indicated in
ppm using TMS as internal standard. Coupling con-
stants (J) are given in hertz. Mass spectra were ob-
tained on a GC/MS Saturn 2000 spectrometer and
Heteroatom Chemistry DOI 10.1002/hc

246 Abrunhosa-Thomas et al.
(dd, 2 JHH = 10.9 Hz, 3 JHH = 8.7 Hz, 1H, SCHH), 4.03
ing mixture was stirred until completion (about
1 h, monitored by TLC). The solvent was evap-
orated, and the product was purified by column
chromatography.
3
3
(dd, JHH = 10.7 Hz, JHH = 8.7 Hz, 1H, CHtBu),
7.25–7.34 and 7.51–7.55 (m, 5H, C6H5). 13C NMR
(CDCl3, 101 MHz): δ = 26.8 (C(CH3)3), 28.2 and
28.8 (C(CH3)2), 34.6 (SCH2), 35.0 (C(CH3)3), 52.3
(C(CH3)2), 87.3 (CHtBu), 128.6 (C6H5), 128.9 (C6H5),
132.1 (Cipso), 136.2 (C6H5), 174.4 (SCN).
(S) - 4 - Benzyl - 2 - [2 - phenylsulfanyl - 2 - methy-
lpropyl]thiazoline (5a): Prepared by the general pro-
cedure from 4a and thiophenol, purified by chro-
matography on silica gel (eluent: pentane/Et2O 95:5);
(S)-4-Benzyl-2-(1-phenylsulfanyl-1-methylethyl)-
thiazoline (2c): Prepared by the general procedure
from 1c and diphenyl disulfide, purified by chro-
matography on silica gel (eluent: pentane/Et2O 95:5);
yellow oil, 65% yield. 1H NMR (CDCl3, 250 MHz) δ =
1.57 and 1.59 (2s, 6H, C(CH3)2), 2.53 (dd, 2 JHH = 13.6,
1
yellow oil, 64% yield, [α]2D0 −79 (c 1, acetone). H
NMR (CDCl3, 250 MHz) δ = 1.46 and 1.48 (2s, 6H,
2
3
(CH3)2C), 2.51 (dd, JHH = 13.6, JHH = 9.2, 1H,
2
CHHPh), 2.64 (s, 2H, CH2C N), 3.07 (dd, JHH
=
13.6, JHH = 4.9, 1H, CHHPh), 3.35 (dd, 3 J = 9.4,
3
2 JHH = 10.9, 1H, CHHS), 3.51 (dd, JHH = 8.8,
3
3 JHH = 9.3, 1H, CHHPh), 3.00 (dd, 2 JHH = 13.6, 3 JHH
=
2 JHH = 10.9, 1H, CHHS), 4.62 (m, 1H, CHN), 7.26–
7.63 (m, 10Har). 13C NMR (CDCl3, 63 MHz) δ =
27.6 and 28.1 (CH3), 37.6 (CH2Ph), 42.8 (CH2S),
44.1 (CH2C N), 47.6 (C(CH3)2), 80.3 (CHPh), 125.6,
126.5, 127.7, 142.2, 170.8 (S C N).
2
3
4.9, 1H, CHHPh), 3.01 (dd, JHH = 11.1, JHH = 6.2,
2
3
1H, CHHS), 3.18 (dd, JHH = 11.1, JHH = 8.5, 1H,
CHHS), 4.59 (m, 1H, CHN), 7.11–7.35 and 7.54–7.58
(m, 10H, Har). 13C NMR (CDCl3, 63 MHz) δ = 28.2
and 28.3 (C(CH3)2), 37.4 (CH2Ph), 39.8 (CH2S), 51.8
(C(CH3)2), 78.3 (CHN), 126.4, 128.4, 128.6, 129.3,
129.4, 131.7, 136.3, 138.5, 176.3 (S C N). IR (cm−1):
3010, 2960, 2920, 2850, 1640, 1490, 1450, 1030.
