Synthesis of new chiral thiazoline-containing ligands

Article abstract of DOI:10.1016/S0957-4166(01)00481-5

New chiral ligands, including bi- and tridentate thiazoline derivatives, analogues of known oxazolines, have been synthesized by a general and convenient procedure, starting from dithioesters and commercial enantiopure 2-aminoalcohols. A preliminary test shows the ability of such ligands to act as asymmetric catalysts in Pd-catalyzed allylic substitution reaction.

Full text of DOI:10.1016/S0957-4166(01)00481-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2851–2859
Synthesis of new chiral thiazoline-containing ligands
Isabelle Abrunhosa, Mihaela Gulea, Jocelyne Levillain and Serge Masson*
Laboratoire de Chimie Mole´culaire et Thioorganique (UMR CNRS 6507), ISMRA-Universite´ de Caen, 6 Bd. Mare´chal Juin,
F-14050 Caen, France
Received 18 October 2001; accepted 26 October 2001
Abstract—New chiral ligands, including bi- and tridentate thiazoline derivatives, analogues of known oxazolines, have been
synthesized by a general and convenient procedure, starting from dithioesters and commercial enantiopure 2-aminoalcohols. A
preliminary test shows the ability of such ligands to act as asymmetric catalysts in Pd-catalyzed allylic substitution reaction.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
have been used for this purpose: Rh(I) complexes in
hydrosilylation2 and Cu(II) complexes in cyclopropana-
tion.3 We recently described a facile access to chiral
phosphonylated thiazolines (used as new Horner–
Wadsworth–Emmons reagents) starting from ethyl
phosphonodithioacetate and enantiopure 2-aminoalco-
hols.4 We have now extended and adapted this proce-
dure, by using dithioesters, easily accessible in a wide
variety of structures, as sulfur sources replacing
aminothiols. This method allowed us to prepare new
ligands, including alkylidene bis(thiazolines), 2-pyridyl
and 2-quinolyl thiazolines and 2,6-pyridyl bis(thiazoli-
nes), analogous of the well known corresponding oxazo-
lines (Scheme 1). A first estimation of the ability of these
new ligands to act in asymmetric Pd-catalyzed reactions
has also been demonstrated by using one of them in
allylic substitution.
Chiral oxazolines and bis-oxazolines are well known
ligands for metals, used as efficient asymmetric catalysts
in various reactions.1 Several of their sulfur analogues
are known, but the variety of structures is very restricted
as far as chiral bis-thiazolines are concerned.2,3 This is
probably because the most usual sulfur-containing pre-
cursors, the 2-aminothiols, are not easily available (com-
pared to the corresponding aminoalcohols). Electronic
and steric effects, resulting from the substitution of the
oxygen by the sulfur, could change the behavior of the
chelating heterocycle towards metals. Thus, the explo-
ration of thiazolines as ligands in asymmetric catalysis
and their comparison with oxazolines represents an
attractive study. Furthermore, to the best of our knowl-
edge, only two examples of thiazoline metal complexes
Scheme 1.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00481-5

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I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
Scheme 2.
Table 1.
Starting dithioester
Aminoalcohol
R
R%,R%
Product
Overall yield of 12 and 13 (%)
1
1
2
2
3a
3b
3a
3b
Et
iPr
Et
Me,Me
Me,Me
(CH2)5
(CH2)5
12a
12b
13a
13b
78
76
75
73
iPr
2. Results and discussion
ates), we were able to prepare respectively functional-
ized thiazolines 16 and 19 and bis-thiazoline 22,
potential bidentate and tridentate ligands (Scheme 3).
Based on starting dithioester, the overall yields are
given in Table 2.
2.1. Synthesis of bidentate bis(thiazolines) 12 and 13
The general synthetic route is summarized in Scheme 2.
The thioamides 4a,b and 5a,b were readily prepared in
nearly quantitative yield by thioacylation of the com-
mercially available aminoalcohols 3a,b with the appro-
priate starting dithioesters 1 or 2. The intramolecular
cyclization via an S-alkylation, using mesyl chloride
and triethylamine in dichloromethane, led to alkyl thia-
zolines 6a,b and 7a,b. The yield of isolated thiazolines
(95–99%) was much improved by this method, in com-
parison to the Mitsunobu procedure, previously used in
phosphonate series4 (due to the formation of Ph3PO,
purification is more difficult). The intermediate thiazo-
line-dithioesters 8a,b and 9a,b were obtained by a-
metallation of thiazolines 6 or 7, using t-BuLi, followed
by the condensation of the carbanion with carbon
disulfide and S-alkylation with methyl iodide (yield=
79–85%).5 From 8 or 9 the same subsequent two-step
process (amination with 3a,b and cyclization of 10 and
11) led to bis(thiazolines) 12 and 13. Based on 1 or 2,
the overall yields of 12a,b and 13a,b are given in Table
1.
2.3. Preliminary test of new ligand 12a in a Pd-cata-
lyzed allylic substitution
Palladium-catalyzed asymmetric allylic substitution,
especially the alkylation of 1,3-diphenyl-2-propenyl ace-
tate with malonate (Scheme 4), is a significant CꢀC
bond-forming reaction in organic synthesis.9 This
model reaction was carried out as a preliminary test on
the possibility of using these type of thiazoline ligand in
an asymmetric catalyst. With the first tested bis(thiazo-
line) 12a, we obtained a very good yield (90%) and high
enantiomeric excess (87%). The comparison of our
HPLC data with that described in the literature10
allowed us to assign the absolute configuration S to the
major enantiomer of the (E)-methyl 2-methoxycar-
bonyl-3,5-diphenylpent-4-enoate. A systematic study on
the efficiency of all the new prepared ligands in this
allylation reaction will be undertaken and published in
due course.
2.2. Synthesis of 2-pyridyl thiazolines 16, 2-quinolyl
thiazolines 19 and 2,6-pyridyl bis-thiazolines 22
3. Conclusion
Starting from the corresponding dithioesters 14, 17 and
20, prepared respectively from 2-picolyl chloride,6,7 2-
chloromethyl quinoline6 and 2,6-di(chloromethyl) pyri-
dine,8 and using the same procedure (involving the
generation of intermediate thioamides 15, 18 and 21
and in situ intramolecular cyclization of their mesyl-
In summary, we have developed a convenient and
general route to various new chiral bi- and tridentate
ligands based on the thiazoline ring, starting from
dithioesters and commercial enantiopure 2-aminoalco-
hols. The high enantiomeric excess (87%) observed in a
Pd-catalyzed allylic substitution using one of the syn-

I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
2853
Scheme 3.
thesized bis(thiazolines), indicates that these ligands are
promising in asymmetric catalysis using this transition
metal. Further studies concerning their complexing
properties towards various metal cations and applica-
tions in other type of metal-catalyzed reactions will be
undertaken in order to determine their specificity com-
pared to that of bis-oxazolines.
4.2. General procedure A for the preparation of
thioamides 4, 5, 10, 11, 15, 18 and 21†
A mixture of dithioester (1, 2, 8, 9, 14 or 17, 15 mmol),
aminoalcohol (the commercial aminoalcohols used in
the reaction were (R)-(−)-2-aminobutanol, (R)-(−)-vali-
nol, (R)-(−)-phenylglycinol and (S)-(+)-tert-leucinol) 3
(15 mmol) and triethylamine (19 mmol) was stirred at
room temperature (for the dithioesters 14, 17 and 20, 1
mL THF/mmol dithioester was used as solvent). The
end of the reaction was controlled by TLC (time: 2 h to
4 days). Then, the mixture was concentrated under
reduced pressure. The crude product was purified by
flash chromatography on silica gel to afford the
thioamide.
4. Experimental
4.1. General
Most of reactions were carried out under a nitrogen
atmosphere with magnetic stirring, unless otherwise
specified and monitored by TLC using silica plates.
