Modular synthesis of chiral pentadentate bis(oxazoline) ligands

Article abstract of DOI:10.1016/j.tet.2006.08.003

Highly modular N,Y,Z,Y,N-ligands (Y=N, O, S; Z=N, NO, OH, OMe) have been prepared using bis(oxazoline) building blocks either as nucleophiles or as electrophiles in coupling reactions with central aromatic units. This way, a great variety of pentadentate

Full text of DOI:10.1016/j.tet.2006.08.003

Tetrahedron 62 (2006) 9973–9980
Modular synthesis of chiral pentadentate bis(oxazoline) ligands
Michael Seitz, Anja Kaiser, Alexander Tereshchenko, Christian Geiger,
*
Yukitaka Uematsu and Oliver Reiser
Institut fu€r Organische Chemie, Universita€t Regensburg, Universita€tsstr. 31, D-93040, Germany
Received 14 July 2006; accepted 1 August 2006
Available online 23 August 2006
Abstract—Highly modular N,Y,Z,Y,N-ligands (Y¼N, O, S; Z¼N, NO, OH, OMe) have been prepared using bis(oxazoline) building blocks
either as nucleophiles or as electrophiles in coupling reactions with central aromatic units. This way, a great variety of pentadentate bis(oxazo-
line) ligands in diastereo- and enantiomerically pure form become readily available, which are useful for the construction of helical metal
complexes with predetermined chirality.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
mononuclear metal complexes as well as polymeric
organic–inorganic hybrid materials.7 As part of our efforts
to extend the versatility of this system we have worked out
a modular synthesis for a variety of diverse bis(oxazoline)
ligands of the general structure 1 (Scheme 1), demonstrating
the use of oxazolines both as nucleophilic and electrophilic
building blocks.
Modular ligand design allows for the facile tailoring of
properties of the corresponding metal complexes for a given
application. This concept has especially been utilized in
asymmetric catalysis for the fine-tuning of reactivity as
well as the geometric environment of a chiral catalyst.
One of the most successful ligand motifs for this purpose
over the last decades has been the oxazoline moiety.1 Since
their chiral information in most cases stems from readily
available enantiopure amino acids, oxazoline ligands with
broad stereochemical diversity are available. Beyond this
intrinsic modularity, many successful oxazoline-based
ligand systems have been developed with additional degrees
of structural variability.2–5 Generally, oxazoline ligands are
build up by coupling of an amino acid derivative—most
prominently amino alcohols—to a backbone followed by
cyclization, the latter step often requiring forcing conditions.
The incorporation of already preformed oxazoline moieties
into a backbone has hardly been explored so far,6 despite
the potential advantage of a more convergent assembly of
such structures. Difficulties with respect to the stability of
the oxazoline units are often encountered in such trans-
formations,6a,6h which have prevented by enlarge the
identification of suitable oxazoline building blocks as trans-
ferable units and reaction conditions amenable for such an
approach.
The generic structure 1 features a number of attractive char-
acteristics to be explored for metal complexes. Firstly, the
range of central units Z can be broadly varied. Besides a pyr-
idine moiety that proved to be useful to generate a number of
mononucleating complexes,7 we also aimed at the synthesis
of ligands with pyridine-N-oxide and related phenol/anisol
building blocks being known to be able to accommodate
two metal centers in close proximity, which could lead to bi-
nucleating ligands that could bear significance for a number
of applications like asymmetric catalysis8 or bioinorganic
chemistry.9 Secondly, the benzylic heteroatoms Y allow for
facile variation of the donor set around the metal. In addi-
tion, they also serve as the nucleophilic part in the connec-
tion of the central unit Z and the peripheral oxazolines via
a synthetically universal nucleophilic displacement reaction
(Scheme 1, reaction between 2 and 5, 4 and 7). Thirdly, the
variation of R1 and R2 on the oxazoline moieties enables the
tuning of the steric bulk around the metal center in a straight-
forward manner.
The outlined synthetic strategy has the following advantages:
(a) Generation of diversity is efficiently achieved in the final
assembly step by the coupling of entire oxazoline units with
the central building blocks Z. This appears to be more eco-
nomic than in many other oxazoline containing systems
with early introduction of the diversifying element (usually
amino alcohols) followed by subsequent manipulations
We recently reported on metal complexes of pentadentate
bis(oxazoline) ligands 1 (Z¼pyridinyl) for the construction
of enantiomerically pure helical assemblies, including
* Corresponding author. Tel.: +49 941 9434631; fax: +49 941 9434121;
e-mail: oliver.reiser@chemie.uni-regensburg.de
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.003

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M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
Z
Y
N
Y
Z
=
R2
R2
N
OH
OMe
O
O
OMe
R1
R1
1
N
N
O
Z
Z
Z
YH
YH
OH
OH
X
X
2 (Electrophile)
3
4 (Nucleophile)
Y
= O, S, NMe
X
= Cl, Br, OMs, OTs
+
+
R1 = Ph, Me, t-Bu
R2
R2
R2
O
O
O
N
R2 = H, p-MeS-C6H4
R1
R1
R1
X
YH
OH
N
N
5 (Nucleophile)
6
7 (Electrophile)
Scheme 1. Synthetic strategy for the modular bis(oxazoline) ligand system 1.
14
(e.g., ring closure to the oxazoline); (b) The final SN2 reaction
in principle has an almost universal scope. In addition, the
reactionpartners Z and the oxazoline can both serve as nucleo-
philes (4 or 5), as well as electrophiles (2 or 7), making this
process very flexible. Conveniently, each set of building
blocks can be derived from common precursors (Scheme 1,
3 for 2 and 4, 6 for 5 and 7).
(Scheme 3). Oxidation with SeO2 to bis(aldehyde) 14
and formation of the bis(imine) with methylamine in anal-
ogy to a reported procedure15 was followed by reduction
with NaBH4 to yield the previously unknown air-sensitive
bis(amine) 15. Equally air-sensitive bis(thiol) 16 was acces-
sible with improved yields from dibenzyl chloride 8 in a
modified7d two-step procedure reported by Chiotellis10 and
co-workers.
