Desymmetrisation of C2-symmetric (2S,3S)-diazidobutane-1,4-diol with benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2004.01.027

Surprisingly, doubly functionalised (2S,3S)-diazidobutane-1,4-diol under modified Boyer conditions reacted with only 1equiv of benzaldehyde yielding a mono oxazoline, whereas quantum chemical studies favour the formation of the C₂-symmetric bio

Full text of DOI:10.1016/j.tetasy.2004.01.027

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 867–872
Desymmetrisation of C2-symmetric (2S,3S)-diazidobutane-1,4-diol
with benzaldehyde
Andreas Scheurer,a,* Walter Bauer,a Frank Hampel,a Christine Schmidt,a
Rolf W. Saalfrank,a,* Paul Mosset,b,* Ralph Puchtac and Nico J. R. van Eikema Hommesc
aInstitut f €ur Organische Chemie, Universit€at Erlangen-N€urnberg, Henkestrasse 42, 91054 Erlangen, Germany
bLaboratoire de Synthꢀeses et Activations de Biomolꢁecules, ENSCR et CNRS, Avenue du Gꢁenꢁeral Leclerc, 35700 Rennes, France
cComputer-Chemie-Centrum, Universit€at Erlangen-N€urnberg, N€agelsbachstrasse 25, 91052 Erlangen, Germany
Received 10 December 2003; accepted 23 January 2004
Dedicated to Prof. Hans Hofmann on the occasion of his 75th birthday
Abstract—Surprisingly, doubly functionalised (2S,3S)-diazidobutane-1,4-diol under modified Boyer conditions reacted with only
1 equiv of benzaldehyde yielding a mono oxazoline, whereas quantum chemical studies favour the formation of the C2-symmetric
bioxazoline. In addition, the oxazoline formation was indirectly confirmed via detailed NMR studies and X-ray structure analysis of
the oxazoline p-nitrobenzoic acid ester derivative.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
our catalysis studies, we intended to prepare novel
substituted bioxazolines, where the chirality is incorpo-
rated in the backbone of the ligand. Starting from
The first synthesis of achiral bisoxazolines was esta-
blished in the early sixties by Witte and Seeliger.1 Phe-
nyl-spaced, achiral bisoxazolines were obtained by
reacting aromatic dinitriles with amino alcohols in the
presence of a catalytic amount of different M(II)-salts.
Subsequently, due to their good donor properties, a
large number of optically active enantiomerically pure
bisoxazolines were generated and widely used in metal-
catalysed asymmetric syntheses.2
L
-tartaric acid, the three differently functionalised chiral
building blocks 1–3 are accessible.4 These are potential
educts for the synthesis of C2-symmetric bioxazolines 4
(Scheme 1). Whereas a synthesis starting with diami-
nodiol 1 did not lead to the parent products 4 (Witte–
Seeliger conditions),5 several substituted bioxazolines 4
(R ¼ alkyl, aryl) were synthesised in a three step
sequence starting from 2,6 involving a debenzylation
reaction, which does not tolerate sensitive functional
groups in R.
2. Results and discussion
HO
OH
BnO
OBn
H2N
NH2
H2N
NH2
The initial step in the preparation of bisoxazoline
ligands is the condensation of oxalic, malonic or succinic
acid chlorides and esters with enantiomerically pure
amino alcohols. The intermediate bis(hydroxyl)diamides
are subsequently cyclised to the corresponding bisox-
azolines with the help of different activating reagents
(SOCl2/OHꢀ,3a MsCl/OHꢀ,3b Bu2SnCl2,2b ZnCl2,1;3c
DAST,3d BF3ÆOEt2,3e TfOH,3f . . .). Over the course of
1
2
O
O
N
N
R
R
4
HO
OH
N3 N3
3
Scheme 1. Retrosynthetic analysis for the preparation of bioxazolines
(S,S)-4.
* Corresponding authors. E-mail: saalfrank@chemie.uni-erlangen.de
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.027

868
A. Scheurer et al. / Tetrahedron: Asymmetry 15 (2004) 867–872
1,2-cyclisation
O
OH
O
O
-H2O -N2
-H2O, -N2
N
N3
N
N
1
+
5
2
3
-43,15
-46,11
kcal/mol
HO
OH
kcal/mol
N3 N3
6
8
CHO
i
+
N3
N3
3
5
1
2
OH
OH
N
O
HO
N3
-H2O, -N2
-H2O -N2
O
N
+
5
3
-41,09
kcal/mol
-40,92
O
N
kcal/mol
1,3-cyclisation
7
9
Scheme 2. Synthesis, structures and calculated energies (PM3) for compound 6–8. Reagents and conditions: (i) BF3ÆOEt2, 0 ꢁC to rt, 18 h, CH2Cl2.