Synthesized products were purified by flash column
chromatography on silica gel or recrystallised if neces-
sary. Solvents were dried by distillation prior use. The
NMR spectra were recorded in CDCl3, with a ‘Bruker
AC 250’ or a ‘Bruker AC 400’ spectrometer. The
chemical shifts (l) are expressed in ppm relative to
TMS for H and C nuclei, the coupling constants (J) are
given in Hz; conventional abbreviations are used. Opti-
cal rotation values were measured on a Perkin–Elmer
241 polarimeter for the sodium D line at 20°C. Melting
points are uncorrected. The infrared spectra were
recorded with a Perkin–Elmer 16 PC spectrometer on
the liquid film, w (cm−1) are given. Mass spectra were
recorded with a Nermag R 10 10H spectrometer in
electronic-impact mode at 70 eV, m/z and relative
abundance are given. HRMS were obtained with a
JEOL JMS-AX 500 mass spectrometer. Elemental
microanalyses were performed at Caen with an auto-
matic apparatus CHNS-O ThermoQuest. Microanaly-
ses or HRMS and specific rotation are given only for
the final compounds (thiazolines 12a,b, 13a,b, 16a–c,
19a–d, 22c,d). The abbreviations used for the solvents
are: P=pentane, DEE=diethylether).
Table 2.
Starting
dithioester
Aminoalcohol
R
Product
Overall yield
(%)
14
14
14
17
17
17
17
20
20
3a
3b
3c
3a
3b
3c
3d
3c
3d
Et
16a
16b
16c
19a
19b
19c
19d
22c
22d
91
90
90
90
87
85
82
56
55
iPr
Ph
Et
iPr
Ph
tBu
Ph
tBu
† For the bis-thioamides 21, the corresponding stoichiometry was
used: bis-dithioester 20 (15 mmol) aminoalcohol 3 (30 mmol) and
NEt3 (38 mmol) in 15 mL of THF.

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I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
Scheme 4.
4.2.1.
(R)-N-[1-(Hydroxymethyl)propyl]-2-methylpro-
J2=4.7, 1H, CHHO), 4.60 (m, 1H, CHNH), 7.27 (br s,
1H, NH); 13C NMR: l 19.5 and 19.7 (CH(CH3)2), 26.0,
26.3, 26.4, 29.4 (CH(CH3)2), 33.2, 33.3, 61.5 (CHNH),
63.0 (CH2OH), 211.3 (CꢁS); IR (NaCl): 3205 (wOH),
3060 (wNH), 2920, 2852, 1654, 1564, 1450, 1350, 1056.
panethioamide 4a. Prepared according to the general
procedure A starting from dithioester 1 and aminoalco-
hol 3a (time: 12 h); yellow oil, yield=98%, Rf=0.4
(P/DEE: 30/70); 1H NMR: l 0.98 (t, J=7.5, 3H,
CH3CH2), 1.26 (d, J=6.8, 6H, HC(CH3)2), 1.64–1.78
(m, 2H, CH3CH2), 2.76 (br s, 1H, OH), 2.81 (sept.,
J=6.8, 1H, HC(CH3)2), 3.79 (dd, J1=11.1, J2=3.7,
1H, CHHO), 3.83 (dd, J1=11.1, J2=4.5, 1H, CHHO),
4.63 (m, 1H, CHN), 7.3 (br s, 1H, NH); 13C NMR: l
10.8 (CH2CH3), 22.9 and 23.0 (CH(CH3)2), 23.7
(CH2CH3), 45.0 (CH(CH3)2), 58.0 (CHNH), 63.5
(CH2OH), 212.2 (CꢁS).
4.2.5. (R,R)-4-Ethyl-2-{1-[N-(1-(hydroxymethyl)propyl)-
thiocarbamoyl]-1-methylethyl}-2-thiazoline 10a. Pre-
pared according to the general procedure A starting
from dithioester 8a and aminoalcohol 3a (24 h); yellow
1
oil, yield=98%, Rf=0.55 (P/DEE: 50/50); H NMR: l
0.93 (t, J=7.4, 6H, CH3CH2), 1.04 (t, J=7.4, 6H,
CH3CH2), 1.53–1.85 (m, 4H, 2×CH3CH2), 1.65 and
1.66 (2s, 6H, C(CH3)2), 2.6 (br s, 1H, OH), 3.04 (dd,
J1=11.0, J2=8.6, 1H, CHHS), 3.28 (dd, J1=11.0, J2=
8.4, 1H, CHHS), 3.71 (dd, J1=11.2, J2=3.9, 1H,
CHHO), 3.90 (dd, J1=11.2, J2=4.3, 1H, CHHO), 4.10
(m, 1H, CHN), 9.35 (br s, 1H, NH); 13C NMR: l 10.8
(CH2CH3), 11.0 (CH2CH3), 23.7 (CH2CH3), 28.3
(CH2CH3), 29.8 and 30.3 (C(CH3)2), 37.6 (CH2S), 53.0
(C(CH3)2), 59.0 (CHNH), 63.6 (CH2OH), 79.1 (CHN),
177.8 (SꢀCꢁN), 205.9 (CꢁS).
4.2.2.
(R)-N-[1-(Hydroxymethyl)-2-methylpropyl]-2-
methylpropanethioamide 4b. Prepared according to the
general procedure A starting from dithioester 1 and
aminoalcohol 3b (time: 12 h); yellow oil, yield=98%,
1
Rf=0.42 (P/DEE: 30/70); H NMR: l 0.98 (d, J=6.9,
6H, HC(CH3)2), 1.28 (d, J=6.8, 6H, C(S)HC(CH3)2),
2.06 (m, 1H, HC(CH3)2), 2.49 (br s, 1H, OH), 2.81
(sept., J=6.8, 1H, C(S)HC(CH3)2), 3.78 (dd, J1=11.2,
J2=3.8, 1H, CHHO), 3.85 (dd, J1=11.2, J2=4.8, 1H,
CHHO), 4.58 (m, 1H, CHN), 7.56 (br s, 1H, NH); 13C
NMR: l 19.4 and 19.7 (HC(CH3)2), 22.9 and 23.0
(HC(CH3)2), 29.3 (HC(CH3)2), 45.4 (C(CH3)2), 61.7
(CHN), 62.7 (CH2O), 212.5 (CꢁS); IR (NaCl): 3260
(wOH), 3050 (wNH), 2960, 2870, 1520 (wNꢀCꢁS), 1430, 1070,
1010.
4.2.6. (R,R)-4-Isopropyl-2-{1-N-[(1-hydroxymethyl)-2-
methylpropyl)thiocarbamoyl]-1-methylethyl}-2-thiazoline
10b. Prepared according to the general procedure A
starting from dithioester 8b and aminoalcohol 3b (time:
2 days); yellow oil, yield=98%, Rf=0.6 (P/DEE: 50/
1
50); H NMR: l 0.97 and 1.03 and 1.08 (3d, J=6.8,
12H, 4×CH3), 1.67 and 1.71 (2s, 6H, C(CH3)2), 2.04
(sept., J=6.8, 2H, 2×CH(CH3)2), 2.6 (br s, 1H, OH),
2.98 (dd, J1=11.4, J2=8.9, 1H, CHHS), 3.27 (dd,
J1=11.4, J2=10.1, 1H, CHHS), 3.72 (dd, J1=11.2,
J2=3.6, 1H, CHHO), 3.88 (dd, J1=11.2, J2=5.3, 1H,
CHHO), 4.28 (dt, J1=8.9, J2=6.5, 1H, CHNꢁC), 4.56
(m, 1H, CHNH), 9.75 (br s, 1H, NH); 13C NMR: l
19.3, 19.4, 19.8, 20.0, 29.4, 30.0, 30.8, 33.4, 35.3
(CH2S), 53.17 (C(CH3)2), 63.0 (CHNH), 63.1 (CH2O),
83.9 (CHN), 178.0 (SCꢁN), 206.5 (NHCꢁS); IR (NaCl):
3400 (wOH), 3350 (wNH), 2930, 2870, 1600, 1520 (wNꢀCꢁS),
1460, 1040.