2. Results and discussion
1. MeNH3Cl, K2CO3
N
2. NaBH4, EtOH
51%
N
2.1. Synthesis of the central units
NH
HN
O
O
Me
Me
14
15
For the synthesis of the electrophilic pyridine building blocks
(Scheme2), commerciallyavailable 2,6-bis(hydroxymethyl)-
pyridinewas converted to the dibenzyl chloride 8 with SOCl2
and subsequent treatment with base.10 The corresponding
N-oxide 10 was prepared under standard conditions with
AcOH/H2O2.11 The more reactive dibenzyl bromide 9 was
accessible from 2,6-lutidine by radical bromination with
NBS.12 The phenol- or anisol-based electrophilic building
blocks 11–13 were readily accessible from 4-methyl- and
4-tert-butylphenol.13
1. thiourea, EtOH,
reflux, Ar-atmosphere
N
N
2. NaOH, H2O, reflux
64%
Cl
Cl
SH
SH
8
16
Scheme 3. Synthesis of pyridine building blocks used as nucleophiles.
2.2. Synthesis of the oxazoline units
The range of nucleophilic oxazoline units was restricted to
compounds of type 6 having alcohol functionalities. The cor-
responding primary amines and thiols proved to be unstable
due to the formation of the corresponding imidazolines and
thiazolines by attack on the oxazoline ring. The stable
primary alcohol building blocks 20, 22–24 were prepared
from amino alcohols and imidates or nitriles (Scheme 4).
Compound 20 was synthesized by condensation of imidate
18a with (S)-serine methyl ester hydrochloride (17), followed
by reduction of the corresponding methyl ester 19 with
LiAlH4.16 Oxazoline 23 was accessible starting from benzo-
nitrile and commercially available aminodiol 21.17 The
methyl substituted analog 22 could also be prepared by this
methodology, whereas the tert-butyl derivative 24 required
the use of more reactive imidate 18b instead of pivalonitrile.
X
X
Cl
Cl
N
N
O
8: X = Cl
9: X = Br
10
CH3
R
Br
Br
Br
Br
OH
O
11
12: R = Me
13: R = t-Bu
Scheme 2. Pyridine, phenol, and anisol building blocks used as electro-
philes.
Transformation of these nucleophilic building blocks to
electrophiles was conveniently achieved by their conversion
The preparation of nucleophilic pyridine building
blocks again started from 2,6-bis(hydroxymethyl)pyridine

M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
9975
NH
O
N
Ph OEt
18a
NH3Cl
OH
Ph
O
N
N
OH
Ph
O
N
O
N
20
MeO2C
(CH2Cl)2
CO2Me
N
NaH, DMF
0°C to rt
reflux, 20 h
90%
Cl
Cl
O
O
19
17
8
Ph
Ph
O
N
LiAlH4
29 (88%)
Ph
THF
–35°C to 0°C
Ar
O
OH
64%
R
N
OH
23-24
N
20
O
N
O
N
N
SMe
NaH, DMF
0°C to rt
Ar
Ar
Br
Br
MeS
NH2
OH
9
O
O
O
N
R-CN
R
R
R
K2CO3, ∆
Ar = 4-MeS-Ph
OH
30 (R = Ph): 83%
31 (R = t-Bu): 62%
OH
21
22 (R = Me): 70%
23 (R = Ph): 86%
O
SMe
NH
Ph
N
OH
t
N
20
OEt
18b
Bu
O
N
O
O
N
O
N
N
O
t
Bu
NaH, DMF
0°C to rt
Cl
Cl
Ph-Cl, reflux
62%
OH
O
O
24
10
Ph
Ph
Scheme 4. Synthesis of oxazoline building blocks used as nucleophiles.
32 (53%)
to the corresponding sulfonic acid esters (Scheme 5). Com-
pounds 25a18a and 25b18b were synthesized according to
literature precedence. For the sterically more hindered oxa-
zolines 22–24, the tosylates proved to be ineffective in
subsequent transformations. Therefore, the more reactive
mesylates 26–28 were prepared.
R
O
R
Ph
OH
N
20
O
N
OR1
O
N
NaH, DMF
0°C to rt
Br OR1 Br
O
O
N
O
O
MsCl or TsCl
NEt3
Ph
Ph
Ph
Ph
OR1
OH
N
11-13
33 (R = Me, R1 = H): 35%
25a (R1 = Ms): 96%
25b (R1 = Ts): 78%
34 (R = Me, R1 = Me): 69%
20
35 (R = t-Bu, R1 = Me): 54%
SMe
SMe
Scheme 6. Ligand synthesis with nucleophilic oxazoline building blocks.
O
O
N
Ms-Cl, NEt3
CH2Cl2, rt
While with 20, 23, and 24 the reactions proceeded already at
0 ꢀC, the sterically more hindered oxazolines 26–28 required
elevated temperatures (70–80 ꢀC) and more reactive electro-
philes (benzyl bromide 9 and mesylates 26–28). In the case
of 2-methyl substituted oxazolines 22 and 26, only the thio-
ether ligand 37 (reaction of 16 with 26) but not the corre-
sponding oxoether ligand (reaction of 9 with 22 in analogy
to the preparation of 30–31) could be obtained and only in
low yield, presumably due to side reactions originating
from competing deprotonation at the methyl group.
R
R
OMs
N
OH
22 (R = Me)
23 (R = Ph)
24 (R = t-Bu)
26 (R = Me): 89%
27 (R = Ph): 92%
28 (R = t-Bu): 68%
Scheme 5. Synthesis of oxazoline building blocks used as electrophiles.
2.3. Assembly of the bis(oxazoline) ligands
The connection between the central aromatic unit and the
peripheral oxazolines was achieved via SN2 displacement
reactions, combining the appropriate electrophilic and
nucleophilic building blocks. Oxazolines 20, 23, and 24
smoothly reacted as nucleophiles upon deprotonation with
sodium hydride with the biselectrophiles 8–13 to give rise
to the bis(oxazolines) 29,7b 30–35 (Scheme 6). Likewise,
oxazolines 25–28 could be reacted as nucleophiles to yield
the ligands 36,7d 37–41 (Scheme 7), however, for the bis-
amine 15 K2CO3 instead of NaH had to be employed.
All ligands were obtained as single stereoisomers, as judged
by their NMR spectra, HPLC traces, and spectroscopical
data (NMR, CD) of their corresponding metal complexes.7
Consequently, no racemization of the oxazoline building
blocks introduced here for the modular assembly of the pen-
tadentate bis(oxazoline) ligands should have occurred.