In order to introduce functionalities in the final step, our
attention was drawn to the modified Boyer reaction,
reported in 1996 by Aube. In this case, aldehydes and
1,2- or 1,3-azidoalcohols were converted in the presence
of Lewis acids to oxazolines or 5,6-dihydro-4H-1,3-ox-
azines, respectively. Interestingly, for the reaction of
indicated that only 1 equiv of benzaldehyde 5 had
reacted with (2S,3S)-diazidobutane-1,4-diol 3 (yield:
86%).10 This was evident from the MS-CI-spectrum
{(CH4) [M+H]þ ¼ 233}, from the IR-spectrum
2102 cmꢀ1) and from the NMR data (e.g., four signals
were observed for the aliphatic carbons in the 13C
spectrum). Unfortunately, these spectroscopic data did
not allow us to unequivocally distinguish between the
two possible mono condensation isomers 6 and 7.
Therefore, the reaction product was esterified with
benzoic acid chlorides with either the oxazoline esters 10
or the oxazine esters 11 being expected (Scheme 3).
ꢁ 7
~
(remaining OH- and N3-function, m ¼ broad 3369,
C2-symmetric (2S,3S)-diazidobutane-1,4-diol
3 with
carbonyl compounds, two pathways are conceivable
(Scheme 2): reaction as a 1,2-azidoalcohol, leading to
five-membered ring product 6, or as a 1,3-azidoalcohol,
resulting in the formation of six-membered ring 7.
Subsequently, in both cases a second carbonyl addition
may take place, giving rise to a product with two five-
membered rings 8 or with two fused six-membered rings
9, respectively.
2.3. NMR studies
2.1. Quantum chemical calculations
A detailed NMR study was carried out in order to dis-
tinguish between the formation of 10a or 11a (for
assignment, use the numbering given in Scheme 3). The
experimental 13C NMR data recorded for the reaction
product (166.0, 126.9 ppm) almost matched exactly with
the values simulated for C5 and C6 of hypothetical 10a
(165.2, 127.1 ppm) by using the CSEARCH software
package by Robien.11 However, the experimental data
mismatched the values calculated for C5 and C6 of
We investigated the two pathways, 1,2- and 1,3-cycli-
sation leading to 6 or 7 (Scheme 2), using PM3 semi-
empirical MO calculations.8;9 Both pathways are
computed to be exothermic. However, five-membered 6
is computed to be 5 kcal/mol more stable than six-
membered 7. The energy difference of 2 kcal/mol be-
tween 8 and 9, generated in the second reaction step, is
less pronounced, but still significant. The thermo-
dynamic preference of 8 over 9 amounts to 7.3 kcal/mol
starting from 3. Furthermore, the formation of 6 in the
first step is calculated to be only 3 kcal/mol more exo-
thermic than the formation of 8 in the second step.
Therefore, a two-step reaction of 3 with benzaldehyde 5
was expected to lead to the desired bioxazoline 8. Note
that these calculations refer to isolated molecules in the
gas phase, so computed reaction energies may be inac-
curate. Relative energies for the isomeric products,
however, can be compared reliably.
O
1
4
18
13
2
3
17
16
O
5
O
12
14
N
N3
6
X
11
10
15
7
10a,b
6
7
9
8
i
2N3
O
4
18
15
13
3
1
17
16
O
12
O
N
14
X
5
6
7
11
10
8
9
2.2. Synthesis
11a,b
The calculations prompted us to react 3 (CH2Cl2 at
0 ꢁC) with 2 equiv of benzaldehyde 5 in the presence of
4 equiv of BF3ÆOEt2.7a To our surprise, the analysis of
the spectroscopic data of the purified reaction product
Scheme 3. Conversion of hypothetical 6 or 7 into the corresponding
benzoic ester derivatives 10a and b or 11a and b. Reagents and con-
ditions: (i) p-NO2C6H4COCl, NEt3, CH2Cl2, rt, 76%; 10a, 11a:
X ¼ NO2; p-BrC6H4COCl, NEt3, CH2Cl2 rt, 69%; 10b, 11b: X ¼ Br.