4.2.3. (R)-N-[1-(Hydroxymethyl)propyl]cyclohexanethio-
carboxamide 5a. Prepared according to the general pro-
cedure A starting from dithioester 2 and aminoalcohol
3a (time: 2 days); yellow oil, yield=98%, Rf=0.24
(P/DEE: 50/50); 1H NMR: l 0.91 (t, J=7.5, 3H,
CH3CH2), 1.1–1.8 (m, 12H, CH3CH2 and (CH2)5), 2.35
(m, 1H, OH), 3.72 (dd, J1=11.1, J2=3.7, 1H, CHHO),
3.83 (dd, J1=11.1, J2=4.5, 1H, CHHO), 4.63 (m, 1H,
CHN), 7.45 (br s, 1H, NH); 13C NMR: l 10.8
(CH3CH2), 23.7 (CH3CH2), 25.9, 26.2, 26.3, 33.1, 33.2,
55.5, 57.9 (CHN), 63.5 (CH2O), 210.9 (NCꢁS); IR
(NaCl): 3600, 3450 (wOH), 3320 (wNH), 2980, 2850, 1550
(wNꢀCꢁS), 1440, 1370.
4.2.7. (R,R)-4-Ethyl-2-{1-[N-(1-(hydroxymethyl)propyl)-
thiocarbamoyl]cyclohexyl}-2-thiazoline 11a. Prepared
according to the general procedure A starting from
dithioester 9a and aminoalcohol 3a (time: 4 days);
yellow solid, mp=86°C, yield=98%, Rf=0.69 (P/DEE:
4.2.4. (R)-N-[1-(Hydroxymethyl)-2-methylpropyl]cyclo-
hexanethiocarboxamide 5b. Prepared according to the
general procedure A starting from dithioester 2 and
aminoalcohol 3b (time: 2 days); white solid, mp=90°C,
1
1
yield=98%, Rf=0.36 (P/DEE: 50/50); H NMR: l 0.99
20/80); H NMR: l 0.97 (t, J=7.4, 3H, CH3CH2), 1.05
and 1.01 (2d, J=6.7, 6H, CH(CH3)2), 1.31–2.01 (m,
10H, (CH2)5), 2.54 (m, 1H, CH(CH3)2), 2.74 (br s, 1H,
OH), 2.85 (sept., J=6.8, 1H, CH(CH3)2), 3.75 (dd,
J1=11.2, J2=3.8, 1H, CHHO), 3.87 (dd, J1=11.2,
(t, J=7.4, 3H, CH3CH2), 1.56–2.17 (m, 15H, 2×
CH3CH2 and (CH2)5 and OH), 2.97 (dd, J1=10.9,
J2=7.7, 1H, CHHS), 3.37 (dd, J1=10.9, J2=8.6, 1H,
CHHS), 3.64 (dd, J1=11.2, J2=4.0, 1H, CHHO),

I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
2855
3.87 (dd, J1=11.2, J2=3.5, 1H, CHHO), 4.62 (m, 1H,
CHNH), 4.48 (m, 1H, CHNꢁC), 8.05 (br s, 1H, NH);
13C NMR: l 10.8 (CH3CH2), 11.3 (CH3CH2), 23.3,
23.4, 23.7, 25.4, 28.1, 37.0, 37.2, 37.6 (CH2S), 58.0, 58.4
(CHNH), 63.2 (CH2OH), 78.9 (CHN), 175.6 (NHCꢁS),
205.3 (SCꢁN); IR (KBr): 3340 (wOH), 3260 (wNH), 2960,
2850, 1600 (wSꢀCꢁN), 1502 (wNꢀCꢁS), 1450, 1195, 1018.
1.7, J3=7.7, 1H, CHPy), 8.52 (d, J=4.5, 1H, CHPy),
8.68 (d, J=8, 1H, CHPy), 10.95 (br s, 1H, NH); 13C
NMR: l 60.6 (CHN), 66.1 (CH2O), 125.4, 126.5, 127.4,
128.4, 129.4, 137.7, 138.5, 147.4, 151.5, 191.4 (NCꢁS);
IR (KBr): 3648 (wOH), 3255 (wNH), 2940, 2792, 1624
(wNꢀCꢁS).
4.2.12.
(R)-N-[1-(Hydroxymethyl)propyl]-2-quinoline-
4.2.8. (R,R)-4-Isopropyl-2-{1-[N-(1-(hydroxymethyl)-2-
methylpropyl)thiocarbamoyl]cyclohexyl}-2-thiazoline
11b. Prepared according to the general procedure A
starting from dithioester 9b and aminoalcohol 3b (4
days); yellow solid, yield=98%, Rf=0.92 (P/DEE: 20/
thiocarboxamide 18a. Prepared according to the general
procedure A starting from dithioester 17 and aminoal-
cohol 3a (time: 24 h); yellow oil, yield=95%, Rf=0.54
(P/DEE: 30/70); 1H NMR: l 1.07 (t, J=7.5, 3H,
CH3CH2), 1.9 (q, J=7.5, 2H, CH3CH2), 2.24 (s, 1H,
OH), 3.85 (dd, J1=11.2, J2=4.8, 1H, CHHO), 3.95
(dd, J1=11.2, J2=3.8, 1H, CHHO), 4.81 (m, 1H,
CHN), 7.59 (ddd, J1=8.2, J2=6.9, J3=1.4, 1H, CHQi),
7.76 (ddd, J1=8.4, J2=6.9, J3=1.1, 1H, CHQi), 7.85 (d,
J=8.2, 1H, CHQi), 8.11 (d, J=8.4, 1H, CHQi), 8.26 (d,
J=8.6, 1H, CHQi), 8.83 (d, J=8.65, 1H, CHQi), 10.45
(br s, 1H, NH); 13C NMR: l 14.2 (CH3CH2), 24.2
(CH3CH2), 58.9 (CHN), 64.4 (CH2O), 122.1, 128.2,
122.6, 130.4, 130.8, 137.5, 145.6, 150.6, 174.8 (NCꢁS);
IR (NaCl): 3380 (wOH), 3280 (wNH), 2960, 2900, 1500
(wNꢀCꢁS).
1
80); H NMR: l 0.97 and 1.01 and 1.09 (3d, J=7.8,
12H, 2×CH(CH3)2), 1.02–2.45 (m, 13H, OH, (CH2)5,
2×CH(CH3)2), 3.01 (dd, J1=10.9, J2=9.9, 1H, CHHS),
3.28 (dd, J1=10.9, J2=8.9, 1H, CHHS), 3.69–3.84 (m,
2H, CH2O), 4.26 (m, 1H, CHNꢁC), 4.51 (m, 1H,
CHNH), 8.15 (br s, 1H, NH); 13C NMR: l 19.3, 19.8,
20.2, 23.3, 23.6, 25.4, 29.3, 33.3, 35.4, 36.9, 37.3
(CH2S), 58.3, 62.4 (CHNH), 66.2 (CH2O), 83.9 (CHN),
175.5 (SCꢁN), 205.6 (NHCꢁS); IR (NaCl): 3500 (wOH),
3330 (wNH), 2930, 2870, 1600 (wSꢀCꢁN), 1520 (wNꢀCꢁS),
1460, 1390, 1228, 1070.
4.2.9. (R)-N-[1-(Hydroxymethyl)propyl]-2-pyridinethio-
carboxamide 15a. Prepared according to the general
procedure A starting from dithioester 14 and aminoal-
cohol 3a (time: 2 h); yellow oil, yield=93%, Rf=0.34
(P/DEE: 50/50); 1H NMR: l 0.94 (t, J=7, 3H,
CH3CH2), 1.75 (m, 2H, CH2CH3), 2.58 (br s, 1H, OH),
3.76 (dd, J1=11.2, J2=4.8, 1H, CHHO), 3.86 (dd,
J1=11.2, J2=3.9, 1H, CHHO), 4.35 (m, 1H, CHN),
7.33 (ddd, J1=4.7, J2=7.5, J3=1.1, 1H, CHPy), 7.74
(dt, J1=7.5, J2=1.8, J3=7.5, 1H, CHPy), 8.41 (d, J=4,
1H, CHPy), 8.6 (d, J=8, 1H, CHPy), 10.20 (br s, 1H,
NH); 13C NMR: l 10.78 (CH2CH3), 23.78 (CH2CH3),
58.4 (CHN), 60.6 (CH2O), 125.4, 126.4, 137.6, 147.3,
151.6, 191.4 (NCꢁS); IR (NaCl): 3380 and 3460 (wOH),
3260 (wNH), 2950, 1505 (wNꢀCꢁS), 1455, 1430, 1370, 1330.
