Hydroxyalkyl thiazolines, a new class of highly efficient ligands for carbonyl additions

Article abstract of DOI:10.1055/s-0028-1087366

Hydroxyalkyl thiazoline ligands can easily be obtained in an isonitrile-based multicomponent reaction. These ligands are significantly more stable than the comparable oxazoline ligands, and give excellent enantiomeric excess in carbonyl additions of alkyl- and arylzinc compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087366

LETTER
3203
Hydroxyalkyl Thiazolines, a New Class of Highly Efficient Ligands for
Carbonyl Additions
H
ydroxyalkyl Thiazoli
i
nes chael Bauer, Frauke Maurer, Svenja M. Hoffmann, Uli Kazmaier*
Institut für Organische Chemie, Universitaet des Saarlandes, 66123 Saarbruecken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 27 August 2008
F3C
Abstract: Hydroxyalkyl thiazoline ligands can easily be obtained
in an isonitrile-based multicomponent reaction. These ligands are
significantly more stable than the comparable oxazoline ligands,
and give excellent enantiomeric excess in carbonyl additions of
R
N
N
HO
CHO
alkyl- and arylzinc compounds.
HO
Key words: carbonyl additions, ligands, multicomponent reac-
tions, nonlinear effect, thiazolines
+
Et2Zn
R =
R =
t-Bu
t-Bu
94% ee (S)
12% ee (R)
During the past twenty years, chiral oxazolines have de-
veloped to an important class of ligands, used in many
asymmetric reactions.1 By far less evaluated are the struc-
turally related imidazoline2 and thiazoline3 ligands. Espe-
cially the later one’s are described only marginally.
Helmchen et al. were the first reporting on Rh-catalyzed
hydrosilylation of ketones, where they observed big dif-
ferences between oxazoline and thiazoline ligands.4 Sim-
ilar is the situation in Pd-catalyzed allylic alkylations,
where the two ligand types give rise to the enantiomeric
substitution products.5 NMR studies indicated that the
reason for this behavior could be found in a different co-
ordination mode of the ligands. While oxazolines coordi-
nate exclusively via the nitrogen atom towards the metal,
with thiazolines also a S-coordination is possible, espe-
cially in reactions of late transition metals. In contrast, a
comparable reaction behavior was observed in Cu- and
Zn-catalyzed Henry6 and Diels–Alder reactions,7 indicat-
ing a similar binding mode of the ligand towards the cata-
lytically active metal.
Scheme 1 Carbonyl additions using chiral hydroxyalkyl imidazoli-
nes
O
N
OH
HO
ZnEt2
+
CHO
toluene–hexanes
18 h, r.t.
100%, 92% ee
Scheme 2 Asymmetric carbonyl additions using hydroxyalkyl oxa-
zolines
stereomeric mixture of the ligand. The isomers could eas-
ily be separated by flash chromatography and were
evaluated separately also in the ZnEt2 addition towards al-
dehydes.
Interestingly, only the S,S-isomer showed a strong ligand
acceleration, giving a high enantiomeric excess of the ad-
dition product. In contrast, with the R,S-isomer the reac-
tion was very slow and rather unselective. Therefore, we
decided to use also the diastereomeric mixture of the
ligand and obtained results comparable to the pure S,S-
isomer (Scheme 2). The only disadvantage was the insta-
bility of the ligand towards hydrolysis, what forced the
idea to investigate also the analogous thiazoline ligands.
Casey et al. reported on the use of bidentate hydroxyalkyl
imidazolines as ligands in the ZnEt2 addition towards al-
dehydes.8 These ligands were obtained as a 1:1 diastereo-
meric mixture via addition of lithiated imidazolines
towards pivalaldehyde. In some cases the ligands could be
separated and evaluated in diastereomerically pure form.
A strong matched/mismatched situation was observed,
and the stereochemical outcome of the reaction strongly
depends on the steric and electronic properties of the
ligands. The substituent at the hydroxy group determines
the configuration of the addition product (Scheme 1).
