Enantioselective addition of methyllithium to a prochiral imine - The substrate in the Pomeranz-Fritsch-Bobbitt synthesis of tetrahydroisoquinoline derivatives mediated by chiral monooxazolines

Article abstract of DOI:10.1016/j.tetasy.2004.08.011

A series of chiral monooxazoline ligands 7-24 with substituents at C-2 and C-4, differing in electronic and steric properties, has been synthesized from (+)-thiomicamine 6. The effect of the oxazoline structure on the course of addition of methyllithium to imine 1 has been studied. The addition product, amine 3, which is the key intermediate in the Pomeranz-Fritsch-Bobbitt synthesis of tetrahydroisoquinoline derivatives, has been obtained in high yield (92%) and with up to 76% ee.

Full text of DOI:10.1016/j.tetasy.2004.08.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3289–3295
Enantioselective addition of methyllithium to a prochiral imine—the
substrate in the Pomeranz–Fritsch–Bobbitt synthesis of
tetrahydroisoquinoline derivatives mediated by chiral
monooxazolines
*
´
Agata Głuszynska and Maria D. Rozwadowska
´
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
Received 29 July 2004; accepted 16 August 2004
Available online 1 October 2004
Abstract—A series of chiral monooxazoline ligands 7–24 with substituents at C-2 and C-4, differing in electronic and steric prop-
erties, has been synthesized from (+)-thiomicamine 6. The effect of the oxazoline structure on the course of addition of methyllith-
ium to imine 1 has been studied. The addition product, amine 3, which is the key intermediate in the Pomeranz–Fritsch–Bobbitt
synthesis of tetrahydroisoquinoline derivatives, has been obtained in high yield (92%) and with up to 76% ee.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
chiral ligands, most of which contained nitrogen and/
or oxygen functional groups, such as (À)-sparteine,7,8
bisoxazolines,8–10 aminoethers,11–13 and diol ethers,13
have been recently developed. A number of monooxaz-
olines derived from (1S,2S)-2-amino-1-aryl-1,3-pro-
pandiols have been synthesized and tested as ligands in
enantioselective additions of organometallic reagents
to imines, cyclic14 and Schiff base-type.15
Asymmetric addition of carbon nucleophiles to the car-
bon–nitrogen double bond of imines with the introduc-
tion of a stereogenic center at the a-position has
provided rapid access to enantiomerically pure or en-
riched amines. The stereoselectivity of this process has
been accomplished either by diastereoselective synthesis,
requiring the covalent attachment of a chiral auxiliary to
substrates, or in reactions mediated by external chiral
ligands. The literature of the past decade, concerning
diastereoselective and enantioselective nucleophilic
additions to imines and their derivatives, has been re-
viewed in several comprehensive articles.1–5
2. Results and discussion
One aspect of our interest in the asymmetric synthesis of
isoquinoline alkaloids16 has been directed toward the
enantioselective modification of the Pomeranz–Frit-
sch–Bobbitt synthesis.15 This approach, realised for
the first time in this manner, afforded enantiomerically
enriched (S)-salsolidine 4 and (S)-carnegine 5 (Scheme
1).
The synthetic approach, involving reactions of prostereo-
genic imines with organometallic reagents, carried out in
the presence of stoichiometric or catalytic amounts of
external chiral ligands, has recently gained growing
attention and successfully competes with the more com-
mon diastereoselective synthesis.6 In this regard, the de-
sign and synthesis of new and efficient chiral ligands
plays a crucial role. For enantioselective addition of
organometallic reagents to the C@N bond, a variety of
The modification involved addition of methyl organo-
metallic reagents to the ꢀPomeranz–Fritschꢁ imine 1 car-
ried out in the presence of oxazolines 2 (R = SCH3, H;
R2 = H, CH3) derived from (+)-thiomicamine 6, and
its desulfurated analogue, (1S,2S)-2-amino-1-phenyl-
1,3-propanodiol, used as external chiral ligands (Fig.
1). The resulting amine 3 was obtained in high yield
but with only 49% ee. To improve the enantioselectivity
*
Corresponding author. Tel.: +48 61 8291322; fax: +48 61 658008;
e-mail: mdroz@amu.edu.pl
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.011

´
A. Głuszynska, M. D. Rozwadowska / Tetrahedron: Asymmetry 15 (2004) 3289–3295
3290
H3CO OCH3
H3CO
H3CO
H3CO
H3CO
MeMet / 2
N R
CH3
N
NH
CH3
H3CO
H3CO
H3CO
OCH3
4
5
R=H
R=CH3
3
1
Scheme 1.
R1
N
C6H5
OH
O
O
N
OH
NH2
H3CS
H3CS
R
R2
OR2
6
7-24 (Table 1)
2
R1
N
25 R=SCH3 R1=C6H5 R2=H21
26 R=SCH3 R1=C6H5 R2=Ts12
O
20
27 R=H
28 R=H
R1=C6H5 R2=CH3
R1=CH3 R2=CH3
R
OR2
Figure 1.
of the addition step, crucial for the synthesis, we have
undertaken a further study focused mainly on structural
modifications of ligands.
with R1 and R2 substituents differing in steric and elec-
tronic properties (Table 1). Since hydroxy oxazolines
of type 7–11 have been found15 to give poor asymmetric
induction in these additions O-protected derivatives, 14–
24, along with two known others, 2715 and commercially
available 28, were tested for their ability to control the
steric course of the addition of methyllithium to imine
1, in the hope that amine 3 could be produced with high-
er enantiomeric purity (Table 2). Imine 1 was chosen as
the sole object of our study not only because the result-
ing chiral amine 3 could be used as substrate in asym-
metric synthesis of tetrahydroisoquinoline derivatives
according to the Pomeranz–Fritsch–Bobbitt method,
but because the addition of organometallic reagents to
Chiral oxazolines were chosen as ligands in this reaction
not only because of the well documented efficiency of
monooxazolines17 and bisoxazolines18 in introducing
chirality in many asymmetric reactions, in particular
as most promising in additions to imines, but also be-
cause they were prepared from (1S,2S)-2-amino-1-aryl-
1,3-propandiols, industrial waste products.