A. Scheurer et al. / Tetrahedron: Asymmetry 15 (2004) 867–872
869
hypothetical 11a (156.2, 137.2 ppm). A combination of
1H,1H-COSY, 1H,13C-HMQC and 1H,13C-HMBC al-
lowed complete assignment of all carbon and proton
resonances and coupling pathways. The diastereotopic
protons at C4 were easily assigned both from their
splitting pattern (Fig. 1) as well as from a cross peak
in the 1H,13C-HMBC-spectrum between the carbonyl
signal C12 and the protons at C4. Since the COSY
coupling pattern leads to a circular argument, an
unequivocal differentiation between 10a and 11a was not
possible. The definite proof for only the formation of
10a was achieved from a 1H,15N-HMBC spectrum
(natural abundance 15N). An expanded region of this
spectrum is depicted in Figure 1.
Figure 2. Molecular structure of 9a (PLUTON presentation15). H:
void; C: shaded; N: blue; O: red.
Table 1. Crystallographic data for compound 10a
Formula
Mr
C18H15N5O5
381.35
Crystal size [mm]
Crystal system
Space group
T [K]
0.30 · 0.30 · 0.25
monoclinic
P21
173(2)
ꢂ
a [A]
5.0702(2)
30.3384(11)
5.63050(10)
90ꢁ
ꢂ
b [A]
ꢂ
c [A]
a [ꢁ]
b [ꢁ]
c [ꢁ]
94.589(2)
90ꢁ
3
ꢂ
V [A ]
863.32(5)
2
1.467
Z
Pcalcd [Mg mꢀ3
h range [ꢁ]
]
Figure 1. 1H,15N-HMBC spectrum (CDCl3, 26 ꢁC) of 10a, expanded
region; natural abundance 15N. The one-dimensional 1H-spectrum is
a high-resolution spectrum, the one-dimensional 15N-spectrum is a
projection along f2.
3.87–27.49ꢁ
2462
2462
Reflections collected
Unique reflections
Refl. observed [I > 2rðIÞ]
Parameters
1317
253
Final R1 [I > 2rðIÞ]
0.0467
0.0881
With respect to the 15N-chemical shifts of the three
nitrogen atoms in an azido group, the shift of the
proximal C-bound nitrogen is )321.2 ppm in H3CN3
and )287.9 ppm in PhN3.12 The 15N–C azido signal
recorded at )308 ppm and the cross peak 2 in Figure 1 is
compatible with both structures 10a and 11a (inter-
change of positions 2 and 3). However, the cross peaks
4A and 4B in Figure 1 unequivocally prove the validity
wR2 (all data)
Largest residuals [e A
ꢀ3
ꢂ
]
0.175/)0.184
3
of structure 10a. The peaks 4A and 4B arise from J-
coupling between the N–C azido nitrogen and protons
4A/4B. In case that 11a were the species present, these
cross peaks would involve a long-range 4J-coupling,
incompatible with the cross peak intensity found. Thus,
species 10a indirectly proves the formation of 6 instead
of 7 during the reaction discussed in Scheme 2.
Figure 3. Crystal packing of 10a (stereoview, PLUTON presenta-
tion15). H: void, C: shaded; N: net; O: diagonal. Xꢁ ꢁ ꢁH–C H-bonds,
highlighted via dots. H omitted for clarity except hydrogens involved
in weak H-bonds.
2.4. X-ray structure analysis
The NMR based structure of 10a was unequivocally
confirmed by single crystal X-ray determination. Crys-
tals of 10a suitable for X-ray diffraction were grown
from CDCl3.13;14 Compound 10a crystallises in the chiral
space group P21 with two independent molecules in the
unit cell (Fig. 2, Table 1).
stacked like an angle steel caused by weak p–p inter-
actions.17 The interplanar distance of the nitro benzoic
ꢂ
moiety is 3.44 A with an interplanar shift of the mole-
ꢂ
ꢂ
cules of 3.64 A, and a lateral shift of 0.77 A. The angular
staples of 10a are horizontally connected via weak H-
bonds.18 The aromatic hydrogens interact with oxygens
ꢂ
of the nitro and ester function (N–Oꢁ ꢁ ꢁH–C ¼ 2.45 A
ꢂ
In the crystal, two structural motifs determine the
stacking of 10a (Fig. 3), which is mainly due to the p-
nitrobenzoic ester group.16 Compound 10a is vertically
and C@Oꢁ ꢁ ꢁH–C ¼ 2.42 A), while aliphatic hydrogens
adjacent to the ester group are directed to the N3-
ꢂ
functions (C–N3ꢁ ꢁ ꢁH–C ¼ 2.58 A).