4.2.13.
(R)-N-[1-(Hydroxymethyl)-2-methylpropyl]-2-
quinolinethiocarboxamide 18b. Prepared according to
the general procedure A starting from dithioester 17
and aminoalcohol 3b (time: 24 h); orange oil, yield=
1
92%, Rf=0.6 (P/DEE: 30/70); H NMR: l 1.13 and
1.14 (2d, J=6.8, 6H, CH(CH3)2), 2.1 (s, 1H, OH), 2.31
(m, 1H, CH(CH3)2), 3.97 (dd, J1=11.4, J2=5.5, 1H,
CHHO), 4.05 (dd, J1=11.4, J2=3.8, 1H, CHHO), 4.77
(m, 1H, CHN), 7.63 (ddd, J1=8.1, J2=7.6, J3=1.0,
1H, CHQi H9), 7.78 (ddd, J1=8.4, J2=7, J3=1.4, 1H,
CHQi), 7.88 (d, J=8.1, 1H, CHQi), 8.13 (d, J=8.4, 1H,
CHQi), 8.29 (d, J=8.6, 1H, CHQi), 8.85 (d, J=8.6, 1H,
CHQi), 10.62 (br s, 1H, NH); 13C NMR: l 19.4 and 20.0
(CH(CH3)2), 29.7 (CH(CH3)2), 62.6 (CHN), 63.4
(CH2O), 122.1, 128.0, 128.4, 129.6, 130.4, 130.7, 137.4,
145.8, 150.6, 192.1 (NCꢁS); IR (NaCl): 3280 (wOH),
3060 (wNH), 2960, 2870, 1590 (wNꢀCꢁS), 1500, 1380.
4.2.10.
(R)-N-[1-(Hydroxymethyl)-2-methylpropyl]-2-
pyridinethiocarboxamide 15b. Prepared according to the
general procedure A starting from dithioester 14 and
aminoalcohol 3b (time: 2 h). yellow oil, yield=92%,
4.2.14.
(R)-N-(2-Hydroxy-1-phenylethyl)-2-quinoline-
thiocarboxamide 18c. Prepared according to the general
procedure A starting from dithioester 17 and aminoal-
cohol 3c (time: 24 h); orange oil, yield=90%, Rf=0.50
1
Rf=0.61 (P/DEE: 40/60); H NMR: l 1.04 and 1.07
(2d, J=6.7, 6H, CH(CH3)2), 2.20 (m, 1H, CH(CH3)2),
2.55 (s, 1H, OH), 3.91–4.15 (m, 2H, CH2O), 4.70 (m,
1H, CHN), 7.41 (m, 1H, CHPy), 7.82 (m, 1H, CHPy),
8.49 (m, 1H, CHPy), 8.68 (dd, J1=8.0, J2=1.0, 1H,
CHPy), 10.25 (br s, 1H, NH); 13C NMR: l 19.3 and
19.8 (CH(CH3)2), 29.5 (CH(CH3)2), 62.4 (CHN), 63.0
(CH2O), 125.5, 126.3, 137.5, 147.3, 151.4, 191.6
(NCꢁS); IR (NaCl): 3280 (wOH), 3050 (wNH), 2960, 2880,
1580 (wNꢀCꢁS), 1460, 1340.
1
(P/DEE: 50/50); H NMR: l 2.1 (s, 1H, OH), 4.20 (d,
J=4.5, 2H, CH2O), 5.96 (dt, J1=7.0, J2=4.5, 1H,
CHN), 7.61 (ddd, J1=8.1, J2=6.9, J3=1.1, 1H, CHQi),
7.28–7.47 (m, 5H, C6H5), 7.76 (ddd, J1=8.4, J2=6,
J3=1.5, 1H, CHQi), 7.86 (d, J=8.1, 1H, CHQi), 8.15 (d,
J=8.4, 1H, CHQi), 8.25 (d, J=8.6, 1H, CHQi), 8.81 (d,
J=8.65, 1H, CHQi), 11.02 (d, J=7.0, 1H, NH); 13C
NMR: l 60.82 (CHN), 66.0 (CH2O), 121.9, 127.0,
127.4, 128.0, 128.4, 128.4, 129.3, 129.6, 130.4, 137.3,
138.1, 145.8, 150.5, 191.4 (NCꢁS); IR (KBr): 3400
(wOH), 3280 (wNH), 2960, 2900, 1590 (wNꢀCꢁS), 1490, 1370.
4.2.11. (R)-N-[2-Hydroxy-1-phenylethyl]-2-pyridinethio-
carboxamide 15c. Prepared according to the general
procedure A starting from dithioester 14 and aminoal-
cohol 3c (time: 4 h); yellow solid, mp=132°C, yield=
95%, Rf=0.46 (P/DEE: 30/70); 1H NMR: l 2.05 (s, 1H,
OH), 4.15 (m, 2H, CH2O), 5.92 (m, 1H, CHN), 7.27–
7.46 (m, 6H, CHPy and C6H5), 7.83 (dt, J1=7.7, J2=
4.2.15. (S)-N-[1-(Hydroxymethyl)-2,2-dimethylpropyl]-2-
quinolinethiocarboxamide 18d. Prepared according to
the general procedure A starting from dithioester 17
and aminoalcohol 3d (time: 24 h); orange oil, yield=

2856
I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
1
87%, Rf=0.6 (P/DEE: 50/50). H NMR: 1.17 (s, 9H,
C(CH3)3), 2.2 (s, 1H, OH), 3.92–4.18 (m, 2H, CH2O),
4.88 (m, 1H, CHN), 7.65 (t, J=8.1, 1H, CHQi), 7.80 (t,
J=8.4, 1H, CHQi), 7.91 (d, J=8.1, 1H, CHQi), 8.13 (d,
J=8.4, 1H, CHQi), 8.32 (d, J=8.6, 1H, CHQi), 8.87 (d,
J=8.6, 1H, CHQi), 10.60 (br s, 1H, NH); 13C NMR: l
27.5 (C(CH3)3), 34.9 (C(CH3)3), 63.9 (CHN), 65.4
(CH2O), 122.2, 128.1, 128.5, 129.7, 130.4, 130.7, 137.5,
145.8, 150.6, 192.6 (NCꢁS).
4.3.2. (R)-2,4-Diisopropyl-2-thiazoline 6b. Prepared
according to the general procedure B starting from
thioamide 4b; yellow oil, yield=98%, Rf=0.95 (P/DEE,
70/30); 1H NMR: l 0.93 and 1.01 (2d, J=6.8, 6H,
CH(CH3)2), 1.19 and 1.21 (2d, J=3.2, 6H,
C(N)CH(CH3)2), 2.01 (sept., J=6.8, 1H, CH(CH3)2),
2.97 (dd, J1=10.9, J2=8.9, 1H, CHHS), 3.22 (dd,
J1=10.9, J2=8.6, 1H, CHHS), 4.26 (m, 1H, CHN); 13C
NMR: l 18.4 and 19.4 (CH(CH3)2), 21.1 and 21.3
(C(N)CH(CH3)2),
32.8
(CH(CH3)2),
34.0
4.2.16. (R)-2,6-Pyridine bis[N-(2-hydroxy-1-phenyl-
ethyl)thiocarboxamide] 21c. Prepared according to the
general procedure A starting from dithioester 20 and
aminoalcohol 3c (time: 48 h); yellow oil, yield=70%,
Rf=0.32 (P/DEE: 30/70); 1H NMR: l 2.48 (s, 2H,
2×OH), 4.08–4.21 (m, 4H, 2×CH2O), 5.74 (m, 2H,
2×CHN), 7.29–7.43 (m, 5H, C6H5), 7.98 (t, J=7.8, 1H,
CHPy), 8.76 (d, J=7.8, 2H, H3 and 2×CHPy), 10.65 (d,
J=9.5, 2H, 2×NH); 13C NMR: l 60.14 (CHN), 66.14
(CH2O), 127.29, 127.72, 128.4, 129.35, 137.92, 139.1,
149.53, 190.50 (NCꢁS).