In principle, three different approaches are suitable for the
synthesis of thiazolines: 1. Reaction of nitriles with ami-
nothiols;10 2. Cyclization of hydroxyamides in the pres-
ence of P2S511 or Lawesson’s reagent;12 3. Cyclization of
hydroxythioamides using MsCl/Et3N,13 DAST,14 or
Mitsunobu conditions.13
Our group developed a straightforward approach towards
structurally related hydroxyalkyl oxazolines based on a
Passerini-type one-pot reaction,9 giving rise to a 1:1 dia-
We decided to use an approach comparable to the previ-
ous synthesis of the oxazoline ligands (Scheme 3). Sodi-
um thiosulfate was added for the incorporation of sulfur.15
Best results were obtained in the presence of pyridinium
p-toluenesulfonate (PPTS) giving rise to a 1:1 diastereo-
SYNLETT 2008, No. 20, pp 3203–3207
1
6
.1
2
.2
0
0
8
Advanced online publication: 24.11.2008
DOI: 10.1055/s-0028-1087366; Art ID: G27508ST
© Georg Thieme Verlag Stuttgart · New York

3204
M. Bauer et al.
LETTER
Table 1 Et2Zn Addition towards Aldehydes
OH
Na2S2O3
+
+
OH
H3O+
t-BuCHO
ligand
CN
RCHO
+ Et2Zn
toluene–hexanes
r.t., 22 h
R
1) PPTS, H2O, 0 °C
Entry
R
Ligand Conversion ee (%) Configuration
(%)
2) crystallization (benzene)
1
2
3
4
5
6
7
Ph
(S,S)-2 100
(R,S)-2 55
(S,S)-2 99
(R,S)-2 57
92
2
S
t-Bu
t-Bu
H
H
N
N
Ph
+
HO
OH
HO
OH
S
S
Tol
Tol
94
2
S
(S,S)-1
(R,S)-1
36%, >99% ds
41%, 81% ds
4-BrC6H4 (S,S)-2 100
92
70a
88a
S
S
S
MsCl, Et3N
MsCl, Et3N
n-Pent
(S,S)-2 89
Cy
(S,S)-2 96
t-Bu
HO
t-Bu
HO
S
N
S
N
a Determined after acetylation.
(S,S)-2
(R,S)-2
85%, >99% ds
96%, 81% ds
39%, >99% ds
(after crystallization)
Scheme 3 Synthesis of hydroxyalkyl thiazolines
meric mixture of 1. The diastereomers could easily be
separated by crystallization of the crude product. The R,S-
isomer (R,S)-1 crystallized in pure form (>99% ds), while
the S,S-isomer remained in solution.16 Both isomers could
be converted into the desired ligands using MsCl and
Et3N.17 Fortunately, also (S,S)-2 could be obtained in pure
form after crystallization. The X-ray structure analysis
confirmed the configuration of this ligand. By this proto-
col, both stereoisomers of 2 could be obtained in only two
steps in multigram scale as crystalline material, which is
stable towards air and hydrolysis.
Figure 1 Nonlinear effect caused by the thiazoline ligand (S,S)-2
With these ligands in hand, we investigated their potential
in asymmetric reactions. First of all we chose the ‘stan-
dard reaction’ for ligand evaluation, the ZnEt2 addition to-
wards aldehydes (Table 1).18 The thiazoline ligand
behaved similar to the analogous oxazolines giving ee
>90% with aromatic aldehydes (entries 1, 3, and 5), but
also relatively good values for aliphatic aldehydes (entries
6 and 7), if (S,S)-2 was used. In contrast, the mismatched
ligand (R,S)-2 gave more or less racemic products in sig-
nificantly lower yield (entries 2 and 4).
fulness. Therefore, we were interested to find other cata-
lytic applications for our ligands.
Diarylmethanols are interesting intermediates for the syn-
thesis of druglike molecules. They can easily be obtained
by addition of arylmetal compounds towards aromatic al-
dehydes, although the stereocontrol is not a trivial issue.