In conclusion, we have developed oxazoline building blocks
that can be employed both as nucleophiles as well as

9976
M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
MeOH, and hexanes for chromatographic separations were
O
N
distilled before use. For column chromatography silica gel
Geduran 60 (Merck, 0.063–0.200 mm) was used. TLC
analysis was done on silica gel 60 F254 (Merck) coated on
aluminum sheets.
Ph
N
OTs
25b
S
N
S
N
NaH, DMF
0°C to rt
O
O
Ph
Ph
3.1.1. 2,6-Bis(N-methylaminomethyl)pyridine (15). A so-
lution of methylamine hydrochloride (3.95 g, 58.5 mmol,
2.4 equiv) in MeOH (100 mL) was cooled to 0 ꢀC and
treated with K2CO3 (9.42 g, 68.2 mmol, 2.8 equiv). After
stirring for 1 h in an ice bath, pyridine-2,6-dicarbaldehyde
(14) (3.29 g, 24.3 mmol, 1.0 equiv) was added. The mixture
was stirred at ambient temperature for further 3 h and the
solvent was evaporated. The solid residue was taken up in
150 mL CH2Cl2 and the suspension stirred for 1 h. After
filtering off the solid, the solvent was evaporated to yield
2,6-bis(methyliminomethyl)pyridine as a yellow oil (2.97 g,
76%). No further purification of the product was necessary
for the next step. The analytical data correspond with the
literature.15 1H NMR (300 MHz, CDCl3): d 8.31 (s, 1H),
8.32 (s, 1H), 7.85 (d, J¼7.7 Hz, 2H), 7.68 (t, J¼7.7 Hz,
1H), 3.48 (s, 3H), 3.47 (s, 3H); 13C NMR (75.5 MHz,
CDCl3): d 163.0, 154.2, 137.0, 121.9, 48.0.
36 (72%)
16
Ar
OMs
O
N
R
N
26-28
NaH, DMF
60°C
S
S
Ar
Ar
N
R
N
O
O
(Ar = 4-MeS-Ph)
R
37 (R = Me): 32%
38 (R = Ph): 71%
39 (R = t-Bu): 65%
O
Ph
N
OMs
N
NMe MeN
25a
K2CO3, CH3CN
reflux
To a solution of 2,6-bis(methyliminomethyl)pyridine (2.62 g,
16.3 mmol, 1.0 equiv) in dry EtOH (40 mL) was added
NaBH4 (1.23 g, 32.5 mmol, 2.0 equiv) in portions. The solu-
tion was stirred for 16 h and water (40 mL) was added cau-
tiously. This solution was extracted with 3ꢁ40 mL CH2Cl2,
the combined organic phases dried (MgSO4), and the solvent
evaporated. The residue was distilled (bp 97–100 ꢀC/
0.08 mbar) to yield 15 as a yellow oil (1.81 g, 67%), which
N
N
O
O
Ph
Ph
40 (62%)
15
Ar
OMs
O
N
Ph
N
27
NMe MeN
1
was stored under nitrogen at 4 ꢀC. H NMR (300 MHz,
K2CO3, CH3CN
reflux
CDCl3): d 7.60 (t, J¼7.6 Hz, 1H), 7.16 (d, J¼7.6 Hz, 2H),
3.85 (s, 4H), 2.48 (s, 6H), 1.78 (br s, 2H); 13C NMR
(75.5 MHz, CDCl3): d 159.3, 136.7, 120.4, 57.2, 36.2; MS
(DCI, NH3): m/z (%)¼167.2 (10), 166.2 (100); HRMS (EI)
calcd for C9H14N3 [MꢂH]+ 164.1188, found 164.1189.
Ar
Ar
N
N
O
O
(Ar = 4-MeS-Ph)
Ph
Ph
41 (51%)
Scheme 7. Ligand synthesis with electrophilic oxazoline building blocks.
3.1.2. 2,6-Bis(mercaptomethyl)pyridine10 (16). 2.49 g
(14.2 mmol, 1.0 equiv) of 2,6-bis(chloromethyl)pyridine
(8) was reacted under Argon atmosphere with 2.16 g
(28.4 mmol, 2.0 equiv) of thiourea in refluxing ethanol
(30 mL, degassed) for 30 min. After cooling to ambient tem-
perature, 11.2 mL of 5 M NaOH (degassed) was added and
the solution was refluxed for additional 4 h. Afterward the
pH was adjusted to 5–6 with 6 M HCl and the mixture
extracted twice with 30 mL CHCl3. The organic layers
were combined and dried over MgSO4. Evaporation of the
solvent followed by vacuum Kugelrohr distillation afforded
electrophiles, this way opening up a facile strategy to new
structures containing such moieties. This approach was
applied to the synthesis of pentacoordinating bis(oxazoline)
ligands containing a central pyridine unit, which have shown
a rich coordination chemistry to arrive at helical metal com-
plexes.7 Moreover, the strategy could be extended to novel
ligands with central pyridine-N-oxide, phenol, and anisole
units that might have potential for the construction of bi-
nucleating complexes.
1
1.53 g (9.0 mmol, 63%) of 16 as a colorless oil. H NMR
3. Experimental
3.1. General
(300 MHz, CDCl3): d 7.62 (t, J¼7.7 Hz, 1H), 7.21 (d,
J¼7.7 Hz, 2H), 3.82 (d, J¼8.0 Hz, 4H), 2.03 (t, J¼8.0 Hz,
2H); 13C NMR (75.5 MHz, CDCl3): d 159.9, 137.8, 120.5,
30.8.
All reactions were carried out under a dry, oxygen-free
atmosphere of N2 using Schlenk technique, unless otherwise
noted. Commercially available reagents were used as
received. DMF, CH3CN, and CH2Cl2 were distilled over
3.1.3. (4S,5S)-4-Hydroxymethyl-2-methyl-5-(4-methyl-
sulfanylphenyl)-oxazoline
(22).
(1S,2S)-2-Amino-1-
(4-methylsulfanylphenyl)-1,3-propandiol (21) (5.00 g,
23.4 mmol, 1.00 equiv) and K2CO3 (0.500 g, 3.60 mmol,
0.15 equiv) were suspended in a mixture of ethylene glycol
(10 mL) and glycerine (5 mL). Acetonitrile (2.5 mL, 1.92 g,
46.8 mmol, 2.0 equiv) was added and the resulting mixture
˚
P4O10 and stored under N2 over molecular sieves 3 A.