In continuation of this project, we have synthesized
from (+)-thiomicamine 6 several new oxazolines 7–24,
Table 1. Oxazolines 7–24 synthesized from (1S,2S)-(+)-thiomicamine 6
Oxazoline no. R1
R2
Y (%) Mp (ꢁC)/solvent* [a]D
HRMS (M+)
Calcd
Found
7
o-C6H4OH
m-C6H4Me
OH
OH
60
71
104–107 (a)
162–164(b)
109–111 (c)
127–129 (d)
81.5–84(c)
+91.9 (c 0.47, MeOH)
+61.4( c 0.50, CH2Cl2)
315.09524 315.09293 C17H17NO3S
313.11532 313.11365 C18H19NO2S
8
9
Me
Et
OH
OH
63
28
À147.9 (c 1.03, CH2Cl2) 237.08156 237.08235 C12H15NO2S
À121.7 (c 1.02, CH2Cl2) 251.09823 251.09801 C13H17NO2S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
i-Pr
Ph
Ph
OH
OMs
SCOCH3
7
89
À92.5 (c 1.02, CH2Cl2)
+29.8 (c 0.99, CHCl3)
+79.3 (c 1.00, CHCl3)
265.11303 265.11365 C14H19NO2S
377.07375 377.07556 C18H19NO4S2
357.08539 357.08572 C19H19NO2S2
343.12358 343.12421 C19H21NO3S
327.12700 327.12930 C19H21NO2S
103–105 (c)
123–126 (e)
72
o-C6H4OMe OMe
94Oil
95
96
+50.6 ( c 0.89, CH2Cl2)
+66.1 (c 1.03, CH2Cl2)
m-C6H4Me
OMe
OMe
OMe
OMe
OTs
69–72 (f)
Oil
Oil
Me
Et
À119.5 (c 0.98, CH2Cl2) 251.09791 251.09801 C13H17NO2S
À102.7 (c 1.08, CH2Cl2) 265.11431 265.11365 C14H19NO2S
95
94Oil
70
i-Pr
Me
Me
Ph
À87.1 (c 0.99, CH2Cl2)
À127.9 (c 0.88, MeOH)
À77.7 (c 1.10, CH2Cl2)
+55.4( c 0.57, CH2Cl2)
À22.0 (c 1.01, CHCl3)
279.12876 279.12930 C15H21NO2S
391.09125 391.09122 C19H21NO4S2
351.17058 351.16882 C18H29NO2SSi
413.18516 413.18448 C23H31NO2SSi
375.12686 375.12930 C23H21NO2S
116.5–119.5 (g)
Oil
Oil
Si(Me)2t-Bu 99
Si(Me)2t-Bu 98
Ph
Ph
OPh
SMe
STol
40
48
68
123–125 (h)
122–125 (c)
78–80 (f)
+130.1 (c 0.98, CH2Cl2) 329.08941 329.09082 C18H19NOS2
Ph
+142.1 (c 0.99, MeOH)
405.12105 405.12210 C24H23NOS2
* Crystallization solvents: (a) CCl4, (b) CH2Cl2, (c) CH2Cl2/hexane, (d) CH2Cl2/i-Pr2O, (e) CHCl3, (f) Et2O, (g) MeOH, (h) EtOH/i-Pr2O.

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3291
Table 2. Addition of methyllithium to imine 1 in the presence of ligands 2 (R = SCH3), 14–24, and 26–28a
Oxazolines
R1
Addition product 3b
2.6equiv of ligand 0.5equiv of ligand
Y (%) Y (%)
Ee (%)c Ee (%)c
Entry
No.
R2
1
2
27
14
15
16
28
17
18
26
19
20
21
22
23
24
Ph
Ph
OMe
OMe
92
89
59
88
92
89
8452
57
72
75
80
77
48
58
50
49
42
8d
20
76
76
44
—
—
8414
90
82
4
22
—
—
2
3
o-C6H4OMe
OMe
OMe
4
m-C6H4Me
Me
Me
5
OMe
OMe
65
67
6
7
Et
OMe
OMe
90 1
8
i-Pr
Ph
16
15
83
745
11
—
—
—
—
—
6
9
OTs
OTs
10
11
12
13
14
15
Me
Me
1476
27
15
30
6
OSi(Me)2-t-Bu
OSi(Me)2-t-Bu
OPh
—
—
—
—
—
Ph
Ph
Ph
Ph
SMe
STol
2
a Reaction conditions: toluene, MeLi (2.5equiv), T = À65ꢁC, preliminary interaction of imine 1 with ligand 1.0h, reaction time 2.5h.
b Absolute configuration of amine 3 was determined to be (S) by conversion of (À)-3 to (S)-(À)-salsolidine 4.15
c Established by HPLC with Chiracel OD-H column.
d (R)-configuration of the major enantiomer (HPLC).
imines strongly depends on the structure of substrates
(imine and nucleophile) as well as on the ligand. This ap-
proach allowed the evaluation of the effectiveness of the
ligands employed (Table 2).
tions, the amount of the ligand was successively reduced
to 0.5equiv, but in all cases the enantioselectivity was
higher with large excess (2.6equiv) of the ligand, noticed
also by others8,22 (Table 2, column 6 vs column 8). It
should be added that in the absence of ligands no addi-
tion to imine 3 occurred, under these reaction condi-
tions. Unchanged ligands could be recovered from the
crude reaction products by column chromatography.