(C(N)CH(CH3)2), 34.3 (CH2S), 83.0 (CHN), 175.3
(SꢀCꢁN); IR (NaCl): 2960, 2870, 1630 (wSꢀCꢁN), 1460,
1380, 1360.
4.3.3. (R)-2-Cyclohexyl-4-ethyl-2-thiazoline 7a. Pre-
pared according to the general procedure B starting
from thioamide 5a; yellow oil, yield=98%, Rf=0.78
(P/DEE: 50/50); 1H NMR: l 0.92 (t, J=7.5, 3H,
CH3CH2), 1.08–1.97 (m, 12H, CH3CH2 and (CH2)5),
2.40 (m, 1H, CH), 2.81 (dd, J1=10.7, J2=7.8, 1H,
CHHS), 3.21 (dd, J1=10.7, J2=7.7, 1H, CHHS), 4.28
(m, 1H, CHN); 13C NMR: l 12.0 (CH3CH2), 26.2, 28.4,
32.0, 31.9, 37.2 (CH2S), 43.8, 78.6 (CHN), 174.9
(SꢀCꢁN); IR (NaCl): 2920, 2840, 1620 (wSꢀCꢁN), 1450,
1370, 1175.
4.2.17. (S)-2,6-Pyridine bis[N-(1-(hydroxymethyl)-2,2-
dimethylpropyl)thiocarboxamide] 21d. Prepared accord-
ing to the general procedure A starting from dithioester
20 and aminoalcohol 3d (time: 24 h); yellow oil, yield=
65%, Rf=0.6 (P/DEE: 50/50); 1H NMR: l 1.12 (s, 18H,
2×C(CH3)3), 1.95 (s, 2H, 2×OH), 3.89 (dd, J1=11.3,
J2=5.5, 1H, CHHO), 4.03 (dd, J1=11.3, J2=3.4, 1H,
CHHO), 5.74 (ddd, J1=9.9, J2=5.5, J3=3.4, 2H, 2×
CHN), 8.01 (t, J=7.8, 1H, CHPy), 8.87 (d, J=7.8, 2H,
2×CHPy), 10.09 (d, J=9.9, 2H, 2×NH); 13C NMR: l
27.7 (2×C(CH3)3), 35.4 (2×C(CH3)3), 62.9 (CHN), 64.5
(CH2O), 128.6, 138.8, 149.8, 191.8 (NCꢁS).
4.3.4. (R)-2-Cyclohexyl-4-isopropyl-2-thiazoline 7b. Pre-
pared according to the general procedure B starting
from thioamide 5b; yellow oil, yield=98%, Rf=0.83
1
(P/DEE: 50/50); H NMR: l 0.92 and 1.01 (2d, J=6.8,
6H, HC(CH3)2), 1.08–2.08 (m, 11H, HC(CH3)2 and
(CH2)5), 2.41 (m, 1H), 2.94 (dd, J1=10.9, J2=8.6, 1H,
CHHS), 3.21 (dd, J1=10.9, J2=9.0, 1H, CHHS), 4.28
(m, 1H, CHN); 13C NMR: l 18.8 and 19.8 (HC(CH3)2),
26.2, 31.9, 32.1, 33.3 (HC(CH3)2), 34.5 (CH2S), 43.9,
83.3 (CHN), 174.7 (SꢀCꢁN); IR (NaCl): 2930, 2860,
1630 (wSꢀCꢁN), 1450, 1340, 1160.
4.3. General procedure B for the preparation of thiazo-
lines 6, 7, 12, 13, 16, 19 and 22‡
To a stirred mixture of thioamide (4, 5, 10, 11, 15 or 18,
10 mmol) and mesylchloride (14 mmol) in THF (50
mL) were added dropwise NEt3 (28 mmol) at room
temperature. Stirring was maintained for 10 min then
water (20 mL) was added and the mixture extracted
with dichloromethane (2×20 mL). The organic phase
was dried (MgSO4), solvents were evaporated and the
residual oil was purified by flash chromatography on
silica gel (P/DEE) to provide the thiazoline.
4.3.5. (R,R)-2,2%-(1-Methylethylidene)bis[4,5-dihydro-4-
ethylthiazoline] 12a. Prepared according to the general
procedure B starting from thioamide 10a; yellow oil,
[h]2D0 +161 (c 1.3, acetone), yield=98%, Rf=0.53 (P/
DEE: 70/30); 1H NMR: l 1.00 (t, J=7.4, 6H, 2×
CH3CH2), 1.54 (s, 6H, C(CH3)2), 1.57–1.82 (m, 4H,
2×CH3CH2), 2.95 (dd, J1=10.8, J2=7.1, 2H, 2×
CHHS), 3.40 (dd, J1=10.8, J2=8.6, 2H, 2×CHHS),
4.34–4.50 (m, 2H, 2×CHN); 13C NMR:
l 11.0
(CH2CH3), 27.0 and 27.8 (C(CH3)2), 28.4 (CH3CH2),
37.9 (CH2S), 47.6 (C(CH3)2), 78.7 (CHN), 173.8
4.3.1. (R)-4-Ethyl-2-isopropyl-2-thiazoline 6a. Prepared
according to the general procedure B starting from
thioamide 4a; yellow oil, yield=92%, Rf=0.69 (P/DEE:
(SꢀCꢁN); IR (NaCl): 2966, 2930, 2872, 1614 (wCꢁN),
+
’
1458, 1378 (wCH), 1162, 1040; MS m/z: 270 (M /100),
1
70/30); H NMR: l 0.99 (t, J=7.5, 3H, CH3CH2), 1.2
255 (24), 242 (62), 241 (35), 214 (38), 183 (49), 153 (16),
105 (31), 77 (24), 68 (28), 55 (43), 44 (29). Anal. calcd
for C13H22N2S2: C, 57.73; H, 8.20; N, 10.36; S, 23.71.
Found: C, 57.41; H, 8.23; N, 10.31; S, 23.55.
and 1.21 (2d, J=6.9, 6H, HC(CH3)2), 1.55–1.92 (m,
2H, CH3CH2), 2.80 (sept., J=6.9, 1H, HC(CH3)2), 2.90
(dd, J1=10.8, J2=7.8, 1H, CHHS), 3.30 (dd, J1=10.8,
J2=8.5, 1H, CHHS), 4.36 (m, 1H, CHN); 13C NMR: l
11.0 (CH2CH3), 21.5 and 21.6 (CH(CH3)2), 28.3
(CH2CH3), 34.3 (CH(CH3)2), 37.4 (CH2S), 78.7 (CHN),
175.9 (SꢀCꢁN).
4.3.6. (R,R)-2,2%-(1-Methylethylidene)bis[4,5-dihydro-4-
isopropylthiazoline] 12b. Prepared according to the gen-
eral procedure B starting from thioamide 10b; yellow
oil, [h]2D0 +130 (c 1, acetone), yield=98%, Rf=0.87
1
‡ For the bis-thiazoline 22, the corresponding stoichiometry was used:
bis-thioamide 20 (10 mmol), mesylchloride (28 mmol) and NEt3 (56
mmol).
(P/DEE: 70/30); H NMR: l 0.89 and 0.97 (2d, J=6.7,
12H, 2×CH(CH3)2), 1.56 (s, 6H, C(CH3)2), 2.00–2.10
(m, 2H, 2×CH(CH3)2), 3.04 (dd, J1=10.9, J2=8.5, 2H,

I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
2857
2×CHHS), 3.26 (dd, J1=10.9, J2=9.0, 2H, 2×CHHS),
4.23–4.40 (m, 2H, 2×CHN); 13C NMR: l 18.9 and 19.9
(CH(CH3)2), 27.1 (C(CH3)2), 33.1 (HC(CH3)2), 35.5
(CH2S), 47.9 (C(CH3)2), 83.5 (CHN), 173.6 (SCꢁN); IR
(NaCl): 2960, 2870, 1620 (wSꢀCꢁN), 1460, 1380, 1270;
HRMS calcd for C15H26N2S2: 298.1537. Found:
298.1516.