EtOH and MeOH were dried over Mg and stored under
N2. THF, 1,4-dioxane, and Et2O were dried with Na/benzo-
phenone and stored over Na wire under N2. EtOAc, CH2Cl2,

M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
9977
stirred at 110 ꢀC for 24 h. The product crystallized upon
cooling to room temperature. The crystallization was com-
pleted by adding water (100 mL). The precipitate was col-
3.2. General procedure (GP1) for the synthesis
of mesylates 26–28
€
lected on a Buchner funnel, washed with water (100 mL),
The oxazoline (22–24) (1.0 equiv) and triethylamine
(2.0 equiv) were dissolved in dry dichloromethane (20 mL)
and cooled down to 0 ꢀC. Methanesulfonyl chloride
(2.0 equiv) was added dropwise. The mixture was allowed
to warm up to room temperature and stirred for additional
12 h, before satd NaHCO3 (20 mL) was added. The organic
phase was separated and the aqueous layer was extracted
three times with dichloromethane (20 mL). The combined
organic layers were dried (MgSO4) and the solvent evapo-
rated under reduced pressure. The crude product was puri-
fied by chromatography or recrystallization.
and n-hexane (50 mL). The crude product was recrystallized
from dichloromethane yielding 22 as a colorless solid
(3.87 g, 70%). Rf 0.27 (CHCl3/MeOH 19:1); mp 99–100 ꢀC;
[a]2D0 ꢂ154.0 (c 1.01, CHCl3); 1H NMR (400 MHz, DMSO-
d6): d 7.27–7.20 (m, 4H), 5.24 (d, J¼6.3 Hz, 1H), 4.88 (t,
J¼5.7 Hz, 1H), 3.80–3.74 (m, 1H), 3.61–3.54 (m, 1H),
3.45–3.38 (m, 1H), 2.45 (s, 3H), 1.97 (d, J¼1.3 Hz, 3H);
13C NMR (100.6 MHz, DMSO-d6): d 163.3, 138.2, 137.7,
126.1, 126.0, 82.0, 76.6, 63.0, 14.7, 13.6; IR (KBr): 3240,
2950, 2921, 2867, 1673; MS (PI-DCI, NH3): m/z
(%)¼238.0 (100, [MH]+); elemental analysis calcd (%) for
C12H15NO2S (237.32): C 60.73, H 6.37, N 5.90, found: C
60.49, H 6.21, N 5.84.
3.2.1. (4S,5S)-2-Methyl-4-mesyloxymethyl-5-(4-methyl-
sulfanylphenyl)-oxazoline (26). Compound 22 (1.00 g,
4.21 mmol) was reacted according to GP1 to yield 26
(1.18 g, 89%) as a colorless solid after recrystallization
from CH3CN. Rf 0.41 (CHCl3/MeOH 19:1); mp 70–73 ꢀC;
[a]2D0 ꢂ46.5 (c 0.99, CHCl3); 1H NMR (250 MHz, CDCl3):
d 7.28–7.18 (m, 4H), 5.28 (d, J¼6.9 Hz, 1H), 4.39 (dd,
J¼10.4, 4.6 Hz, 1H), 4.34 (dd, J¼10.4, 5.0 Hz, 1H), 4.21
(dddq, J¼6.9, 5.0, 4.6, 1.3 Hz, 1H), 3.06 (s, 3H), 2.48 (s,
3H), 2.11 (d, J¼1.3 Hz, 3H); 13C NMR (62.0 MHz,
CDCl3): d 166.8, 139.5, 136.2, 126.9, 126.2, 82.7, 73.4,
69.8, 37.7, 15.7, 14.2; IR (KBr): 3011, 2928, 1672; MS
(PI-DCI, NH3): m/z (%)¼316.0 (100, [MH]+); elemental
analysis calcd (%) for C13H17NO4S2 (315.41): C 49.50, H
5.43, N 4.44, found: C 48.97, H 5.41, N 4.34.
3.1.4. (4S,5S)-4-Hydroxymethyl-5-(4-methylsulfanyl-
phenyl)-2-tert-butyl-oxazoline (24). 2,2-Dimethyl-propio-
nimidic acid ethyl ester (18b) (0.381 g, 2.95 mmol,
1.0 equiv) was dissolved in dry chlorobenzene (10 mL)
and (1S,2S)-2-amino-1-(4-methylsulfanylphenyl)-1,3-prop-
andiol (21) (0.756 g, 3.54 mmol, 1.2 equiv) was added.
The resulting mixture was refluxed for 18 h. After cooling
to room temperature, the solvent was evaporated and the
residue purified by column chromatography (SiO2, hex-
anes/EtOAc 1:3) to yield 24 (0.513 g, 62%) as a colorless
solid. Rf 0.12 (hexanes/EtOAc 1:3); mp 66–68 ꢀC; [a]D20
ꢂ62.6 (c 1.25, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.23–7.15 (m, 4H), 5.20 (d, J¼7.5 Hz, 1H), 3.97 (ddd,
J¼7.5, 4.4, 4.3 Hz, 1H), 3.82 (dd, J¼11.6, 4.3 Hz, 1H),
3.64 (dd, J¼11.6, 4.4 Hz, 1H), 2.44 (s, 3H), 1.28 (s, 9H);
13C NMR (100.6 MHz, CDCl3): d 175.5, 138.6, 137.8,
126.9, 126.1, 82.5, 76.4, 63.9, 33.5, 27.9, 15.8; IR (KBr):
3360, 3222, 2974, 2930, 2870, 1735, 1657, 1600; MS (CI,
NH3): m/z (%)¼280.1 (100, [MH]+); elemental analysis
calcd (%) for C15H21NO2S (279.40): C 64.48, H 7.58, N
5.01, found: C 64.01, H 7.21, N 4.68.
3.2.2. (4S,5S)-4-Mesyloxymethyl-5-(4-methylsulfanyl-
phenyl)-2-phenyl-oxazoline (27). Compound 23 (0.500 g,
1.67 mmol) was reacted according to GP1 to yield 27
(0.58 g, 92%) as a slightly yellow solid after recrystalliza-
tion from CH3CN. Rf 0.34 (hexanes/EtOAc 1:1); mp 102–
1
104 ꢀC; [a]D20 +29.6 (c 0.90, CHCl3); H NMR (250 MHz,
CDCl3): d 8.05–8.00 (m, 2H), 7.59–7.40 (m, 3H), 7.34–
7.28 (m, 4H), 5.50 (d, J¼6.6 Hz, 1H), 4.52–4.47 (m, 2H),
4.46–4.38 (m, 1H), 3.05 (s, 3H), 2.46 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): d 165.3, 139.5, 136.3, 132.0, 128.6,
128.5, 126.9, 126.7, 126.2, 82.7, 73.8, 69.9, 37.7, 15.6; IR
(KBr): 3012, 2923, 1645, 1494, 1450, 1357, 1329, 1170,
1090, 1063, 978, 958, 916, 844, 800, 692, 534; MS (PI-
DCI, NH3): m/z (%)¼378.1 (100, [MH]+); elemental analy-
sis calcd (%) for C18H19NO4S2 (377.48): C 57.27, H 5.07, N
3.71, found: C 57.26, H 5.06, N 3.79.