Enantiomerically pure oxazoline ligands 14–24, listed in
Table 1, have been prepared by the reaction of (+)-thio-
micamine 6 with the appropriate nitrile according to the
known procedure,19 via the 4-hydroxymethyl precursors
7–11 or esters 12, 13. Oxazoline 9 with the methyl sub-
stituent at C-2 has been prepared by the orthoester
method.20 O-Methylation of alcohols 7–11 to give meth-
oxy derivatives 14–18, proceeded in high yield when
treated with NaH/CH3I reagents in DMF or THF. Sul-
fonyl esters 12 and 19 have been prepared by reacting
oxazolines 25 and 9, respectively, with mesyl chloride
in THF and tosyl chloride in methylene chloride, in
the presence of triethylamine. O-Silylated derivatives
20 and 21 have been obtained from alcohols 9 and 25,
respectively, in the reaction with TBDMSCl/imidazole/
DMF reagents system. A three-step procedure was
needed for the synthesis of O-phenyl 22 and S-tolyl 24
oxazolines in which intermediate sulfonates 26 and 12
were reacted with sodium phenolate and sodium thio-
phenolate in DMF, respectively. Oxazoline 23 with
methylthiomethyl group at C-4was prepared from sulf-
onate 12 via thioacetate 13 in a sequence of reactions
involving substitution of mesylate with potassium thio-
acetate and in situ hydrolysis/methylation of the latter.
The best results, in terms of the yield (92% and 89%) and
enantioselectivity (76% ee), were obtained in the reac-
tions carried out in the presence of oxazolines 16 and
28, substituted with methyl groups at the C-2 and the
C-4side chain (entries 5, 6). In general, oxazolines with
methyl group at the C-2, 16, 20, 28, produced amine 3
with a higher degree of enantioselectivity then 2-phenyl
analogues, 2, 21, 27, as evidenced by comparison of en-
tries 5, 11, 6 with entries 1, 12, 2. On the other hand,
with the increasing size of the C-2 substituent the ee of
amine 3 decreased. In the aromatic series, introduction
of o-methoxy and m-methyl group into the phenyl ring,
as in compounds 14 and 15, resulted in a decrease of ee
proportional to the size and site of the substitution,
when compared with the reaction using 2 (entries 1, 3,
4). Going from oxazoline 16 with methyl substituent at
C-2 to 17 (C-2 ethyl) and 18 (C-2 iso-propyl), the ee
dropped dramatically in the same direction (entries 5,
7, 8).
The substituent at the C-4side chain is important for the
steric course of this process as well. Introduction of
groups bulkier then methyl onto the oxygen, as in lig-
ands 19, 26, 20, 21 or phenyl in 22, resulted in reduction
of ee significantly (entries 9–13), while sulfur analogues
23 and 24 led to a nearly racemic product (entries 14,
15).
The results of the addition reactions of methyllithium to
E-imine 115 carried out in the presence of (4S,5S)-oxaz-
olines 2 (R = SCH3), 14–24, and 26–28 affording amine
3, are shown in the Table 2.
The reaction conditions, that is: toluene as the solvent,
2.5equiv of methyllithium and 2.6equiv of the ligand,
followed those established previously,8,15,22 while the
temperature was kept at À65ꢁC. In the subsequent reac-
All the (4S,5S)-ligands tested (but one, 14, entry 3) have
produced amine 3 with (S) configuration as the domi-

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3292
nant enantiomer. The absolute configuration was estab-
lished by comparison (HPLC, Chiracel OD-H column)
with a sample of (S)-(À)-3 of known configuration.15
Formation of the (R) isomer, albeit with very poor selec-
tivity, could be associated with the presence of a
third coordinating site22 in 14 at the C-2 aromatic
substituent.
tive. In the latter case the combined organic extracts
were dried and worked-up in the usual way.
4.2.1.1. (4S,5S)-4-Hydroxymethyl-2-(2-hydroxyphen-
yl)-5-[4-(methylthio)phenyl]-2-oxazoline 7. The reaction
with 2-hydroxybenzonitrile (3.6g, 30mmol) was carried
at 120ꢁC for 35h. IR (KBr), m (cmÀ1): 3225 (OH), 1640
(C@N); 1H NMR (CDCl3 + D2O) d: 2.49 (s, 3H, SCH3),
3.79 (dd, J = 11.8, 3.8Hz, 1H, CHHOH), 3.99 (dd,
J = 11.8, 3.8Hz, 1H, CHHOH), 4.31 (td, J = 7.4,
3.8Hz, 1H, H-4), 4.80 (br s, 1H, HOD), 5.50 (d,
J = 7.4Hz, 1H, H-5), 6.87–6.93 (m, 1H, ArH), 7.04
(dd, J = 8.2, 0.8Hz, 1H, ArH), 7.19–7.44 (m, 4H,
ArH), 7.73 (dd, J = 8.0, 1.6Hz, 1H, ArH); EIMS m/z
(%): 315 (M+, 47), 195 (41), 178 (12), 165 (48), 163
(7), 150 (42), 146 (11), 137 (17), 121 (100), 117 (18), 92
(13), 65 (15).