Soai et al. were the first reporting on an arylzinc chloride
(obtained from the corresponding aryllithium and -mag-
nesium compound via transmetalation) addition in the
presence of norephedrine derivatives.20 The selectivities
were moderate, probably because of strong background
reactions caused by the original organometallics. Better
results were reported for ZnPh2 additions by Fu using an
azaferrocene ligand,21 and by Pu et al. using substituted
BINOL ligands,22 although these systems require high
catalyst loadings (20 mol%). High enantioselectivities
were obtained also in the presence of amino alcohols,23
and amino thiol derivatives.24 Bolm et al. were able to get
ee of up to 98% by using various hydroxyoxazoline
To get informations concerning the reaction mechanism,
we investigated the reaction of benzaldehyde with ligand
(S,S)-2 of different ee and observed a very strong nonlin-
ear effect (Figure 1). A ligand with only 4% ee gave rise
to a product with 72% ee. This result indicates the forma-
tion of an inactive catalyst aggregate, according to the
mechanism proposed by Noyori for the amino alcohol cat-
alyzed additions.19
Although the ZnEt2 addition is a good candidate to start a
ligand evaluation, it is synthetically only of moderate use-
Synlett 2008, No. 20, 3203–3207 © Thieme Stuttgart · New York

LETTER
Hydroxyalkyl Thiazolines
3205
This observation forced us to investigate this reaction in
the presence of our hydroxyalkyl thiazoline (S,S)-2. The
required arylzinc species can be obtained via transmetala-
tion from triarylboranes26 or phenylboronic acids.27
Table 2 Optimization of the Phenylzinc Additions towards Alde-
hydes
S
HO
HO
CHO
B(OR)2
+
N
We began our investigation with phenylboronic acid 3a
and its reaction with p-methylbenzaldehyde.28 According
to a protocol described by Uang,24a three equivalents of
ZnEt2 were used relative to the boronic acid (Table 2, en-
try 1). In a clean reaction, the desired diarylmethanol 4
was obtained with high ee,29 but as a 1:1 mixture together
with the ethyl addition product 5. Attempts to suppress
this ethyl addition by reducing the reaction temperature to
–30 °C, or by using equimolar amounts of the reaction
partners, were unsuccessful, only traces of product were
obtained. Although three equivalents of ZnEt2 were used,
the excess, which is responsible for this side reaction, is
probably lower because of the partial decomposition of
the zinc reagent by the acidic protons of the boronic acid.
To avoid this decomposition, we switched to the corre-
sponding pinacol ester of phenylboronic acid.30 If the two
organometallic reagents where reacted in a 1:1 ratio and in
a twofold excess relative to the aldehyde, still some 5 was
formed, although less than before (entry 2). This side re-
action could completely be suppressed if the excess of the
organometallics was increased to three equivalents. Under
these conditions not only the best yield but also the best ee
could be obtained (entry 3). These experiments were car-
ried out in the presence of 10 mol% of the chiral ligand.
This amount can be reduced to 5 mol% without significant
effect on the selectivity (entry 4).
HO
(S,S)-2
+
+
ZnEt2
toluene–hexanes
r.t.
3a R = H
3b R,R =
4a
5a
Entry ArB(OR)2 ArB(OR)2 ZnEt2 Yield (%)
ee (%)
(equiv)
(equiv)
4a
5a
4a
1
2
3
4
3a
3b
3b
3b
2
2
3
3
6
2
3
3
49
60
85
67
49
22
–
93a
87a
94a
92b
–
a (S,S)-2 (10 mol%) was used.
b (S,S)-2 (5 mol%) was used.
Table 3 Phenyl Additions towards Aldehydes
S
OH
N
HO
O
O
B
(5 mol%)
Ar
ArCHO +
+
ZnEt2
toluene–hexanes
r.t.
Under these optimized conditions we investigated the re-
action of a wide range of other aldehydes (Table 3). Ex-
cellent ee values were obtained for all aromatic aldehydes,
relatively independent on the substitution pattern (entries
1–7). Heteroaromatic aldehydes are also good substrates
(entries 8 and 9) as long as they do not contain nitrogen at-
oms. The ee dropped dramatically in the reaction of
pyridinecarbaldehyde (entry 10), and no reaction was ob-
served with indolecarbaldehyde. Probably these N-
heterocycles coordinate towards the zinc reagent.
4
3b
Entry Aldehyde
Product Yield (%) ee (%)
1
2
2-Methylbenzaldehyde
3-Methylbenzaldehyde
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4b
4c
4d
4e
90
83
83
68
87
85
80
79
84
49
97
87
94
93
98
96
93
85
85
7
3
4
In conclusion we showed that hydroxyalkyl thiazolines,
such as (S,S)-2, are an interesting new class of chiral
ligands which are easy to synthesize and to handle. They
give excellent results in addition reaction towards aromat-
ic and heteroaromatic aldehydes. Further applications of
this ligand are currently under investigation.