3.1.5. (S)-2-Phenyl-4-mesyloxymethyl-oxazoline (25a).
Under N2 (R)-4-hydroxymethyl-2-phenyl-oxazoline (20)
(3.01 g, 17.0 mmol, 1.0 equiv) was dissolved in 40 mL dry
THF and cooled to ꢂ25 ꢀC (external temperature). Dry
NEt3 (2.60 mL, 1.89 g, 18.7 mmol, 1.1 equiv) and methane-
sulfonyl chloride (1.38 mL, 2.04 g, 17.8 mmol, 1.05 equiv)
were added subsequently. The mixture was stirred at
ꢂ25 ꢀC for 30 min, before water (50 mL) and CH2Cl2
(80 mL) were added. The organic layer was separated, dried
(MgSO4), and the solvent evaporated under reduced pres-
sure. The crude yellow oil (4.17 g, 96%) was used for the
subsequent steps without further purification. An analytical
sample of 25a was obtained by column chromatography
(SiO2, hexanes/EtOAc 1:1). [a]2D0 +54.5 (c 1.56, CH2Cl2);
1H NMR (300 MHz, CDCl3): d 8.00–7.88 (m, 2H), 7.57–
7.36 (m, 3H), 4.69–4.49 (m, 2H), 4.47–4.30 (m, 3H), 3.03
(s, 3H); 13C NMR (75.5 MHz, CDCl3): d 166.1, 131.9,
128.5, 128.4, 127.0, 70.4, 69.3, 65.4, 37.6; IR (film): 3080,
3040, 2980, 2950, 2920, 1728, 1645, 1603, 1580, 1496,
1452, 1356, 1277, 1242, 1174, 1061, 1025, 961, 833, 786,
695; MS (DCI, NH3): m/z (%)¼258.2 (9), 257.2 (20),
256.1 (100, [MH]+); HRMS (EI) calcd for C11H13NO4S
([M]+) 255.0565, found 255.0565.
3.2.3. (4S,5S)-4-Mesyloxymethyl-5-(4-methylsulfanyl-
phenyl)-2-tert-butyl-oxazoline (28). Compound 24
(0.500 g, 1.79 mmol) was reacted according to GP1 to yield
28 (0.436 g, 68%) as a slightly yellow solid after purification
by column chromatography (SiO2, hexanes/EtOAc 1:1). Rf
0.44 (hexanes/EtOAc 1:3); mp 107–108 ꢀC; [a]D20 ꢂ103.8
(c 1.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.29–7.23
(m, 2H), 7.20–7.15 (m, 2H), 5.28 (d, J¼6.5 Hz, 1H), 4.40
(dd, J¼10.3, 4.0 Hz, 1H), 4.32 (dd, J¼10.3, 5.5 Hz, 1H),
4.19 (ddd, J¼6.5, 5.5, 4.0 Hz, 1H), 3.06 (s, 3H), 2.48 (s,
3H), 1.29 (s, 9H); 13C NMR (75.5 MHz, CDCl3): d 176.2,
139.2, 136.9, 126.8, 126.0, 82.4, 73.3, 70.1, 37.6, 33.5,
27.8, 15.7; IR (KBr): 3431, 2962, 2929, 2372, 2734, 1656,
1600, 1489, 1474, 1414, 1344, 1209, 1175, 1141, 1082,
1032, 1000, 977, 953, 881, 827, 809, 771, 714, 530, 447;

9978
M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
MS (CI, NH3): m/z (%)¼358.1 (100, [MH]+); elemental
analysis calcd (%) for C16H23NO4S2 (357.49): C 53.76, H
6.48, N 3.92, found: C 53.68, H 6.08, N 3.75.
3059, 2919, 2869, 1899, 1648; MS (ESI): m/z (%)¼702.3
(100, [MH+]); elemental analysis calcd (%) for
C41H39N3O4S2 (701.90): C 70.16, H 5.60, N 5.99, found:
C 70.17, H 5.75, N 5.71.
3.3. Assembly of the bis(oxazoline) ligands
3.4.2. Ligand 31. Compound 24 (0.307 g, 1.10 mmol) and 9
(0.132 g, 0.50 mmol) were reacted according to GP2 to yield
31 (0.205 g, 62%) as a colorless solid after recrystallization
from CH3CN. Rf 0.13 (EtOAc); mp 98–99 ꢀC; [a]D20 ꢂ122.7
3.3.1. Ligand 29. (R)-4-Hydroxymethyl-2-phenyl-oxazo-
line (20) (13.86 g, 78.2 mmol, 2.2 equiv) was dissolved in
dry DMF (200 mL) under N2 and cooled to 0 ꢀC. NaH
(60% suspension in mineral oil) (3.27 g, 81.5 mmol,
2.3 equiv) was added in portions and the mixture was stirred
for 15 min. 2,6-Bis(chloromethyl)pyridine (8) (6.26 g,
35.6 mmol, 1.0 equiv) was added as a solid and the ice
bath was removed. Stirring was continued at ambient tem-
perature for 20 h. Water (200 mL) and CH2Cl2 (150 mL)
were added cautiously and the phases were separated. The
aqueous layer was extracted with CH2Cl2 (2ꢁ150 mL).