3. Conclusion
A series of homochiral monooxazoline ligands 7–24 de-
rived from (+)-thiomicamine 6 has been synthesized and
the influence of oxazoline structure on the yield and the
enantioselectivity of addition of methyllithium to pro-
chiral imine 1 has been studied. Since the addition of
organometallic reagents to imines is a substrate specific
process, the maintenance of standard reagents and con-
ditions in these experiments is an important factor.
Thus, by testing oxazolines with substituents at C-2
and C-4, of different properties, it was possible to show
that both types of effects, electronic and steric play
important roles in this process (Table 2). The addition
product, amine 3, which is a key substrate in the enan-
tioselective Pomeranz–Fritsch–Bobbitt synthesis of
tetrahydroisoquinoline derivatives, has been obtained
in high yield (up to 92%) and with enantiomeric excess
reaching 76%, when ligands 16 or 28, with methyl sub-
stituents, were applied to control this process.
4.2.1.2. (4S,5S)-4-Hydroxymethyl-5-[4-(methylthio)-
phenyl]-2-(3-tolyl)-2-oxazoline 8. The reaction with m-
tolunitrile (4.8mL, 40mmol) was carried at 125ꢁC for
1
18h. IR (KBr), m (cmÀ1): 3204(OH), 1644(C @N); H
NMR (CDCl3 + D2O) d: 2.35 (s, 3H, PhCH3), 2.48 (s,
3H, SCH3), 3.75 (dd, J = 11.8, 3.8Hz, 1H, CHHOH),
4.09 (dd, J = 11.8, 3.3Hz, 1H, CHHOH), 4.21 (td,
J = 8.0, 3.5Hz, 1H, H-4), 4.73 (br s, 1H, HOD), 5.52
(d, J = 8.0Hz, 1H, H-5), 7.22–7.34(m, 6H, ArH), 7.71
(s, 2H, ArH); EIMS m/z (%): 313 (M+, 42), 282 (28),
165 (43), 161 (100), 144 (75), 137 (26), 119 (76), 91
(46), 65 (13).
4. Experimental
4.1. General
4.2.1.3. (4S,5S)-2-Ethyl-4-hydroxymethyl-5-[4-(meth-
ylthio)phenyl]-2-oxazoline 10. The reaction using pro-
pionitrile (3.56mL, 50mmol) was carried at 115ꢁC for
1
11h. IR (KBr), m (cmÀ1): 3161 (OH), 1669 (C@N); H
Melting points: determined on a Koffler block and are
not corrected. IR spectra: Perkin–Elmer 180 in KBr pel-
lets and films. NMR spectra: Varian Gemini 300, in
CDCl3 and DMSO-d6, with TMS as internal standard.
Mass spectra (EI): Joel D-100, 75eV. Optical rotations:
Perkin–Elmer polarimeter 243B at 20ꢁC. Merck Kiesel-
gel 60 (70–230mesh) was used for column chromatogra-
phy and Merck DC-Alufolien Kieselgel 60254 for TLC.
Analytical HPLC: Waters HPLC system with Mallink-
rodt-Baker Chiracel OD-H column. (+)-Thiomicamine
was purchased from the Aldrich Chemical Co. and
used as received. MeLi was purchased from the
Acros Organics (1.6M solution in diethyl ether, low
chloride).
NMR (CDCl3 + D2O) d: 1.26 (t, J = 7.7Hz, 3H,
CH2CH3), 2.41 (dq, J = 7.6, 1.2Hz, 2H, CH2CH3),
2.48 (s, 3H, SCH3), 3.64(dd, J = 11.8, 4.1Hz, 1H,
CHHOH), 3.90 (dd, J = 11.8, 3.6Hz, 1H, CHHOH),
4.01 (ttd, J = 7.7, 3.8, 1.2Hz, 1H, H-4), 4.77 (br s, 1H,
HOD), 5.26 (d, J = 7.7Hz, 1H, H-5), 7.19–7.27 (m,
4H, ArH); EIMS m/z (%): 251 (M+, 48), 165 (17), 137
(19), 117 (11), 99 (100), 82 (44), 57 (18).
4.2.1.4. (4S,5S)-4-Hydroxymethyl-2-iso-propyl-5-[4-
(methylthio)phenyl]-2-oxazoline 11. The reaction with
iso-butyronitrile (3.6mL, 40mmol) was carried at
105ꢁC for 7.5h. IR (KBr), m (cmÀ1): 3313 (OH), 1661
(C@N); 1H NMR (CDCl3 + D2O) d: 1.27 (d,
J = 7.1Hz, 6H, CH(CH3)2), 2.48 (s, 3H, SCH3), 2.69
(dsp, J = 7.1, 1.0Hz, 1H, CH(CH3)2), 3.65 (dd,
J = 11.5, 4.4Hz, 1H, CHHOH), 3.89 (dd, J = 11.5,
3.8Hz, 1H, CHHOH), 4.01 (dtd, J = 7.5, 4.1, 1.0Hz,
1H, H-4), 4.76 (br s, 1H, HOD), 5.24 (d, J = 7.7Hz,
1H, H-5), 7.17–7.28 (m, 4H, ArH); EIMS m/z (%): 265
(M+, 59), 165 (19), 137 (17), 113 (100), 96 (47), 54
(10), 43 (30), 18 (11).