5
3-Methoxybenzaldehyde 4f
4-Methoxybenzaldehyde 4g
2-Naphthylcarbaldehyde 4h
6
7
8
2-Furylcarbaldehyde
2-Thiophenecarbaldehyde 4k
2-Pyridinecarbaldehyde 4l
4i
9
Acknowledgment
10
This work was supported by the Deutsche Forschungsgemeinschaft
and by the Fonds der Chemischen Industrie.
ligands.25 Interestingly, a mandelic acid derived hydroxy-
alkyl oxazoline gave only moderate results (20% yield,
31% ee), probably because of an isomerization of the con-
figurationally labile benzylic stereogenic center.
References and Notes
(1) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151;
and references cited therein.
Synlett 2008, No. 20, 3203–3207 © Thieme Stuttgart · New York

3206
M. Bauer et al.
LETTER
(2) (a) Botteghi, C.; Schionato, A.; Chelucci, G.; Brunner, H.;
Kürzinger, A.; Obermann, U. J. Organomet. Chem. 1989,
370, 17. (b) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett.
2002, 4, 4713. (c) Boland, N. A.; Casey, M.; Hynes, S. J.;
Matthews, J. W.; Smyth, M. P. J. Org. Chem. 2002, 67,
3919. (d) Busacca, C. A.; Grossbach, D.; So, R. C.; O’Brien,
E. M.; Spinelli, E. M. Org. Lett. 2003, 5, 595. (e) Bastero,
A.; Claver, C.; Ruiz, A.; Castillón, S.; Daura, E.; Bo, C.;
Zangrando, E. Chem. Eur. J. 2004, 10, 3747. (f) Bhor, S.;
Anilkumar, G.; Tse, M. K.; Klawonn, M.; Döbler, C.;
Bitterlich, B.; Grotevendt, A.; Beller, M. Org. Lett. 2005, 7,
3393. (g) Weiss, M. E.; Fischer, D. F.; Xin, Z.; Jautze, S.;
Schweizer, W. B.; Peters, R. Angew. Chem. Int. Ed. 2006,
45, 5694; Angew. Chem. 2006, 118: 5823. (h) Ma, K.; You,
J. Chem. Eur. J. 2007, 13, 1863. (i) Arai, T.; Mizukami, T.;
Yanagisawa, A. Org. Lett. 2007, 9, 1145.
(3) Molina, P.; Tárraga, A.; Curiel, D. Synlett 2002, 435.
(4) Helmchen, G.; Krotz, A.; Ganz, K.-T.; Hansen, D. Synlett
1991, 257.
(5) (a) Le, M. a. u. x. P.; Abrunhosa, I.; Berchel, M.;
Simonneaux, G.; Gulea, M.; Masson, S. Tetrahedron:
Asymmetry 2004, 15, 2569. (b) Abrunhosa, I.; Delain-
Bioton, L.; Gaumont, A.-C.; Gulea, M.; Masson, S.
Tetrahedron 2004, 60, 9263.
(6) (a) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahedron:
Asymmetry 2004, 15, 3433. (b) Du, D.-M.; Lu, S.-F.; Fang,
T.; Xu, J. J. Org. Chem. 2005, 70, 3712.
(7) (a) Nishio, T.; Kodama, Y.; Tsurumi, Y. Phosphorus, Sulfur
Silicon Relat. Elem. 2005, 180, 1449. (b) Yamakuchi, M.;
Matsunaga, H.; Tokuda, R.; Ishizuka, T.; Nakajima, M.;
Kunieda, T. Tetrahedron Lett. 2005, 46, 4019.
(8) Casey, M.; Smyth, M. P. Synlett 2003, 102.
(9) Kazmaier, U.; Bauer, M. J. Organomet. Chem. 2006, 691,
2155.
(10) Yamakuchi, M.; Matsunaga, H.; Tokuda, R.; Ishizuka, T.;
Nakajima, M.; Kunieda, T. Tetrahedron Lett. 2005, 46,
4019.