(R,Rs)-4-Ethyl-2-(1-tert-butylsulfinyl-1-methy-
lethyl)thiazoline (3a): Prepared by the gen-
eral procedure from 1a and (R)-tert-butyl-tert-
butanethiosulfinate, purified by chromatography on
silica gel (eluent: pentane/AcOEt 50:50), [α]2D0 +128
(R) - 4 - Phenyl - 2 - [2 - phenylsulfanyl - 2methy-
lpropyl]thiazoline (5b): Prepared by the general pro-
cedure from 4b and thiophenol, purified by chro-
matography on silica gel (eluent: pentane/Et2O 95:5);
1
yellow oil, 68% yield. H NMR (CDCl3, 250 MHz)
δ (ppm): 1.45 and 1.50 (2s, 6H, (CH3)2C), 2.64
3
(s, CH2C N), 3.35 (t, JHH = 7.50, 1H, CHHS),
3
2
3.42 (dd, JHH = 7.5, JHH = 10.0, 1H, CHHS),
3
1
5.46 (t, JHH = 10.0, 1H, CHN), 7.26–7.63 (m,
(c 0.9, acetone). H NMR (CDCl3, 400 MHz): δ =
10Har). 13C NMR (CDCl3, 63 MHz) δ (ppm): 27.9
(CH3), 28,8(CH3), 42.8 (CH2S), 44.2 (CH2C N), 47.8
(C(CH3)2), 80.3 (CHPh), 125.6, 126.5, 127.7, 142.2,
171.5 (S C N). IR (cm−1): 2900, 1600, 1440, 1020.
Anal. calcd for: C19H21NS2: C, 69.68%; H, 6.46%; N,
4.28; S 19.58%. Found: C, 69.62%; H, 6.46%; N, 4.38;
S 19.32%.
3
1.01 (t, JHH = 7.4 Hz, 3H, CH2CH3), 1.31 (s, 9H,
C(CH3)3), 1.53–1.89 (m, 2H, CH2CH3), 1.57 (s, 3H,
2
C(CH3)2), 1.59 (s, 3H, C(CH3)2), 2.95 (dd, JHH
=
11.0 Hz, 3 JHH = 8.0 Hz, 1H, SCHH), 3.32 (dd, 2 JHH
=
3
11.0 Hz, JHH = 8.6 Hz, 1H, SCHH), 4.28–4.36 (m,
1H, CHEt). ES-MS m/z (%): 262 (M + H, 21), 157
(100), 156 (32).
(R)-4-Phenyl-2-[2-ethylsulfanyl-2methylpropyl]-
thiazoline (5c): Prepared by the general procedure
from 4b and ethanethiol, purified by chromatogra-
phy on silica gel (eluent: pentane/Et2O 95:5); yellow
(R,Ss)-4-Ethyl-2-(1-tert-butylsulfinyl-1-methy-
lethyl)thiazoline (3a): Prepared by the gen-
eral procedure from 1a and (S)-tert-butyl-tert-
butanethiosulfinate, purified by chromatography on
silica gel (eluent: pentane/AcOEt 50:50), [α]2D0 −117
1
oil, 52% yield. H NMR (CDCl3, 250 MHz) δ (ppm):
3
1
1.25 (t, JHH = 7.4, 3H, CH3CH2), 1.46 and 1.47 (2s,
(c 1.1, acetone). H NMR (CDCl3, 400 MHz): δ =
6H, (CH3)2C), 2.62 (q, 3 JHH = 7.4, 2H, CH2CH3), 2.98
3
1.00 (t, JHH = 7.4 Hz, 3H, CH2CH3), 1.29 (s, 9H,
2
3
(s, 2H, CH2C N), 3.20 (dd, JHH = 10.9, JHH = 9.9,
C(CH3)3), 1.54–1.88 (m, 2H, CH2CH3), 1.55 (s, 3H,
2
3
2
1H, CHHS), 3.68 (dd, JHH = 10.9, JHH = 8.9, 1H,
C(CH3)2), 1.59 (s, 3H, C(CH3)2), 2.89 (dd, JHH
=
3
11.0 Hz, 3 JHH = 8.9 Hz, 1H, SCHH), 3.33 (dd, 2JHH
=
CHHS), 5.46 (t, JHH = 9.0, 1H, CHN), 7.26–7.36
(m, 5Har). 13C NMR (CDCl3, 63 MHz) δ (ppm): 13.3
(CH3CH2), 21.3 (CH2CH3), 27.8 and& 28.1 (2CH3),
40.8 (CH2S), 43,0 (CH2C N), 45.8 ((CH3)2C), 79.1
(CHN), 125.6, 126.5, 127.6, 141.1, 167.1 (S C N).
3
11.0 Hz, JHH = 8.6 Hz, 1H, SCHH), 4.26–4.34 (m,
1H, CHEt). ES-MS m/z (%): 262 (M + H, 22), 157
(100), 156 (25).