4.2. Synthesis of oxazoline ligands
4.2.1. Synthesis 4-hydroxymethyl-2-oxazolines.19 General
procedure. To a suspension of (1S,2S)-(+)-thiomicam-
ine 6 (4.26g, 20mmol) and potassium carbonate (0.43g)
in a mixture of ethylene glycol (6.4mL) and glycerol
(3.5mL) was added excess nitrile (30–50mmol). The
mixture was heated at 105–125ꢁC with stirring under
an argon atmosphere until no more oxazoline was pro-
duced (TLC, 7.5–35h). After cooling to ambient temper-
ature water was added to the mixture and the product
was collected by filtration or extracted with CH2Cl2 or
CHCl3/i-PrOH: 3/1 until the Dragendorff test was nega-
4.2.2. (4S,5S)-4-Hydroxymethyl-2-methyl-5-[4-(methyl-
thio)phenyl]-2-oxazoline 9.20 A solution of (2S,3S)-
(+)-thiomicamine 6 (10.66g, 50mmol), triethyl orthoac-
etate (1.2equiv, 10.8mL, 60mmol) and acetic acid
(125lL, 2–4mol%) in 1,2-dichloroethane (100mL) was

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3293
heated at reflux for 1.5h. After cooling to ambient tem-
perature, the mixture was poured into 20% KHCO3 and
extracted with CH2Cl2, dried and condensed under re-
duced pressure to give 11.78g yellow residue. It was
crystallized from CH2Cl2/hexane to afford 7.47g (Y:
63%) of 9. IR (KBr), m (cmÀ1): 3225 (OH), 1672
(C@N); 1H NMR (CDCl3 + D2O) d: 2.10 (d,
J = 1.4Hz, 3H, CCH3), 2.48 (s, 3H, SCH3) 3.63 (dd,
J = 11.8, 4.1Hz, 1H, CHHOCH3), 3.91 (dd, J = 11.8,
3.6Hz, 1H, CHHOCH3), 4.05–4.11 (m, 1H, H-4), 4.78
(br s, 1H, HOD), 5.24(d, J = 7.1Hz, 1H, H-5), 7.20–
7.28 (m, 4H, ArH); EIMS m/z (%): 237 (M+, 55), 165
(17), 151 (12), 137 (23), 117 (17), 85 (100), 68 (44).
4.3.2.2.
(4S,5S)-4-Methoxymethyl-2-methyl-5-[4-
(methylthio)phenyl]-2-oxazoline 16. Yellow oil. IR
(film), m (cmÀ1): 1675 (C@N); 1H NMR (CDCl3) d:
2.09 (d, J = 1.4Hz, 3H, CCH3), 2.48 (s, 3H, SCH3),
3.41 (s, 3H, OCH3), 3.51 (dd, J = 9.6, 6.3Hz, 1H,
CHHOCH3), 3.60 (dd, J = 9.6, 4.4Hz, 1H, CHHOCH3),
4.08 (qddd, J = 7.1, 6.3, 4.4, 1.4Hz, 1H, H-4), 5.24 (d,
J = 7.1Hz, 1H, H-5), 7.20–7.28 (m, 4H, ArH); EIMS
m/z (%): 251 (M+, 54), 206 (100), 192 (37), 165 (44),
137 (33), 117 (27), 99 (53), 84(21), 68 (67), 57 (56).
4.3.2.3. (4S,5S)-2-Ethyl-4-methoxymethyl-5-[4-(meth-
ylthio)phenyl]-2-oxazoline 17. Yellow oil. IR (film), m
(cmÀ1): 1668 (C@N); 1H NMR (CDCl3) d: 1.26 (t,
J = 7.5Hz, 3H, CH2CH3), 2.41 (dq, J = 7.5, 1.3Hz,
2H, CH2CH3), 2.48 (s, 3H, SCH3), 3.41 (s, 3H,
OCH3), 3.49 (dd, J = 9.6, 6.6Hz, 1H, CHHOCH3),
3.62 (dd, J = 9.6, 4.4Hz, 1H, CHHOCH3), 4.08 (tdt,
J = 6.7, 4.4, 1.3Hz, 1H, H-4), 5.24 (d, J = 6.9Hz, 1H,
H-5), 7.17–7.37 (m, 4H, ArH); EIMS m/z (%): 265
(M+, 63), 220 (87), 192 (43), 165 (53), 137 (32), 117
(18), 113 (66), 98 (47), 82 (100), 57 (46), 45 (34), 29
(36), 18 (58).
4.3. O-Methylation of oxazolines 7–11
4.3.1. Reaction in DMF
4.3.1.1. (4S,5S)-4-Methoxymethyl-2-(2-methoxyphen-
yl)-5-[4-(methylthio)phenyl]-2-oxazoline 14. To oxazo-
line 7 (3.15g, 10mmol) in DMF (29mL), NaH (1.2g,
25mmol) was added portionwise at ice-bath tempera-
ture. The mixture was stirred at this temperature for
1h before CH3I (1.6mL, 26mmol) was added. The
whole mixture was stirred at rt for 18h, then poured
onto ice. After rt was reached the mixture was extracted
with ethyl ether until the Dragendorff test was negative.