(s, 9 H), 2.07 (m, 1 H), 3.49 (ddd, J = 9.9, 4.8, 4.6 Hz, 1 H),
3.58 (ddd, J = 9.9, 5.0, 4.8 Hz, 1 H), 4.03 (d, J = 6.0 Hz,
1 H), 4.35 (dddd, J = 9.0, 7.0, 4.8, 4.6 Hz, 1 H), 4.69 (dd,
J = 5.0, 4.8 Hz, 1 H), 5.41 (d, J = 6.0 Hz, 1 H), 9.07 (d,
J = 9.0 Hz, 1 H). 13C NMR (125 MHz, DMSO-d6): d = 18.8,
19.1, 26.6, 27.8, 34.8, 59.5, 60.9, 84.1, 202.5. HRMS (CI):
m/z calcd for C11H24NO2S [M + H]+: 234.1528; found:
234.1530. Anal. Calcd for C11H23NO2S (233.37): C, 56.61;
H, 9.93; N, 6.00. Found: C, 56.60; H, 9.70; N, 5.96.
Compound (S,S)-1: [a]D20 –92 (c 1.7, CHCl3). 1H NMR (500
MHz, DMSO-d6): d = 0.89, 0.91 (2 d, J = 6.9 Hz, 6 H), 0.95
(s, 9 H), 2.07 (m, 1 H), 3.50 (ddd, J = 11.0, 4.9, 4.7 Hz, 1 H),
3.60 (ddd, J = 11.0, 5.0, 4.8 Hz, 1 H), 4.05 (d, J = 5.9 Hz,
1 H), 4.34 (dddd, J = 8.8, 6.9, 4.8, 4.7 Hz, 1 H), 4.68 (dd,
J = 5.0, 4.9 Hz, 1 H), 5.42 (d, J = 5.9 Hz, 1 H), 9.13 (d,
J = 8.8 Hz, 1 H). 13C NMR (125 MHz, DMSO-d6): d = 19.0,
26.7, 28.0, 34.9, 59.3, 61.0, 84.2, 202.7. HRMS (CI): m/z
calcd for C11H24NO2S [M + H]+: 234.1528; found: 234.1547.
Anal. Calcd for C11H23NO2S (233.37): C, 56.61; H, 9.93; N,
6.00. Found: C, 56.61; H, 9.70; N, 5.62.
(17) Synthesis of the Thiazoline Ligand (S,S)-2
Thioamide (S,S)-1 (8.40 g, 36.0 mmol) and Et3N (11.1 mL,
79.2 mmol) were dissolved in abs. THF (180 mL). This
solution was cooled to 0 °C before MsCl (3.09 mL, 39.6
mmol) in THF (35 mL) was added dropwise. After the
addition was complete, the ice bath was removed and the
mixture allowed to warm to r.t. The mixture was diluted with
Et2O and washed with H2O. After drying of the organic layer
(Na2SO4) and evaporation of the solvent a colorless solid
(7.44 g, 34.4 mmol, 96% yield) was obtained. The crude
product was crystallized twice (hexane) giving colorless
crystals (3.02 g, 14.0 mmol, 39% yield); mp 88–90 °C.
Rf = 0.19 (hexane–Et2O, 8:2). [a]D20 –57 (c 1.4, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 0.96 (d, J = 6.8 Hz, 3 H), 0.99
(s, 9 H), 1.03 (d, J = 6.8 Hz, 3 H), 1.97 (m, 1 H), 3.04 (dd,
J = 10.5, 10.1 Hz, 1 H), 3.29 (dd, J = 10.5, 8.7 Hz, 1 H), 3.61
(br s, 1 H), 4.05 (d, J = 4.0 Hz, 1 H), 4.17 (dddd, J = 10.1,
8.7, 6.5, 1.1 Hz, 1 H). 13C NMR (125 MHz, CDCl3):
d = 18.9, 19.6, 25.9, 32.8, 35.2, 35.8, 79.5, 81.6, 172.8.
HPLC: column: LiChrosorb Si 60, hexane–Et2O (90:10),
flow: 2.0 mL/min; tR = 11.80 min. HRMS (CI): m/z calcd for
C11H22NOS [M + H]+: 216.1422. Found: 216.1447. Anal.
Calcd for C11H21NOS (215.35): C, 61.35; H, 9.83; N, 6.50.
Found: C, 61.17; H, 9.50; N, 6.36.