(HC(CH3)2), 33.8 (HC(CH3)2), 34.7 (CH2S), 85.0
(CHN), 122.0, 125.6, 136.8, 149.6, 151.8, 169.0 (SCꢁN);
IR (NaCl): 2960, 2870, 1610 (wSꢀCꢁN), 1470, 1380, 1270;
HRMS calcd for C11H14N2S: 206.0878. Found:
206.0855
4.3.11. 2-[(R)-4,5-Dihydro-4-phenyl-2-thiazolyl]pyridine
16c. Prepared according to the general procedure B
starting from thioamide 15c; yellow solid, mp=79°C,
[h]2D0 −89 (c 1, acetone), yield=95%, Rf=0.38 (P/DEE:
4.3.7. (R,R)-2,2%-Cyclohexylidenebis[4-ethyl-4,5-dihydro-
thiazoline] 13a. Prepared according to the general pro-
cedure B starting from dithioester 11a; yellow oil, [h]D20
+90 (c 1, acetone), yield=98%, Rf=0.75 (P/DEE: 70/
30); 1H NMR: l 0.93 (t, J=7.4, 6H, 2×CH3CH2),
1.32–2.04 (m, 14H, 2×CH3CH2 and (CH2)5), 2.86 and
3.22 (dd, J1=11.0, J2=8.6, 2H, 2×CHHS), 3.35 (dd,
J1=11.0, J2=6.7, 2H, 2×CHHS), 4.29–4.48 (m, 2H,
2×CHN); 13C NMR: l 11.0 (CH3CH2), 23.1, 25.8, 27.8,
35.7, 37.3 (CH2S), 51.8, 78.8 (CHN), 173.1 (SꢀCꢁN);
IR (NaCl): 2920, 2840, 1600 (wSꢀCꢁN), 1440, 1370, 1340,
1310; HRMS calcd for C16H26N2S2: 310.1537. Found:
310.1474.
1
70/30); H NMR: l 3.31 (dd, J1=11.1, J2=9.5, 1H,
CHHS), 3.80 (dd, J1=11.1, J2=9.1, 1H, CHHS), 5.79
(m, 1H, CHN), 7.21–7.45 (m, 6H, CHPy and C6H5),
7.80 (dt, J1=J2=7.7, J3=1.5, 1H, CHPy), 8.11 (d,
J=7.9, 1H, CHPy), 8.59 (d, J=4.6, 1H, CHPy); 13C
NMR: l 40.4 (CH2S), 81.7 (CHN), 122.2, 125.9, 127.1,
128.1, 129.2, 136.9, 142.7, 149.7, 151.5, 169.0 (SCꢁN);
IR (NaCl): 3050, 2940, 1610 (wSꢀCꢁN), 1490, 1340, 1290;
HRMS calcd for C14H12N2S: 240.0721. Found:
240.0746.
4.3.12. 2-[(R)-4,5-Dihydro-4-ethyl-2-thiazolyl]quinoline
19a. Prepared according to the general procedure B
starting from thioamide 18a; yellow solid, mp=76°C,
[h]2D0 +113 (c 1, acetone), yield=95%, Rf=0.65 (P/DEE:
30/70); 1H NMR: l 1.12 (t, J=7.5, 3H, CH3CH2),
1.73–2.03 (m, 2H, CH3CH2), 3.13 (dd, J1=11.1, J2=
9.1, 1H, CHHS), 3.42 (dd, J1=11.1, J2=9.5, 1H,
CHHS), 4.72 (m, 1H, CHN), 7.57 (ddd, J1=8.0, J2=
6.9, J3=1.2, 1H, HQi), 7.73 (ddd, J1=8.4, J2=6.9,
J3=1.5, 1H, HQi), 8.82 (d, J=8.0, 1H, HQi), 8.16–8.19
(m, 3H, HQi); 13C NMR: l 11.44 (CH3CH2), 28.7
(CH3CH2), 36.9 (CH2S), 80.5 (CHN), 119.3, 127.9,
128.0, 129.2, 130.2, 130.5, 136.8, 148.0, 152.0, 169.9
(NCꢁS); IR (KBr): 3060, 2860, 1590 (wSꢀCꢁN), 1560,
1500, 1430, 1374, 1280, 1090; HRMS calcd for
C14H14N2S: 242.0878. Found: 242.0858.
4.3.8.
(R,R)-2,2%-Cyclohexylidenebis[2-(4,5-dihydro-4-
isopropylthiazoline)] 13b. Prepared according to the gen-
eral procedure B starting from thioamide 11b; yellow
oil, [h]2D0 +31 (c 1, acetone), yield=98%, Rf=0.92 (P/
1
DEE: 70/30); H NMR: l 0.96 and 1.03 (2d, J=6.8,
12H, 2×CH(CH3)2), 1.41–1.61 and 2.00–2.12 (2m, 12H,
2×CH(CH3)2 and (CH2)5), 3.01 (dd, J1=10.8, J2=8.4,
2H, 2×CHHS), 3.23 (dd, J1=10.8, J2=9.0, 2H, 2×
CHHS), 4.31–4.48 (m, 2H, 2×CHN); 13C NMR: l 19.0
and 19.9 (CH(CH3)2), 23.1, 25.8, 33.1, 34.8 (CH2S),
35.7, 51.9, 83.6 (CHN), 172.7 (SꢀCꢁN); IR (NaCl):
2940, 2870, 1610 (wSꢀCꢁN), 1460, 1370, 1270; HRMS
calcd for C18H30N2S2: 338.1850. Found: 338.1859.
4.3.9.
2-[(R)-4,5-Dihydro-4-ethyl-2-thiazolyl]pyridine
16a. Prepared according to the general procedure B
starting from thioamide 15a; yellow oil, [h]2D0 +84 (c 1,
acetone), yield=98%, Rf=0.58 (P/DEE: 70/30); 1H
NMR: l 1.11 (t, J=7.5, 3H, CH3CH2), 1.70–2.00 (m,
2H, CH3CH2), 3.01 (dd, J1=11.0, J2=8.7, 1H, CHHS),
3.48 (dd, J1=11.0, J2=8.3, 1H, CHHS), 4.65 (m, 1H,
CHN), 7.35 (ddd, J1=7.5, J2=4.9, J3=1.2, 1H, CHPy),
7.72 (dt, J1=J2=7.5, J3=1.7, 1H, CHPy), 8.08 (d,
J=7.9, 1H, CHPy), 8.65 (d, J=4, 1H, CHPy); 13C
NMR: l 11.3 (CH3CH2), 28.6 (CH3CH2), 36.9 (CH2S),
80.1 (CHN), 122.1, 125.7, 136.8, 149.6, 151.8, 168.8
(SCꢁN); IR (NaCl): 2960, 2870, 1600 (wSꢀCꢁN), 1460,
1370, 1270; HRMS calcd for C10H12N2S: 192.0721.
Found: 192.0752.
4.3.13.
2-[(R)-4,5-Dihydro-4-isopropyl-2-thiazolyl]-
quinoline 19b. Prepared according to the general proce-
dure B starting from thioamide 18b; yellow solid, mp=
88°C, [h]2D0 +115 (c 1, acetone), yield=95%, Rf=0.80
1
(P/DEE: 30/70); H NMR: l 1.08 and 1.18 (2d, J=6.8,
6H, HC(CH3)2), 2.18 (m, 1H, HC(CH3)2), 3.17 (dd,
J1=10.9, J2=9.6, 1H, CHHS), 3.44 (dd, J1=10.9, J2=
9.0, 1H, CHHS), 4.60 (m, 1H, CHN), 7.60 (ddd, 1H,
J1=8.0, J2=6.9, J3=1.1, 1H, HQi), 7.76 (ddd, J1=8.4,
J2=6.9, J3=1.4, 1H, HQi), 8.85 (dd, J1=8.0, J2=1.2,
1H, HQi), 8.19–8.24 (m, 3H, HQi); 13C NMR: l 19.4 and
20.2 (HC(CH3)2), 33.9 (HC(CH3)2), 34.7 (CH2S), 85.2
(CHN), 119.4, 127.9, 128.0, 129.2, 130.1, 130.5, 136.7,
148, 151.8, 177.9 (NCꢁS); IR (KBr): 3050, 2860, 1590
(wSꢀCꢁN), 1500, 1460, 1340, 1305, 1090; HRMS calcd for
C15H16N2S: 256.1034. Found: 256.1056.