Synthesis of β-Sulfanyl Thiazolines 5
Synthesis of (S)-4-Methylsulfanylethyl-2-phenyl-
2-thiazoline 8
General Procedure. Thiophenol (1.2 mmol) and
then NEt3 (0.1 mmol) were added to the α,β-
unsaturated thiazoline 4 (1 mmol), dissolved in dry
THF (20 mL), at room temperature. The result-
Step 1: Thioacylation. Thioamide 7 was pre-
pared from dithiobenzoic acid methyl ester (420 mg,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Chiral Thiazoline Ligands Tethered to a Sulfur Function and First Immobilization of a Thiazoline-Ligand 247
3
2 JHH = 0.8 Hz, JHH = 10.9 Hz, CHCHH), 5.74 (dd,
2.5 mmol) and (S)-methioninol (338 mg, 2.5 mmol)
3
2 JHH = 0.8 Hz, JHH = 17.6 Hz, CHCHH), 6.67 (dd,
according to the procedure described in [8]. Purifi-
cation by column chromatography (EtOAc/pentane:
60/40, Rf = 0.61 in UV) yielded 365 mg (1.43 mmol,
57%) of the title compound as a viscous yellow oil.
[α]2D0 +12 (c 0.9, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ = 2.05–2.23 (m, 2+1H, SCH2CH2 and OH), 2.14
(s, 3H, SCH3), 2.59–2.70 (m, 2H, SCH2CH2), 3.85–
3.94 (m, 2H, CH2OH), 4.93–5.00 (OCH2CH), 7.37–
7.48 (m, 3H, C6H5), 7.75–7.77 (m, 2H, C6H5), 8.04 (br,
1H, NH). 13C NMR (CDCl3, 63 MHz): δ = 15.8 (SCH3),
29.7 (SCH2CH2), 30.7 (SCH2CH2), 56.7 (OCH2CH),
63.2 (CH2OH), 126.9 (C6H5), 128.6 (C6H5), 131.4
(C6H5), 141.9 (Cipso), 199.4 (NCS). IR (cm−1): 3243,
2914, 1516, 1447, 1373, 1231, 1029, 966, 692. TOF
MS ES+ [M + H]+ Calcd for C12H18NOS2: 256.0830;
found: 256.0830. ES-MS m/z (%): 256 (M + H, 27),
238 (11), 208 (100), 121 (5).
3 JHH = 17.6 Hz, 3 JHH = 10.9 Hz, CHCHH), 7.02–7.04
(m, 2H, C6H5), 7.28–7.30 (m, 2H, C6H5), 7.43–7.48
(m, 2H, C6H5), 7.58–7.66 (m, 3H, C6H5). 13C NMR
(CDCl3, 101 MHz) δ = 62.8 (SCH2), 115.0 (CHCH2),
126.5 (C6H5), 127.5 (C6H5), 128.8 (C6H5), 129.0
(C6H5), 131.1 (C6H5), 133.9 (C6H5), 136.2 (CHCH2),
138.0 (C6H5), 138.2 (C6H5). IR (cm−1): 1291, 1145,
1084, 907, 854, 744, 686, 600.
Step 2. Synthesis of 4-Vinyl-dithiobenzoic Acid
Methyl Ester 11. Potassium tert-butoxide (5.72 g,
51.0 mmol) was added to a mixture of sulfone 10
(4.39 g, 17.0 mmol) and sulfur (13.1 g, 51.0 mmol)
in THF (110 mL). The red solution was allowed to
react 14 h before iodomethane (2.12 mL, 34.0 mmol)
was carefully added. After another hour, solvent was
evaporated under vacuum, the residue suspended in
Et2O/pentane (1:1), filtered, and the filtrate concen-
trated. The crude product was purified by column
chromatography (first pentane, then EtOAc/pentane:
2/98, Rf = 0.40, UV or KMnO4) to afford 2.35 g (12.1
mmol, 71%) of the title compound as a red liquid. 1H
NMR (CDCl3, 400 MHz): δ = 2.78 (s, 3H, SCH3), 5.39
(d, 3 JHH = 10.9 Hz, CHCHH), 5.87 (d, 3 JHH = 17.6 Hz,
Step 2: Cyclization. Thioamide 7 (693 mg,
2.7 mmol) was transformed into thiazoline 8 accord-
ing to the procedure described in [8]. Purification by
column chromatography (Et2O/pentane: 10/90, Rf =
0.18 in UV) yielded 560 mg (2.34 mmol, 86%) of the
title compound as a colorless oil. [α]2D0 −97 (c 0.95,
1
CHCl3). H NMR (CDCl3, 400 MHz): δ = 1.93–2.20
3
3
(m, 2H, SCH2CH2), 2.16 (s, 3H, SCH3), 2.70–2.81
CHCHH), 6.74 (dd, JHH = 17.6 Hz, JHH = 10.9 Hz,
CHCHH), 7.41–7.43 (m, 2H, C6H5), 8.00–8.02 (m, 2H,
C6H5). 13C NMR (CDCl3, 101 MHz) δ = 20.7 (SCH3),
116.4 (CHCH2), 126.2 (C6H5), 127.3 (C6H5), 136.1
(CHCH2), 141.6 (C6H5), 144.2 (C6H5), 288.2 (SCS).