(11) Fu, B.; Du, D.-M.; Xia, Q. Synthesis 2004, 221.
(12) Nishio, T. J. Org. Chem. 1997, 62, 1106.
(13) Abrunhosa, I.; Gulea, M.; Levillain, J.; Masson, S.
Tetrahedron: Asymmetry 2001, 12, 2851.
(14) Lafrague, P.; Guenot, P.; Lellouche, J.-P. Synlett 1995, 171.
(15) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I.; Steinbrückner, C. Angew.
Chem. 1960, 72, 267.
Synthesis of the Thiazoline Ligand (R,S)-2
(16) Synthesis of Thioamide 1
Ligand (R,S)-2 was prepared according to the same
procedure from (R,S)-1 (466 mg, 2.00 mmol). The crude
product was purified by flash chromatography giving rise to
colorless crystals (363 mg, 1.69 mmol, 85% yield); mp
69 °C. Rf = 0.38 (hexane–Et2O, 8:2). [a]D20 –71 (c 1.5,
CHCl3). 1H NMR (500 MHz, CDCl3): d = 0.97 (d, J = 6.8
Hz, 3 H), 1.005 (s, 9 H), 1.006 (d, J = 6.8 Hz, 3 H), 1.98 (m,
1 H, 5-H), 3.07 (dd, J = 10.9, 9.1 Hz, 1 H), 3.33 (dd,
J = 10.9, 9.0 Hz, 1 H), 3.59 (d, J = 4.5 Hz, 1 H), 3.99 (m,
1 H), 4.23 (dddd, J = 9.1, 9.0, 6.4, 1.7 Hz, 1 H). 13C NMR
(125 MHz, CDCl3): d = 19.1, 19.4, 26.0, 32.6, 35.4, 35.7,
79.5, 81.5, 171.8. HPLC: column: LiChrosorb Si 60,
hexanes–Et2O (90:10), flow: 2.0 mL/min; tR = 5.65 min.
HRMS (CI): m/z calcd for C11H22NOS [M + H]+: 216.1422;
found: 216.1445. Anal. Calcd for C11H21NOS (215.35): C,
61.35; H, 9.83; N, 6.50. Found: C, 60.93; H, 9.65; N, 6.45.
(18) General Procedure for ZnEt2 Additions towards
Aldehydes
Pivalaldehyde (7.82 mL, 72.0 mmol) and (S)-2-isocyano-3-
methyl-1-butanol (5.46 g, 48.2 mmol) were added to a
solution of Na2S2O3 (11.4 g, 72.0 mmol) and PPTS (18.1 g,
72.0 mmol) in H2O (40 mL) at 0 °C. The mixture was
allowed to stir at 0 °C for further 30 min, before the ice bath
was removed and the solution warmed to r.t. Then, H2O was
added, and the product was extracted three times with
CH2Cl2. The combined organic layers were extracted with aq
NaHCO3, KHSO4, and H2O and dried over Na2SO4. After
evaporation of the solvent, the crude product was purified by
flash chromatography (silica gel, hexanes–EtOAc, 7:3)
giving rise to a colorless solid. The diastereomeric
thioamides could be separated by crystallization from
benzene, providing (R,S)-1 (1.59 g, 6.9 mmol, 36%) as
colorless crystals; mp 129–130 °C. The S,S-isomer was
obtained (1.78 g, 7.7 mmol, 41%) by a second flash
chromatography (silica gel, hexanes–EtOAc, 8:2) as a
colorless oil, which solidified to a wax. Rf = 0.47 [(S,S)-1]
and 0.53 [(R,S)-1] (Et2O).
A solution of ZnEt2 in hexane (15%, 2 mL, 1.76 mmol) was
added to the ligand (S,S)-2 (4.3 mg, 0.02 mmol, 2 mol%) in
toluene (2 mL) in a Schlenk tube under argon. The mixture
was stirred at r.t. for 30 min before the aldehyde (1 mmol) in
Compound (R,S)-1: [a]D20 –57 (c 1.3, CHCl3). 1H NMR (500
MHz, DMSO-d6): d = 0.89, 0.92 (2 d, J = 6.8 Hz, 6 H), 0.94
Synlett 2008, No. 20, 3203–3207 © Thieme Stuttgart · New York

LETTER
toluene (1 mL) was added. After 22 h, 1 N HCl was added.