The combined organic extracts were dried and evapo-
rated. The TLC-pure oxazoline 14 (yellow oil, Y: 94%)
was used as ligand without further purification. IR
(film), m (cmÀ1): 1648 (C@N); 1H NMR (CDCl3) d:
2.48 (s, 3H, SCH3), 3.44 (s, 3H, OCH3), 3.59 (dd,
J = 9.6, 7.1Hz, 1H, CHHOCH3), 3.79 (dd, J = 9.6,
4.1Hz, 1H, CHHOCH3), 3.93 (s, 3H, ArOCH3), 4.34
(ddd, J = 7.1, 6.9, 4.1Hz, 1H, H-4), 5.44 (d,
J = 6.9Hz, 1H, H-5), 6.97–7.03 (m, 2H, ArH), 7.24–
7.35 (m, 4H, ArH), 7.42–7.48 (m, 1H, ArH), 7.83–7.86
(m, 1H, ArH), 8.03–8.06 (m, 2H, ArH); EIMS m/z
(%): 343 (M+, 21), 298 (85), 192 (43), 165 (78), 160
(100), 152 (18), 135 (70), 119 (20), 91 (13), 77 (30).
4.3.2.4. (4S,5S)-2-iso-Propyl-4-methoxymethyl-5-[4-
(methylthio)phenyl]-2-oxazoline 18. Yellow oil. IR
(film), m (cmÀ1): 1665 (C@N); 1H NMR (CDCl3) d:
1.27 (d, J = 6.9Hz, 6H, CH(CH3)2), 2.48 (s, 3H,
SCH3), 2.69 (dsp, J = 6.9, 1.0Hz, 1H, CH(CH3)2), 3.40
(s, 3H, OCH3), 3.46 (dd, J = 9.6, 6.7Hz, 1H,
CHHOCH3), 3.64(dd, J = 9.6, 4.4Hz, 1H, CHHOCH3),
4.07 (ddt, J = 6.6, 4.4, 1.0Hz, 1H, H-4), 5.24 (d,
J = 6.6Hz, 1H, H-5), 7.19–7.30 (m, 4H, ArH); EIMS
m/z (%): 279 (M+, 37), 234(68), 192 (40), 165 (63),
151 (11), 137 (32), 127 (61), 117 (10), 112 (29), 96
(100), 54(24).
4.4. Sulfonation of oxazolines 25 and 9
4.4.1. (4S,5S)-4-Mesyloxymethyl-5-[4-(methylthio)phen-
yl]-2-phenyl-2-oxazoline 12. To a suspension of oxazo-
line 2521 (2.99g, 10mmol) in THF (40mL) mesyl
chloride (1.6mL, 20mmol) and Et3N (2.7mL, 20mmol)
were added at 0ꢁC. The mixture was kept at this temper-
ature for 18h, then at rt it was washed with satd NaH-
CO3. The aqueous phase was extracted with AcOEt
until the Dragendorff test was negative. The combined
organic extracts were washed with brine, dried, and
evaporated to give crude oxazoline 12. IR (KBr), m
4.3.2. Reaction in THF. General procedure. To a sus-
pension of NaH (1.44g, 30mmol), in THF (53mL),
CH3I (2.2mL, 35mmol) was added under an argon
atmosphere at 0ꢁC. Then 4-hydroxymethyl-2-oxazoline
(20mmol) was added slowly in THF (50mL). The mix-
ture was stirred at rt for 17h, then poured onto ice. At
ambient temperature crystalline oxazoline 15 was col-
lected, while in the case of oily products, 16–18, the reac-
tion mixture was extracted with ethyl ether until the
Dragendorff test was negative. Then the organic extracts
were dried and evaporated to give crude products, pure
enough to be used without further purification.
1
(cmÀ1): 1644 (C@N); H NMR (CDCl3) d: 2.48 (s, 3H,
SCH3), 3.05 (s, 3H, SO2CH3), 4.40–4.46 (m, 2H,
CH2OMs), 4.49–4.51 (m, 1H, H-4), 5.50 (d, J = 6.9Hz,
1H, H-5), 7.25–7.28 (m, 4H, ArH), 7.43–7.58 (m, 3H,
ArH), 8.00–8.04(m, 2H, ArH); EIMS m/z (%): 377
(M+, 14), 225 (35), 146 (53), 137 (10), 130 (100), 105
(63), 77 (38).
4.3.2.1.
(4S,5S)-4-Methoxymethyl-5-[4-(methyl-
thio)phenyl]-2-(3-tolyl)-2-oxazoline 15. IR (KBr),
m
(cmÀ1): 1649 (C@N); H NMR (CDCl3) d: 2.39 (s, 3H,
PhCH3), 2.48 (s, 3H, SCH3), 3.43 (s, 3H, OCH3), 3.60
(dd, J = 9.6, 6.6Hz, 1H, CHHOCH3), 3.73 (dd, J = 9.6,
4.4Hz, 1H, CHHOCH3), 4.30 (ddd, J = 6.9, 6.6, 4.4Hz,
1H, H-4), 5.44 (d, J = 6.9Hz, 1H, H-5), 7.24–7.33 (m,
6H, ArH), 7.81–7.88 (m, 2H, ArH); EIMS m/z (%): 327
(M+, 20), 282 (41), 192 (56), 175 (23), 165 (100), 160
(27), 144 (80), 137 (37), 119 (56), 91 (50), 65 (16).