The combined organic layers were washed with water
(3ꢁ100 mL) and dried (Na2SO4). After removal of the sol-
vent in vacuo the residue was purified by column chromato-
graphy (SiO2, EtOAc to EtOAc/MeOH 24:1) to yield 29 as
a colorless solid (14.37 g, 88%). Mp 68–69 ꢀC; [a]D20 +62.5
1
(c 0.88, CHCl3); H NMR (300 MHz, CDCl3): d 7.70 (t,
J¼7.7 Hz, 1H), 7.34 (d, J¼7.7 Hz, 2H), 7.28–7.17 (m,
8H), 5.36 (d, J¼6.3 Hz, 2H), 4.69 (s, 4H), 4.16 (ddd,
J¼6.8, 6.3, 3.8 Hz, 2H), 3.84 (dd, J¼9.6, 3.8 Hz, 2H),
3.65 (dd, J¼9.6, 6.8 Hz, 2H), 2.48 (s, 6H), 1.30 (s, 18H);
13C NMR (75.5 MHz, CDCl3): d 174.8, 157.8, 138.4,
138.3, 137.2, 126.8, 126.0, 119.8, 83.2, 74.4, 75.1, 72.7,
33.4, 27.8, 15.9; IR (KBr): 2964, 2920, 2876, 1656, 1595;
MS (ESI): m/z (%)¼662.4 (100, [MH+]); elemental analysis
calcd (%) for C37H47N3O4S2 (661.92): C 67.14, H 7.16, N
6.35, found: C 66.87, H 6.76, N 6.20.
3.4.3. Ligand 33. Compound 20 (372 mg, 2.1 mmol) and 11
(294 mg, 1.0 mmol) were reacted according to GP2 to yield
33 (171 mg, 35%) as a slightly yellow oil after column chro-
matography (SiO2, hexanes/EtOAc 1:1). Rf 0.19 (hexanes/
EtOAc 1:1); [a]D20 +106.6 (c 1.02, CHCl3); 1H NMR
(300 MHz, CDCl3): d 8.32 (br s, 1H), 8.05–7.90 (m, 4H),
7.47–7.35 (m, 6H), 6.96 (s, 2H), 4.73–4.43 (m, 8H), 4.27
(dd, J¼7.3, 6.5 Hz, 2H), 3.74 (dd, J¼9.9, 5.4 Hz, 2H),
3.64 (dd, J¼9.9, 6.1 Hz, 2H), 2.22 (s, 3H); 13C NMR
(75.5 MHz, CDCl3): d 165.2, 152.1, 131.6, 129.7, 128.6,
128.4, 128.4, 127.4, 123.8, 72.4, 70.5, 70.4, 66.4, 20.4; IR
(ATR): 3371, 3063, 2904, 2863, 1644, 1484, 1450, 1358,
1267, 1220, 1086, 1061, 963, 693 cmꢂ1; MS (ESI): m/z
(%)¼509.3 (15), 488.3 (33), 487.3 (100); HRMS (EI) calcd
for C29H30N2O5 ([M+]) 486.2155, found 486.2154.
1
(c 0.80, CH2Cl2); H NMR (300 MHz, CDCl3): d 8.00–
7.86 (m, 4H), 7.65 (t, J¼7.7 Hz, 1H), 7.51–7.35 (m, 6H),
7.31 (d, J¼7.7 Hz, 2H), 4.68 (s, 4H), 4.61–4.46 (m, 4H),
4.41–4.34 (m, 2H), 3.88–3.80 (m, 2H), 3.66–3.58 (m, 2H);
13C NMR (75.5 MHz, CDCl3): d 165.0, 157.7, 137.2,
131.4, 128.31, 128.30, 127.6, 120.0, 74.2, 72.9, 70.5, 66.4;
IR (KBr): 3060, 3040, 2985, 2958, 2947, 2936, 1642; MS
(DCI, NH3): m/z (%)¼459.2 (25), 458.1 (100, [MH+]);
elemental analysis calcd (%) for C27H27N3O4 (457.52): C
70.88, H 5.95, N 9.18, found: C 70.73, H 5.93, N 9.04.
3.4. General procedure (GP2) for the synthesis of ligands
30, 31, 33–35, 37–39
NaH (2.2 equiv, 60% suspension in mineral oil) was sus-
pended in dry DMF (3–7 mL) and cooled to 0 ꢀC. The nucleo-
phile (16, 20, 23 or 24) was dissolved in dry DMF (5–10 mL)
under N2 and added dropwise. The mixture was stirred until
the evolution of hydrogen had ceased. The electrophile (9,
11–13, 26–28) was dissolved in dry DMF (5–10 mL) and
also added dropwise. The ice bath was removed and stirring
was continued at ambient temperature or at 60 ꢀC (reactions
with 26–28) overnight. DMF was evaporated and water
(10 mL) and EtOAc (20 mL) were added and the phases
were separated. The aqueous layer was extracted with
EtOAc (3ꢁ20 mL) and dried (MgSO4). After removal of
the solvent in vacuo, the residue was purified by chromato-
graphy and/or recrystallization.
3.4.4. Ligand 34. Compound 20 (186 mg, 1.05 mmol) and
12 (154 mg, 0.50 mmol) were reacted according to GP2 to
yield 34 (173 mg, 69%) as a colorless oil after purification
by column chromatography (SiO2, hexanes/EtOAc 1:2).
Rf 0.18 (hexanes/EtOAc 1:2); [a]2D0 +26.1 (c 1.00, CHCl3);
1H NMR (300 MHz, CDCl3): d 7.99–7.92 (m, 4H), 7.52–
7.36 (m, 6H), 7.12 (s, 2H), 4.63–4.30 (m, 10H), 3.85–3.78
(m, 2H), 3.72 (s, 3H), 3.60–3.52 (m, 2H), 2.25 (s, 3H); 13C
NMR (75.5 MHz, CDCl3): d 164.9, 154.6, 133.7, 131.4,
130.7, 130.5, 128.3, 128.3, 127.6, 72.6, 70.8, 68.4, 66.5,
62.8, 20.8 ppm. IR (ATR): 2957, 2904, 2867, 1648, 1477,
1359, 1231, 1098, 1009, 694 cmꢂ1; MS (ESI): m/z
(%)¼502.2 (33), 501.2 (100); HRMS (EI) calcd for
C30H32N2O5 ([M+]) 500.2311, found 500.2308.