IR (cm−1): 2911, 1597, 1402, 1238, 1178, 1050, 884,
841, 773.
(m, 2H, SCH2CH2), 3.10 (dd, 2 JHH = 10.9 Hz, 3 JHH
=
8.1 Hz, 1H, SCHH), 3.53 (dd, 2 JHH = 10.9 Hz, 3 JHH
=
8.4 Hz, 1H, SCHH), 4.74–4.82 (m, 1H, NCH), 7.38–
7.84 (m, 5H, C6H5). 13C NMR (CDCl3, 101 MHz):
δ = 15.8 (SCH3), 31.7 (SCH2CH2), 34.9 (SCH2CH2),
38.2 (SCH2), 76.7 (NCH), 128.5 (C6H5), 128.6 (C6H5),
131.3 (C6H5), 133.5 (Cipso), 167.0 (SCN). IR (cm−1):
2914, 2850, 1597, 1446, 1466, 1245, 936, 764, 689,
610. TOF MS ES+ [M + H]+ Calcd for C12H16NS2:
238.0724; found: 238.0728. ES-MS m/z (%): 238
(M + H, 41), 135 (100), 87 (59).
Synthesis of Monomeric Thiazolines M-12
(S)-4-Methylsulfanylethyl-2-(4-vinyl)phenyl-2-thiazo-
line M-12a. The product was prepared from
dithioester 11 (304 mg, 1.56 mmol) and (S)-
methioninol (211 mg, 1.56 mmol) according to the
procedure described in [8], without isolation of the
thioamide. Purification by column chromatography
(Et2O/pentane: 10/90, Rf = 0.31 in UV or iodine)
yielded 240 mg (0.91 mmol, 58%) of the title com-
pound as a colorless oil. [α]2D0 −90 (c 1.0, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 1.92–2.20 (m, 2H,
SCH2CH2), 2.15 (s, 3H, SCH3), 2.73–2.77 (m, 2H,
Synthesis of Styrene-Dithioester 11
Step 1: Synthesis of 4-benzene Sulfonyl Methyl
Styrene 10. 4-Vinylbenzyl chloride
9 (5.33 g,
31.4 mmol) was added to a mixture of sodium ben-
zenesulfinate (10.31 g, 62.8 mmol) and tetrapropy-
lammonium bromide (0.52 g, 2.3 mmol) in acetoni-
trile. After heating the mixture for 14 h at 80◦C, sol-
vent was evaporated and the residue was quenched
by addition of water (100 mL). The sulfone 11 was
extracted with dichloromethane (3 × 80 mL); the
combined extracts were washed with water (3 ×
100 mL), dried over MgSO4, filtered, and solvent
was evaporated in vacuo to yield 7.71 g (29.8 mmol,
95%) of the title compound as a white solid. 1H NMR
(CDCl3, 400 MHz): δ = 4.30 (s, 2H, SCH2), 5.28 (dd,
2
3
SCH2CH2), 3.09 (dd, JHH = 10.8 Hz, JHH = 8.1 Hz,
1H, SCHH), 3.52 (dd, 2 JHH = 10.8 Hz, 3 JHH = 8.4 Hz,
1H, SCHH), 4.73–4.81 (m, 1H, NCH), 5.33 (d, 3 JHH
=
10.9 Hz, CHCHH), 5.83 (d, 3 JHH = 17.6 Hz, CHCHH),
3
3
6.73 (dd, JHH = 17.6 Hz, JHH = 10.9 Hz, CHCHH),
3
3
7.43 (d, JHH = 7.4 Hz, 2H, C6H5), 7.78 (d, JHH
=
8.4 Hz, 2H, C6H5). 13C NMR (CDCl3, 101 MHz): δ =
15.8 (SCH3), 31.6 (SCH2CH2), 34.9 (SCH2CH2), 38.2
Heteroatom Chemistry DOI 10.1002/hc

248 Abrunhosa-Thomas et al.
(SCH2), 76.7 (NCH), 115.7 (CHCH2), 126.3 (C6H5),
128.8 (C6H5), 132.7 (C6H5), 136.2 (CHCH2), 140.4
(C6H5), 166.6 (SCN).