1
4.4.2. (4S,5S)-2-Methyl-5-[4-(methylthio)phenyl]-4-tosyl-
oxymethyl-2-oxazoline 19. To a solution of oxazoline 9
(0.237g, 1mmol) and triethylamine (0.33mL, 2.5mmol)
in CH2Cl2 (2mL) p-toluenesulfonyl chloride (0.24g,
1.25mmol) was added portionwise at 0ꢁC. The mixture
was kept at this temperature for 48h. After rt was

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3294
reached, the crystals of Et3NÆHCl were removed by fil-
tration and filtrate was washed with 1% NaOH
(2 · 10mL), 20% NH4Cl and water (25mL), dried
(Na2SO4) and concentrated. The crude product was
crystallized from methanol to give pure oxazoline 19
as a colorless crystals. IR (KBr), m (cmÀ1): 1669
4.1Hz, 1H, CHHOPh), 4.55 (ddd, J = 7.7, 6.6, 4.1Hz,
1H, H-4), 5.60 (d, J = 6.6Hz, 1H, H-5), 6.93–7.00 (m,
3H, ArH), 7.26–7.35 (m, 6H, ArH), 7.43–7.57 (m, 3H,
ArH), 8.04–8.07 (m, 2H, ArH); EIMS m/z (%): 375
(M+, 60), 345 (100), 281 (14), 268 (74), 240 (12), 223
(12), 165 (98), 151 (11), 137 (26), 133 (93), 105 (44), 91
(72), 84(60), 68 (100), 44(43).
1
(C@N); H NMR (CDCl3) d: 2.05 (d, J = 1.1Hz, 3H,
CCH3), 2.46 (s, 3H, ArCH3), 2.49 (s, 3H, SCH3),
4.05–4.11 (m, 2H, CH2OTs), 4.28–4.38 (m, 1H, H-4),
5.24(d, J = 6.0Hz, 1H, H-5), 7.13–7.36 (m, 6H, ArH),
7.70–7.81 (m, 2H, ArH); EIMS m/z (%): 391 (M+, 37),
219 (23), 206 (81), 175 (35), 137 (24), 133 (93), 91 (72),
84(60), 68 (100), 44(43).
4.7. (4S,5S)-5-[4-(Methylthio)phenyl]-2-phenyl-4-tolyl-
thiomethyl-2-oxazoline 24
To a mixture of p-methyl-thiophenol (1.24g, 10mmol)
in DMF (8mL), NaH (0.480g, 10mmol) was added at
0ꢁC. After half an hour mesylate 12 (1.51g, 4mmol) in
DMF (10mL) was added. The mixture was stirred at
this temperature for 20h, then poured onto ice. After
rt was reached the solid was filtered off, dissolved in
ethyl ether, washed with 5% NaOH (2 · 10mL) and
20% NH4Cl (2 · 10mL) and dried. The crude product
was crystallized from Et2O to give oxazoline 24 as col-
orless crystals. IR (KBr), m (cmÀ1): 1640 (C@N); 1H
NMR (CDCl3) d: 2.29 (s, 3H, ArCH3), 2.48 (s, 3H,
SCH3), 2.98 (dd, J = 13.5, 9.3Hz, 1H, CHHSAr), 3.49
(dd, J = 13.5, 3.8Hz, 1H, CHHSAr), 4.30 (ddd, J = 9.3,
6.0, 3.8Hz, 1H, H-4), 5.50 (d, J = 6.0Hz, 1H, H-5),
7.03–7.06 (m, 2H, ArH), 7.21–7.28 (m, 6H, ArH),
7.41–7.55 (m, 3H, ArH), 7.98–8.00 (m, 2H, ArH); EIMS
m/z (%): 405 (M+, 12), 358 (59), 268 (59), 165 (100), 137
(52), 130 (86), 123 (12), 105 (69), 91 (16), 77 (56).
4.5. O-Silylation of oxazolines 9 and 25. General
procedure
The oxazoline (1mmol), TBDMSCl (0.30g, 2mmol),
and imidazole (0.15g, 2.2mmol) in DMF (1mL) were
stirred at rt for 1.5h, then poured onto ice (7g). When
the mixture reached rt it was extracted with ethyl ether
until the Dragendorff test was negative. The organic ex-
tracts were dried and the solvent evaporated. TLC-pure
oxazolines 20 and 21 were used as ligand without further
purification.
4.5.1.
(4S,5S)-4-[(t-Butyl)dimethylsilyloxy]methyl-2-
methyl-5-[4-(methylthio)phenyl]-2-oxazoline 20. Color-
less oil. IR (film), m (cmÀ1): 1646 (C@N), 1252, 814
(Si-CH3); 1H NMR (CDCl3) d: 0.07 (s, 3H, SiCH3),
0.08 (s, 3H, SiCH3), 0.90 (s, 9H, SiC(CH3)3), 2.08 (d,
J = 1.1Hz, 3H, CH3), 2.48 (s, 3H, SCH3), 3.63 (dd,
J = 10.2, 6.9Hz, 1H, CHHOSi), 3.87 (dd, J = 10.2,
3.8Hz, 1H, CHHOSi), 3.99 (qddd, J = 6.9, 6.3, 3.8,
1.4Hz, 1H, H-4), 5.32 (d, J = 6.3Hz, 1H, H-5), 7.20–
7.27 (m, 4H, ArH); EIMS m/z (%): 351 (M+, 1), 294
(50), 264 (49), 252 (19), 206 (18), 190 (10), 142 (10),
137 (100), 73 (26).