3.4.1. Ligand 30. Compound 23 (0.659 g, 2.20 mmol) and 9
(0.265 g, 1.00 mmol) were reacted according to GP2 to yield
30 (0.588 g, 83%) as a colorless solid after recrystallization
from CH3CN. Rf 0.14 (EtOAc); mp 128–129 ꢀC; [a]D20 +24.1
(c 0.94, CHCl3); 1H NMR (300 MHz, CDCl3): d 8.07–8.01
(m, 4H), 7.71–7.63 (m, 1H), 7.56–7.48 (m, 2H), 7.47–7.40
(m, 4H), 7.37–7.22 (m, 10H), 5.55 (d, J¼6.8 Hz, 2H), 4.72
(s, 4H), 4.39 (ddd, J¼6.8, 6.7, 4.3 Hz, 2H), 3.93 (dd,
J¼9.8, 4.3 Hz, 2H), 3.77 (dd, J¼9.8, 6.7 Hz, 2H), 2.47 (s,
6H); 13C NMR (75.5 MHz, CDCl3): d 164.3, 157.7, 138.7,
137.6, 131.7, 128.5, 128.4, 127.4, 126.8, 126.5, 126.3,
120.0, 83.6, 74.9, 74.2, 72.5, 15.8; IR (KBr): 3429, 3247,
3.4.5. Ligand 35. Compound 20 (186 mg, 1.05 mmol) and
13 (175 mg, 0.50 mmol) were reacted according to GP2 to
yield 35 (147 mg, 54%) as a colorless solid after purification
by column chromatography (SiO2, hexanes/EtOAc 1:2).
Rf 0.24 (hexanes/EtOAc 1:2); mp 123–126 ꢀC; [a]D20
+23.2 (c 1.02, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.99–7.92 (m, 4H), 7.52–7.36 (m, 6H), 7.32 (s, 2H),
4.66–4.30 (m, 10H), 3.84–3.77 (m, 2H), 3.73 (s, 3H),
3.64–3.53 (m, 2H), 1.24 (s, 9H); 13C NMR (75.5 MHz,
CDCl3): d 165.0, 154.4, 146.9, 131.5, 130.3, 128.4, 128.3,
127.5, 126.8, 72.4, 70.8, 68.6, 66.4, 62.6, 34.4, 31.4. IR

M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
9979
(ATR): 2961, 2901, 2856, 1647, 1483, 1450, 1356, 1086,
1058, 1025, 735, 694 cmꢂ1; MS (EI): m/z (%)¼542.2 (6),
383.2 (26), 382.2 (100), 205.1 (40), 161.1 (47), 146.1 (22),
118.1 (11), 105.0 (51), 91.0 (13); HRMS (EI) calcd for
C33H38N2O5 ([M+]) 542.2781, found 542.2780.
washed with water (3ꢁ20 mL) and dried (Na2SO4). After
removal of the solvent in vacuo the residue was purified by
column chromatography (SiO2, EtOAc to EtOAc/MeOH
5:2) to yield a colorless solid (2.62 g, 53%). Mp 112 ꢀC;
1
[a]2D0 +66.8 (c 1.29, EtOH); H NMR (300 MHz, CDCl3):
d 8.01–7.99 (m, 4H), 7.53–7.04 (m, 8H), 7.25 (t, J¼
7.7 Hz, 1H), 4.84–4.83 (m, 4H), 4.62–4.43 (m, 6H), 3.92–
3.87 (m, 2H), 3.83–3.78 (m, 2H); 13C NMR (75.5 MHz,
CDCl3): 165.13, 148.77, 131.54, 128.36, 127.55, 125.67,
121.22, 73.45, 70.19, 67.50, 66.44; MS (ESI, NH4OAc):
m/z (%)¼474.3 (100, [MH]+), 475.3 (31); elemental analysis
calcd (%) for C27H27N3O5 (473.52): C 68.48, H 5.75, N
8.87, found: C 68.12, H 5.63, N 8.75.
3.4.6. Ligand 37. Compound 16 (0.087 g, 0.51 mmol) and
26 (0.354 g, 1.12 mmol) were reacted according to GP2 to
yield 37 (0.098 g, 32%) as a colorless solid after recrystalli-
zation from CH3CN. Rf 0.29 (EtOAc/MeOH 9:1); mp 62–
65 ꢀC; [a]D20 +8.7 (c 0.87, CHCl3); H NMR (300 MHz,
1
CDCl3): d 7.53 (t, J¼7.7 Hz, 1H), 7.25–7.11 (m, 10H),
5.13 (d, J¼6.5 Hz, 2H), 4.06 (dddd, J¼8.0, 6.5, 5.0,
1.4 Hz, 2H), 3.75 (s, 4H), 2.85 (dd, J¼13.2, 5.0 Hz, 2H),
2.62 (dd, J¼13.2, 8.0 Hz, 2H), 2.47 (s, 6H), 2.05 (d,
J¼1.4 Hz, 6H); 13C NMR (75.5 MHz, CDCl3): d 165.0,
158.0, 138.7, 137.4, 137.3, 126.7, 126.3, 121.3, 85.0, 74.1,
38.0, 36.5, 15.8, 14.1; IR (KBr): 3399, 3081, 2920, 1653;
MS (CI, NH3): m/z (%)¼610.1 (100, [MH+]); HRMS (EI)
calcd for C31H35N3O2S4 ([M+]) 609.1612, found 609.1613.
3.4.10. Ligand 40. A solution of (S)-2-phenyl-4-mesyloxy-
methyl-oxazoline (25a) (1.11 g, 4.35 mmol, 2.1 equiv) in
20 mL dry CH3CN was added dropwise to a solution of
2,6-bis(N-methylaminomethyl)pyridine (15) (0.342 mg,
2.07 mmol, 1.0 equiv) in 10 mL dry CH3CN. K2CO3
(1.14 g, 8.28 mmol, 4.0 equiv) was added and the mixture
was heated to reflux for 31 h. After cooling down, the sus-
pension was filtered and the solvent evaporated. The residue
was purified by column chromatography (SiO2, CH2Cl2/
MeOH 19:1) to give 40 as a yellow oil (623 mg, 62%) that
eventually solidified after a few weeks. [a]2D0 ꢂ14.6 (c
3.4.7. Ligand 38. Compound 16 (0.142 g, 0.83 mmol) and
27 (0.689 g, 1.83 mmol) were reacted according to GP2 to
yield 38 (0.430 g, 71%) as a colorless solid after recrystalli-
zation from CH3CN. Rf 0.19 (hexanes/EtOAc 1:1); mp 124–
1
1
125 ꢀC; [a]D20 +87.5 (c 1.94, CHCl3); H NMR (300 MHz,
0.84, MeOH); H NMR (300 MHz, CDCl3): d 7.98–7.84
CDCl3): d 8.03–7.96 (m, 4H), 7.56–7.37 (m, 7H), 7.28–
7.14 (m, 10H), 5.36 (d, J¼6.3 Hz, 2H), 4.31 (ddd, J¼8.2,
6.3, 4.7 Hz, 2H), 3.81 (s, 4H), 3.00 (dd, J¼13.4, 4.7 Hz,
2H), 2.74 (dd, J¼13.4, 8.2 Hz, 2H), 2.46 (s, 6H); 13C
NMR (75.5 MHz, CDCl3): d 163.8, 158.1, 138.7, 137.4,
137.3, 131.6, 128.5, 128.4, 127.4, 126.7, 126.4, 121.4,
84.9, 74.7, 38.1, 36.5, 15.8; IR (KBr): 3071, 2919, 2806,
1635, 1605; MS (ESI): m/z (%)¼734.2 (100, [MH+]); ele-
mental analysis calcd (%) for C41H39N3O2S4 (734.03): C
67.09, H 5.36, N 5.72, found: C 67.01, H 5.24, N 5.78.