Typical Procedure for the Pd-Catalyzed Allylic
Substitution
(E)-1,3-Diphenyl-2-propenyl acetate (156 mg,
0.62 mmol), ligand (6 mol%, 0.04 mmol), allylpalla-
dium chloride dimer (6 mg, 2.5 mol%, 0.02 mmol),
and potassium acetate (3 mg, 5 mol%, 0.03 mmol)
were introduced into a Schlenk flask and 2 mL
of dichlorormethane was added. The mixture was
stirred for 20 min before the successive addition of
dimethyl malonate (0.21 mL, 1.86 mmol) and N, O-
bis(trimethylsilyl)acetamide (0.49 mL, 1.86 mmol).
The mixture was stirred at room temperature and
monitored by TLC (SiO2, EtOAc/pentane: 10/90).
After completion, solvents were evaporated, the
residue dissolved in ether and filtered (syringe
filter). After evaporation of ether, the residue was
analyzed by HPLC using a Daicel Chiralpak AD
analytical column (n-heptane/2-propanol: 90/10,
flow rate: 1 mL/min, 251.0 nm). Enantiomeric
excess of (E)-dimethyl-(1,3-diphenylallyl)malonate
was measured by HPLC: (R)-enantiomer, t1 = 12.4
min; (S)-enantiomer, t2 = 17.4 min.
(S)-4-Ethyl-2-(4-vinyl)phenyl-2-thiazoline M-12b.
The product was prepared from dithioester 11
(420 mg, 2.5 mmol) and (R)-2-amino-1-butanol
(148 mg, 1.66 mmol) according to the proce-
dure described in [8], without isolation of the
thioamide. Purification by column chromatography
(Et2O/pentane: 10/90, Rf = 0.28 in UV or iodine)
yielded 213 mg (0.98 mmol, 59%) of the title com-
pound as a colorless oil. 1H NMR (CDCl3, 250 MHz):
3
δ = 1.10 (t, JHH = 7.5 Hz, 3H, CH2CH3), 1.60–2.00
(m, 2H, CH2CH3), 3.01–3.52 (m, 2H, SCH2), 4.45–
4.54 (m, 1H, NCH), 5.33 (d, 3 JHH = 10.9 Hz, CHCHH),
3
3
5.83 (d, JHH = 17.6 Hz, CHCHH), 6.77 (dd, JHH
=
=
3
3
17.6 Hz, JHH = 10.9 Hz, CHCHH), 7.42 (d, JHH
7.4 Hz, 2H, C6H5), 7.79 (d, 3 JHH = 7.4 Hz, 2H, C6H5).
Synthesis of Polymeric Thiazolines P-12
General Procedure. Degassed THF (0.9 M in
monomer concentration) was added to the corre-
sponding thiazoline monomer (1 equiv) and AIBN
(0.12 equiv) in a Schlenk tube under nitrogen. The
mixture was heated for 14 h at 80◦C, before the
polymer was precipitated into pentane (10 times the
volume of the reaction mixture). The polymer was
washed with ether, dried first under slight vacuum,
then under oil pump vacuum.
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1
(br, 2H, PhCHCH2), 1.58 (br, 1H, PhCHCH2), 1.95
(br, 2H, SCH2CH2), 2.14 (br, 3H, SCH3), 2.74 (br,
2H, SCH2CH2), 3.05 (br, 1H, SCHH), 3.49 (br, 1H,
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7.52 (br, 2H, C6H5). 13C NMR (CDCl3, 101 MHz):
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31.6 (SCH2CH2), 34.9 (SCH2CH2), 38.2 (SCH2), 76.7
(NCH), 127.5 (C6H5), 128.4 (C6H5), 132.7 (C6H5),
140.4 (C6H5), 166.6 (SCN). Molecular weight (GPC):
MW = 15,700 g/mol; MW/Mn = 1.73.
Thiazoline P-12b. The product was prepared by
the general procedure from monomer M-12b. Yield:
1
51%. H NMR (CDCl3, 250 MHz): δ = 0.90 (br, 3H,
CH2CH3), 1.25 (br, 2H, PhCHCH2), 1.72–2.05 (br,
CH2CH3), 2.87 (br, 1H, PhCHCH2), 3.06 (br, 1H,
SCHH), 3.44 (br, 1H, SCHH), 4.55 (br, 1H, NCH),
6.51 (br, 2H, C6H5), 7.56 (br, 2H, C6H5). Molecular
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Heteroatom Chemistry DOI 10.1002/hc