Hydroxyalkyl Thiazolines
3207
(25) (a) Bolm, C.; Muñiz, K. Chem. Commun. 1999, 1295.
After stirring for 10 min the product was extracted with Et2O
(twice) and the enantiomeric ratio of the crude product was
determined by GC using a chiral cyclodextrin column.
Afterwards the crude product was purified by flash
chromatography.
(b) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muñiz, K.
Angew. Chem. Int. Ed. 2000, 39, 3465; Angew. Chem. 2000,
112, 3607. (c) Bolm, C.; Kesselgruber, M.; Hermanns, N.;
Hildebrand, J. P.; Raabe, G. Angew. Chem. Int. Ed. 2001, 40,
1488; Angew. Chem. 2001, 113, 1536. (d) Bolm, C.; Zani,
L.; Rudolph, J.; Schiffers, I. Synlett 2004, 2173. (e) Bolm,
C.; Schmidt, F.; Zani, L. Tetrahedron: Asymmetry 2005, 16,
1367.
(19) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49; Angew. Chem. 1991, 103, 34. (b) Soai, K.;
Niwa, S. Chem. Rev. 1992, 92, 833. (c) Pu, L.; Yu, H.-B.
Chem. Rev. 2001, 101, 757. (d) Yamakawa, M.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 6327.
(20) (a) Soai, K.; Kawase, Y. J. Chem. Soc., Perkin Trans. 1
1990, 3214. (b) Soai, K.; Kawase, Y.; Oshio, A. J. Chem.
Soc., Perkin Trans. 1 1991, 1613.
(26) (a) Rudolph, J.; Schmidt, F.; Bolm, C. Adv. Synth. Catal.
2004, 346, 867. (b) Dahmen, S.; Lormann, M. Org. Lett.
2005, 7, 4597.
(27) (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124,
14850. (b) Rudolph, J.; Schmidt, F.; Bolm, C. Synthesis
2005, 840. (c) Schmidt, F.; Rudolph, J.; Bolm, C. Adv.
Synth. Catal. 2007, 349, 703.
(21) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
444.
(22) (a) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222.
(b) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64,
7940. (c) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41,
145. (d) Qin, Y.-C.; Pu, L. Angew. Chem. Int. Ed. 2006, 45,
273; Angew. Chem. 2006, 118, 279.
(23) (a) Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4,
3759. (b) Fontes, M.; Verdaguer, X.; Solà, L.; Pericàs,
M. A.; Riera, A. Org. Chem. 2004, 69, 2532. (c) Wu, X.;
Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2005, 16, 2299.
(d) Kim, P. G.; Walsh, P. J. Angew. Chem. Int. Ed. 2006, 45,
4175; Angew. Chem. 2006, 118, 4281. (e) Wang, M.-C.;
Zhang, Q.-J.; Zhao, W.-X.; Wang, X.-D.; Ding, X.; Jing,
T.-T.; Song, M.-P. J. Org. Chem. 2008, 73, 168.
(24) (a) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006,
71, 833. (b) Jin, M.-J.; Sarkar, S. M.; Lee, D. H.; Qiu, H.
Org. Lett. 2008, 10, 1235.
(28) General Procedure for Arylations of Aldehydes
The pinacol ester of phenylboronic acid (306 mg, 1.5 mmol)
was dissolved in toluene (4 mL) in a Schlenk tube. A 1 M
solution of ZnEt2 in hexane (1.5 mL, 1.5 mmol) was added,
and the mixture was heated to 60 °C for 12 h. After cooling
to r.t., this solution was added to the ligand (S,S)-2 (5.4 mg,
0.025 mmol, 5 mol%) in another Schlenk tube. After stirring
for 10 min at r.t., the aldehyde was added in hexane (1 mL).
The reaction was monitored by TLC. After complete
conversion, sat. NH4Cl solution was added to quench the
reaction and the aqueous layer was extracted with CH2Cl2 (2 ×).
The combined organic layers were dried and evaporated.
The product was purified by flash chromatography, and the
enantiomeric ratio was determined by HPLC (Chiracel OD-
H).
(29) The ee was determined by HPLC using the chiral column
Chiracel OD-H.
(30) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi,
N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390.
Synlett 2008, No. 20, 3203–3207 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.