4.8. Synthesis of oxazoline 23
4.8.1. (4S,5S)-5-[4-(Methylthio)phenyl]-2-phenyl-4-thio-
acetoxylmethyl-2-oxazoline 13. Mesylate 12 (2.17g,
5.76mmol) and potassium thioacetate (6.05g, 53mmol)
in DMF (50mL) were stirred at rt for 21h, then poured
onto ice. After rt was reached the solid was filtered off,
air-dried and crystallized from CHCl3 to give colorless
crystals. IR (KBr), m (cmÀ1): 1642 (C@N), 1688
(SCOCH3); 1H NMR (CDCl3) d: 2.38 (s, 3H, SCOCH3),
2.48 (s, 3H, SCH3), 3.31 (dd, J = 13.7, 6.0Hz, 1H,
CHHSCOCH3), 3.43 (dd, J = 13.7, 4.9Hz, 1H,
CHHSCOCH3), 4.40 (ddd, J = 6.9, 6.0, 4.9Hz, 1H, H-
4), 5.22 (d, J = 6.9Hz, 1H, H-5), 7.23–7.29 (m, 3H,
ArH), 7.41–7.55 (m, 4H, ArH), 8.00–8.04 (m, 2H,
ArH); EIMS m/z (%): 357 (M+, 8), 282 (43), 268 (34),
165 (27), 162 (100), 137 (18), 130 (73), 105 (41), 77
(42), 59 (16).
4.5.2. (4S,5S)-4-[(t-Butyl)dimethylsilyloxy]methyl-5-[4-
(methylthio)phenyl]-2-phenyl-2-oxazoline 21. Colorless
oil. IR (film), m (cmÀ1): 1650 (C@N), 1253, 814(Si-
1
CH3); H NMR (CDCl3) d: 0.07 (s, 3H, SiCH3), 0.08
(s, 3H, SiCH3), 0.88 (s, 9H, SiC(CH3)3), 2.48 (s, 3H,
SCH3), 3.74(dd, J = 10.2, 7.1Hz, 1H, CHHOSi), 4.01
(dd, J = 10.2, 3.8Hz, 1H, CHHOSi), 4.22 (ddd, J = 7.1,
6.0, 3.8Hz, 1H, H-4), 5.53 (d, J = 6.0Hz, 1H, H-5),
7.23–7.53 (m, 7H, ArH), 8.00–8.03 (m, 2H, ArH); EIMS
m/z (%): 413 (M+, 1), 356 (100), 326 (52), 268 (22), 165
(17), 137 (80), 105 (58), 77 (22), 73 (18).
4.8.2. (4S,5S)-5-[4-(Methylthio)phenyl]-2-phenyl-4-thio-
methoxymethyl-2-oxazoline 23. The oxazoline 13
(1.071g, 3mmol) was stirred in 5% methanolic KOH
solution (2.1equiv KOH, 7.5mL) at rt for 24h under
an argon atmosphere. The mixture was concentrated un-
der reduced pressure, the residue was dissolved in DMF
(9mL), cooled to 0ꢁC and treated with CH3I (0.77mL,
12mmol). The mixture was stirred at rt for 24h, then
poured onto ice. At ambient temperature it was ex-
tracted with CH2Cl2 until the Dragendorff test was neg-
ative and washed with 20% NH4Cl. The organic extracts
were dried and the solvent evaporated. The residue was
crystallized from CH2Cl2/hexane to afford colorless
4.6. (4S,5S)-5-[4-(Methylthio)phenyl]-2-phenyl-4-phen-
oxymethyl-2-oxazoline 22
Oxazoline 2612 (453mg, 1mmol) was stirred with phenol
(0.113g, 1.2mmol) and K2CO3 (0.70g, 5mmol) in DMF
(10mL) at rt for 48h, then poured onto ice. After rt was
reached the solid was filtered off. It was washed with
water and air-dried to give crude product. Crystalliza-
tion from EtOH/i-Pr2O afforded pure oxazoline 22 as
a colorless crystals. IR (KBr), m (cmÀ1): 1645 (C@N);
1H NMR (CDCl3) d: 2.49 (s, 3H, ArSCH3), 4.11 (dd,
J = 9.3, 7.7Hz, 1H, CHHOPh), 4.38 (dd, J = 9.3,
1
crystals. IR (KBr), m (cmÀ1): 1644 (C@N); H NMR

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A. Głuszynska, M. D. Rozwadowska / Tetrahedron: Asymmetry 15 (2004) 3289–3295
3295
(CDCl3) d: 2.13 (s, 3H, CH2SCH3), 2.48 (s, 3H,
References
ArSCH3), 2.71 (dd, J = 13.5, 8.5Hz, 1H, CHHSCH3),
3.03 (dd, J = 13.5, 4.1Hz, 1H, CHHSCH3), 4.33–4.39
(m, 1H, H-4), 5.47 (d, J = 6.0Hz, 1H, H-5), 7.24–7.33
(m, 4H, ArH), 7.42–7.56 (m, 3H, ArH), 8.02–8.06 (m,
2H, ArH); EIMS m/z (%): 329 (M+, 11), 268 (97), 208
(48), 165 (75), 162 (22), 150 (16), 137 (47), 130 (100),
122 (17), 105 (89), 91 (12), 77 (80), 61 (26), 51 (16).
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of (S)-(À)-3, after transformation into (S)-salsolidine 4
of known absolute stereochemistry.15
´
´
12. Brozda, D.; Chrzanowska, M.; Głuszynska, A.; Rozwa-
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´
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Acknowledgements
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This work was supported by a research grant from the
State Committee for Scientific Research in the year
2003–2006 (KBN grant no. 4T09A 07824).