4.3.10.
2-[(R)-4,5-Dihydro-4-isopropyl-2-thiazolyl]-
pyridine 16b. Prepared according to the general proce-
dure B starting from thioamide 15b; orange oil, [h]D20
−54 (c 1, acetone), yield=98%, Rf=0.81 (P/DEE: 70/
30); 1H NMR: l 1.05 and 1.13 (2d, J=6.8, 6H,
HC(CH3)2), 2.13 (sept., J=6.8, 1H, HC(CH3)2), 3.12
(dd, J1=11.0, J2=9.6, 1H, CHHS), 3.39 (dd, J1=11.0,
J2=9.0, 1H, CHHS), 4.53 (m, 1H, CHN), 7.36 (ddd,
J1=7.5, J2=4.8, J3=1.1, 1H, CHPy), 7.76 (dt, J1=J2=
7.5, J3=1.8, 1H, CHPy), 8.11 (d, J=7.4, 1H, CHPy),
8.59 (d, J=4.8, 1H, CHPy); 13C NMR: l 19.3 and 20.1
4.3.14. 2-[(R)-4,5-Dihydro-4-phenyl-2-thiazolyl]quinoline
19c. Prepared according to the general procedure B
starting from thioamide 18c; white solid, mp=132°C,
[h]2D0 +30 (c 1, acetone), yield=95%, Rf=0.45 (P/DEE:
1
70/30); H NMR: l 3.35 (dd, J1=11.2, J2=9.6, 1H,
CHHS), 3.89 (dd, J1=11.2, J2=9.1, 1H, CHHS), 5.85
(m, 1H, CHN), 7.15–7.40 (m, 5H, C6H5), 7.6 (ddd,
J1=8.0, J2=6.95, J3=1.1, 1H, HQi), 7.76 (ddd, J1=8.2,

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I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
J2=6.95, J3=1.5, 1H, HQi), 8.82 (d, J=8.0, 1H, HQi),
8.22–8.31 (m, 3H, HQi); 13C NMR: l 40.1 (CH2S), 81.7
(CHN), 119.3, 127.0, 128.0, 129.2, 128.1, 128.2, 129.2,
130.3; 130.5, 136.9, 142.4, 148.0, 151.5, 172.1 (NCꢁS);
IR (KBr): 3020, 2900, 1590 (wSꢀCꢁN), 1490, 1450, 1310.
Anal. calcd for C18H14N2S: C, 74.45; H, 4.86; N, 9.65;
S, 11.04. Found: C, 74.13; H, 4.82; N, 9.73; S, 10.68.
stirred at this temperature for 2 h and then methyl
iodide (30 mmol, 3 equiv.) was added at −10°C. The
resulting dark red solution was allowed to react
overnight at room temperature and then poured into
water. The mixture was extracted twice with 100 mL of
diethyl ether. Organic layers were dried over MgSO4,
filtered and solvents were removed under reduced pres-
sure. The crude oil was purified over silica gel (P/DEE).
4.3.15.
2-[(S)-4,5-Dihydro-4-tert-butyl-2-thiazolyl]-
quinoline 19d. Prepared according to the general proce-
dure B starting from thioamide 18d; white solid, mp=
118°C, [h]2D0 −90 (c 1, acetone), yield=90%, Rf=0.87
(P/DEE: 70/30); 1H NMR: l 1.09 (s, 9H, C(CH3)3),
3.22 (t, J1=J2=10.9, 1H, CHHS), 3.35 (dd, J1=10.9,
J2=9.2, 1H, CHHS), 4.51 (dd, J1=10.9, J2=9.2, 1H,
CHN), 7.58 (ddd, J1=8.1, J2=7.4, J3=0.9, 1H, HQi),
7.73 (ddd, J1=8.4, J2=6.9, J3=1.4, 1H, HQi), 8.83 (dd,
J1=8.1, J2=1.4, 1H, HQi), 8.17–8.24 (m, 3H, HQi); 13C
NMR: l 27.3 (C(CH3)3), 33.3 (CH2S), 34.7 (C(CH3)3),
88.9 (CHN), 119.4, 127.9, 128.0, 129.2, 130.1, 130.5,
136.7, 148, 151.9, 169.4 (NCꢁS); IR (KBr): 2950, 2860,
1600 (wSꢀCꢁN), 1500, 1460. Anal. calcd for C16H18N2S:
C, 71.07; H, 6.71; N, 10.36; S, 11.86. Found: C, 71.15;
H, 6.86; N, 10.19; S, 11.72.
4.4.1. (R)-Methyl-2-methyl-2-(4-ethyl-4,5-dihydro-2-thia-
zolyl)propanedithioate 8a. Prepared according to the
general procedure C starting from the thiazoline 6a;
orange oil, yield=85%, Rf=0.44 (P/DEE: 95/5); 1H
NMR: l 1.02 (t, J=7.5, 3H, CH2CH3), 1.63–1.84 (m,
2H, CH2CH3), 1.74 (s, 6H, C(CH3)2), 2.61 (s, 3H,
SCH3), 2.99 (dd, J1=10.8, J2=8.8, 1H, CHHS), 3.35
(dd, J1=10.8, J2=8.7, 1H, CHHS), 4.48 (m, 1H,
CHN); 13C NMR: l 11.1 (CH2CH3), 21.0 (CH3S), 27.7
(CH2CH3), 30.1 and 30.2 (C(CH3)2), 38.2 (CH2S), 60.4
(C(CH3)2), 78.6 (CHN), 173.5 (SꢀCꢁN), 242.8 (CꢁS).
4.4.2. (R)-Methyl-2-methyl-2-(4,5-dihydro-4-isopropyl-2-
thiazolyl)propanedithioate 8b. Prepared according to the
general procedure C starting from the thiazoline 6b;
orange oil, yield=83%, Rf=0.5 (P/DEE: 95/5); 1H
NMR: l 0.97 and 1.03 (2d, J=6.8, 6H, CH(CH3)2),
1.74 (s, 6H, C(CH3)2), 2.09 (m, 1H, CH(CH3)2), 2.61 (s,
3H, CH3S), 3.02 (dd, J1=10.8, J2=8.8, 1H, CHHS),
3.27 (dd, J1=10.8, J2=8.7, 1H, CHHS), 4.32 (m, 1H,
CHN); 13C NMR: l 19.0 and 20.0 (CH(CH3)2), 20.9
(CH3S), 30.0 and 30.2 (C(CH3)2), 33.0 (CH(CH3)2), 35.7
(CH2S), 60.6 (C(CH3)2), 83.4 (CHN), 173.1 (SꢀCꢁN),
243.1 (CꢁS); IR (NaCl): 2960, 2870, 1620 (wSꢀCꢁN), 1460,
1090 (wCꢁS).
4.3.16.
(R,R)-2,6-Bis[4-diphenyl-4,5-dihydro-2-thiazo-
line]pyridine 22c. Prepared according to the general
procedure B starting from thioamide 21c; white solid,
mp=212°C, [h]2D0 +49 (c 1, acetone), yield=69%, Rf=
1
0.78 (P/DEE: 70/30); H NMR: l 3.48 (dd, J1=11.1,
J2=9.6, 2H, 2×CHHS), 3.54 (dd, J1=11.1, J2=9.1, 2H,
2×CHHS), 5.81–5.92 (m, 2H, 2×CHN), 7.32–7.5 (m,
10H, 2×C6H5), 7.87 (t, J=7.8, 1H, HPy), 8.27 (d, J=
7.8, 2H, HPy); 13C NMR: l 40.2 (CH2S), 81.9 (CHN),
123.7, 127.0, 128.2, 129.18, 142.1, 151.0, 177.2 (NCꢁS);
IR (KBr): 2930, 2906, 1600 (wSꢀCꢁN), 1450, 1260, 1114,
1018; HRMS calcd for C23H29N3S2: 401.102. Found:
401.1001.
4.4.3.