(m, 4H), 7.59 (t, J¼7.7 Hz, 1H), 7.50–7.33 (m, 6H), 7.30
(d, J¼7.7 Hz, 2H), 4.56–4.38 (m, 4H), 4.32–4.17 (m, 2H),
3.81 (d, J¼14.3 Hz, 2H), 3.68 (d, J¼14.3 Hz, 2H), 2.90–
2.74 (m, 2H), 2.66–2.47 (m, 2H), 2.37 (s, 6H); 13C NMR
(75.5 MHz, CDCl3): d 164.2, 158.7, 136.8, 131.3, 128.3,
128.2, 127.8, 121.2, 72.0, 65.4, 64.5, 62.1, 43.5; IR (film):
3420, 3076, 2952, 2908; MS (DCI, NH3): m/z (%)¼485.3
(27), 484.2 (100, [MH]+), 337.1 (7); HRMS (EI) calcd for
C29H33N5O2 ([M+]) 483.2634, found 483.2635.
3.4.11. Ligand 41. A mixture of (4S,5S)-4-mesyloxy-
methyl-5-(4-methylsulfanylphenyl)-2-phenyl-oxazoline (27)
(100 mg, 0.26 mmol, 2.2 equiv), 2,6-bis(N-methylamino-
methyl)pyridine (15) (20 mg, 0.12 mmol, 1.0 equiv), and
K2CO3 (66 mg, 0.48 mmol, 4.0 equiv) in 5 mL dry CH3CN
was heated to reflux for 72 h. After cooling down, the suspen-
sion was filtered and the solvent evaporated. The residue was
purified by column chromatography (SiO2, EtOAc) to yield
41 as a colorless solid (45 mg, 52%). Rf 0.08 (EtOAc); mp
143–145 ꢀC; [a]D20 +35.7 (c 0.85, CHCl3); 1H NMR
(300 MHz, CDCl3): d 8.03–7.96 (m, 4H), 7.62–7.55 (m,
1H), 7.52–7.46 (m, 2H), 7.44–7.35 (m, 4H), 7.33–7.19 (m,
10H), 5.41 (d, J¼6.6 Hz, 2H), 4.31 (ddd, J¼8.6, 6.6,
4.9 Hz, 2H), 3.80 (d, J¼14.0 Hz, 2H), 3.70 (d, J¼14.0 Hz,
2H), 2.88 (dd, J¼12.6, 4.9 Hz, 2H), 2.68 (dd, J¼12.6,
8.6 Hz, 2H), 2.46 (s, 6H), 2.30 (s, 6H); 13C NMR
(75.5 MHz, CDCl3): d 163.5, 158.6, 138.4, 138.1, 136.7,
131.5, 128.3, 128.4, 127.2, 126.8, 126.3, 121.3, 84.9, 74.0,
64.6, 43.3, 15.8; IR (KBr): 3460, 3062, 2919, 1647; MS
(ESI): m/z (%)¼728.5 (100, [MH+]); HRMS (EI) calcd for
C43H45N5O2S2 ([M+]) 727.3015, found 727.3012.
3.4.8. Ligand 39. Compound16 (0.044 g, 0.26 mmol)and 28
(0.227 g, 0.63 mmol) were reacted according to GP2 to yield
39 (0.117 g, 65%) as a colorless solid after recrystallization
from CH3CN. Rf 0.47 (EtOAc); [a]2D0 ꢂ32.6 (c 0.92,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.57–7.50 (m, 1H),
7.28–7.12 (m, 10H), 5.16 (d, J¼6.0 Hz, 2H), 4.10 (ddd,
J¼8.2, 6.0, 4.2 Hz, 2H), 3.79 (s, 4H), 2.89 (dd, J¼13.3,
4.2 Hz, 2H), 2.64 (dd, J¼13.3, 8.2 Hz, 2H), 2.47 (s, 6H),
1.28 (s, 18H); 13C NMR (75.5 MHz, CDCl3): d 174.4,
158.1, 138.4, 138.0, 137.3, 126.7, 126.1, 121.3, 84.4, 74.2,
38.2, 36.7, 33.4, 27.8, 15.8; IR (KBr): 3441, 2968, 2921,
1590; MS (ESI): m/z (%)¼694.2 (100, [MH+]); HRMS (EI)
calcd for C37H47N3O2S4 ([M+]) 693.2551, found 693.2546.
3.4.9. Ligand 32. (R)-4-Hydroxy-2-phenyl-oxazoline (20)
(3.70 g, 20.9 mmol, 2.0 equiv) was dissolved in dry DMF
(30 mL) under nitrogen and the solution was cooled to
0 ꢀC. NaH (60% suspension in mineral oil) (923 mg,
23.0 mmol, 2.2 equiv) was added in portions and the mixture
was stirred for 15 min. A solution of 2,6-bis(chloromethyl)-
pyridine-N-oxide (10) (2.00 g, 10.4 mmol, 1.0 equiv) in dry
DMF (5 mL) was added and the ice bath was removed. Stir-
ring was continued at ambient temperature for 20 h. Water
(50 mL) and CH2Cl2 (70 mL) were added cautiously and
the phases were separated. The aqueous layer was extracted
with CH2Cl2 (2ꢁ50 mL). The combined organic layers were
Acknowledgements
This work was supported by the German Research Founda-
tion (DFG) as part of the program SP1118, the Fonds der

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M. Seitz et al. / Tetrahedron 62 (2006) 9973–9980
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