(R)-Methyl-1-(4-ethyl-4,5-dihydro-2-thiazolyl)-
cyclohexanedithiocarboxylate 9a. Prepared according to
the general procedure C starting from the thiazoline 7a;
4.3.17. (S,S)-2,6-Bis[4-(1,1-dimethylethyl)-4,5-dihydro-2-
thiazoline]pyridine 22d. Prepared according to the gen-
eral procedure B starting from thioamide 21d; white
solid, mp=198°C, [h]D20 −123 (c 1, acetone), yield=
70%, Rf=0.60 (P/DEE: 75/25); 1H NMR: l 1.08 (s,
18H, C(CH3)3), 3.21 (t, J1=J2=10.9, 2H, 2×CHHS),
3.32 (dd, J1=10.9, J2=9.3, 2H, 2×CHHS), 4.45 (dd,
J1=10.9, J2=9.3, 2H, 2×CHN), 7.83 (t, J=7.8, 1H,
HPy), 8.18 (d, J=7.8, 2H, HPy); 13C NMR: l 27.1
(C(CH3)3), 33.0 (CH2S), 36.0 (C(CH3)3), 88.1 (CHN),
123.8, 137.5, 150.6, 177.9 (NCꢁS); IR (KBr): 2950,
2860, 1612 (wSꢀCꢁN), 1460, 1360; HRMS calcd for
C21H37N3S2: 361.1646. Found: 361.1680.
1
orange oil, yield=82%, Rf=0.48 (P/DEE: 90/10); H
NMR: l 1.03 (t, J=7.4, 3H, CH2CH3), 1.52–2.49 (m,
12H, CH2CH3 and (CH2)5), 2.59 (s, 3H, SCH3), 2.95
(dd, J1=10.8, J2=6.8, 1H, CHHS), 3.32 (dd, J1=10.8,
J2=8.5, 1H, CHHS), 4.52 (m, 1H, CHN); 13C NMR: l
11.21 (CH2CH3), 20.86 (CH3S), 23.46, 23.50, 25.66,
27.69 (CH2CH3), 37.54, 38.28 (SCH2), 64.59, 78.92
(CHN), 171.85 (SCꢁN), 243.5 (CꢁS); IR (NaCl): 2840,
2910, 1600 (wSꢀCꢁN), 1440, 1230, 1200, 1115 (wCꢁS).
4.4.4. (R)-Methyl-1-(4,5-dihydro-4-isopropyl-2-thiazolyl)-
cyclohexanedithiocarboxylate 9b. Prepared according to
the general procedure C starting from the thiazoline 7b;
1
4.4. General procedure C for the preparation of
dithioesters thiazolines 8 and 9
orange oil, yield=79%, Rf=0.46 (P/DEE: 90/10); H
NMR: l 0.98 and 1.05 (2d, J=6.8, 6H, CH(CH3)2),
1.25–2.50 (m, 11H, (CH2)5 and CH(CH3)2), 2.59 (s, 3H,
CH3S), 3.01 (dd, J1=10.8, J2=8.8, 1H, CHHS), 3.22
(dd, J1=10.8, J2=8.9, 1H, CHHS), 4.32 (m, 1H,
CHN); 13C NMR: l 19.2 and 20.1 (CH(CH3)2), 20.8
(CH3S), 23.5, 25.7, 33.0 (CH(CH3)2), 35.1 (CH2S), 38.3,
38.5, 64.7 (C(CH3)2), 83.8 (CHN), 171.3 (SꢀCꢁN), 243.1
(CꢁS); IR (NaCl): 2850, 2930, 1610 (wSꢀCꢁN), 1450, 1124
(wCꢁS).
In a dry two-necked round-bottomed flask, under nitro-
gen, was introduced a solution of thiazoline (4 or 5, 10
mmol) in freshly distillated THF (20 mL), cooled to
−78°C. A solution of t-BuLi (1.8 M in cyclohexane)
was then added dropwise and the mixture was stirred
for 3 h. Carbon disulfide (30 mmol) was then slowly
added at −40°C. The resulting brown solution was

I. Abrunhosa et al. / Tetrahedron: Asymmetry 12 (2001) 2851–2859
2859
4.5. Preparation of 2,6-pyridyl di(methylthiocarboxylate)
20
‘Contrat de Plan Etat-Re´gions Haute-Normandie et
Basse-Normandie’ for financial support to I.A. We
would also like to thank Margareth Lemarie´ (micro-
analyses and HPLC) and Yves Dat (HRMS) for carry-
ing out analyses.
Prepared according to a general method of the
literature4 using 2,6-di(chloromethyl) pyridine (1.42
mmol, 0.25 g), sulfur S8 (12.8 mmol, 0.41 g), triethyl-
amine (12.8 mmol, 1.8 mL), dimethylformamide (4 mL)
and methyl iodide (2.8 mmol, 0.8 mL); dark red
1
References
needles, mp=140°C, yield=40%, Rf=0.3 (P: 100); H
NMR: l 2.80 (s, 6H, 2×SCH3), 7.89 (t, 1H, J1=J2=7.9,
H4), 8.54 (d, 2H, J1=J2=7.9, H3, H5); 13C NMR: l
20.4 (CH3S), 125.1, 138.0, 154.0, 227.1 (CꢁS); IR (KBr):
1398, 1102, 1056 (wCꢁS).
1. (a) Lutomski, K. A.; Meyers, A. I. In Asymmetric Syn-
thesis. Asymmetric synthesis via chiral oxazolines; Aca-
demic Press: New York, 1984; Vol. 3, p. 213; (b) Pfaltz,
A. J. Heterocyclic Chem. 1999, 36, 1437.
2. Helmchen, G.; Krotz, A.; Ganz, K.-T.; Hansen, D. Syn-
4.6. Typical procedure for the enantioselective
allylation
lett 1991, 257–259.
3. (a) Ikehira Hideyuki, Patent written in Japanese, JP
09194432 A2, 1997; CAN 127:205573; (b) Ikehira
Hideyuki, Patent written in Japanese, JP 11124373 A2,
1999; CAN 130:352267.
4. Leflemme, N.; Marchand, P.; Gulea, M.; Masson, S.
Synthesis 2000, 8, 1143–1147.
5. When this reaction was tried with isopropylthiazoline 6c
(R=Ph), a mixture of products was obtained, probably
resulting from a second undesirable deprotonation in the
a-position of the phenyl group. The desired product 8c
was isolated in a very low yield (:15%). Compounds 6c
and 8c are not described here.
6. Thiel, W.; Mayer, R. J. Prakt. Chem. 1989, 331, 243–262.
7. Lempereur, C.; Ple´, N.; Turk, A.; Que´guiner, G.; Corbin,
F.; Alayrac, C.; Metzner, P. Heterocycles 1998, 48, 2019–
2034.
Under a nitrogen atmosphere, allylpalladium chloride
dimer (4.5 mg, 0.0125 mmol), the ligand 12a (0.0125
mmol) and solid potassium acetate (5 mg, 0.05 mmol)
were mixed in 2 mL of toluene for 30 min. Diphenyl-
propenyl acetate (128 mg, 0.5 mmol) was then added,
followed by N,O-bis(trimethylsilyl)acetamide (BSA)
(250 mL, 1 mmol) and the dimethyl malonate (115 mL,
1 mmol). The reaction mixture was stirred for 3 days at
20°C. The solvent was removed and the residue purified
on silica gel (P/DEE: 75/25) to afford (E)-methyl 2-
methoxycarbonyl-3,5-diphenylpent-4-enoate in 90%
yield. Enantiomeric excess was measured by HPLC
using a Chiralpak AD analytical column Daicel (90/10
n-hexane/2-propanol, flow rate 1 mL/min, 251.3 nm).
The HPLC separation was calibrated using racemic
product ((S): t1=10.5 min, (R): t2=14.4 min).
8. See Section 4.5.
9. For reviews, see: (a) Pfaltz, A.; Lautens, M. In Compre-
hensive Asymmetric Catalysis II; Jacobsen, E. N.; Pfaltz,
A.; Yamamoto, H., Eds. Allylic substitution reactions;
Springer: New York, 1999; pp. 834–884; (b) Trost, B. M.;
Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422.
10. Hashizume, T.; Yonehara, K.; Ohe, K.; Uemura, S. J.
Org. Chem. 2000, 65, 5197–5201.
Acknowledgements
We would like to thank the ‘Poˆle Universitaire Nor-
mand de Chimie Organique’ (PUNCHorga) and the