870
A. Scheurer et al. / Tetrahedron: Asymmetry 15 (2004) 867–872
3. Conclusion
which stopped after 1 h. The reaction mixture was then
allowed to warm to 20 ꢁC and stirred for a further 18 h.
Saturated NaHCO3-solution was added slowly for
hydrolysis (30 mL) and the two-phase system stirred
until the end of gas evolution. The aqueous layer was
extracted with EtOAc (3 · 30 mL), the organic phase
washed with brine, dried over Na2SO4 and concen-
trated. The crude reaction product was purified by silica
gel chromatography (solvent gradient from CH2Cl2 to
CH2Cl2/MeOH 98/2) affording oxazole 6 as a colourless
oil (0.200–0.225 g, 86–97%, Rf ¼ 0:22 (CH2Cl2/MeOH
98/2), colourless crystals after prolonged storage in
refrigerator (0 ꢁC), mp 55–57 ꢁC); IR (neat): ~m 3370
(broad), 2960, 2928, 2905, 2103, 1732, 1645, 1604, 1580,
1496, 1471, 1451, 1370, 1262, 1092, 1060, 1027, 971, 783,
To the best of our knowledge, this contribution
describes for the first time the asymmetric cyclisation of
a C2-symmetric bis-functionalised 2,3-diazido-1,4-diol
with benzaldehyde under modified Boyer conditions. In
addition, the formation of oxazoline 6 was indirectly
proven via 10a by detailed NMR studies and X-ray
structure determination. Due to the remaining func-
tionalities, mono condensation product 6 should allow
the synthesis of new unsymmetric ligands, thus be
interesting for enantioselective catalysis.
1
698 cmꢀ1; H NMR: d 7.97–7.92 (m, 2H, Ar–CHortho),
4. Experimental
4.1. General
7.51 (tt, 1H, J ¼ 7:4, 1.6 Hz, Ar–CHpara), 7.46 (tm, 2H,
J ¼ 7:4 Hz, Ar–CHmeta), 4.60 (ddd, 1H, J ¼ 9:9, 7.5,
4.0 Hz, COCH2CH), 4.51 (dd, 1H, J ¼ 9:9, 8.4 Hz,
COCH2CH), 4.38 (dd, 1H, J ¼ 8:4, 7.5 Hz,
COCH2CH), 4.04 (d, 2H, J ¼ 4:7 Hz, HOCH2CH), 3.53
(td, 1H, J ¼ 4:7, 4.0 Hz, HOCH2CH), 3.48 (s, 1H, OH);
13C NMR: d 166.00 (1C, O–C@N), 131.98 (1C, Ar–
CHpara), 128.54 and 128.46 (4C, Ar–CHortho and meta),
126.75 (1C, Ar–Cipso), 69.71 (1C, COCH2CH, correlates
with protons at 4.51 and 4.38 ppm), 68.32 (1C,
COCH2CH, correlates with proton at 4.60 ppm), 64.14
(1C, HOCH2CH, correlates with proton at 3.53 ppm),
63.37 (1C, HOCH2CH, correlates with protons at
4.04 ppm); MS (CI, CH4) m=z (%): calcd for C1125H12N4O2
CH2Cl2 was distilled over CaH2 before use. All reagents
employed were commercially available, high-grade
purity materials (Fluka, Aldrich), were used as supplied.
All moisture-sensitive and oxygen-sensitive reactions
were conducted under nitrogen. Flash chromatography
was carried out using silica gel 60 (70–230 mesh).
Melting points are not corrected. IR spectra were
recorded with NaCl plates on a Nicolet 204 FT-IR
spectrometer. NMR spectra were obtained in dilute
CDCl3 solutions, using Me4Si as an internal standard at
1
400 MHz for H and 100 MHz for 13C on a BRUKER
233.1 [M+H]þ, found 233.2 (100) [M+H]þ; ½aꢂ ¼ )105,
D
25
25
25
436
ARX 400 spectrometer; d values are given in ppm. Low-
resolution mass spectra were carried out at the Institut
½aꢂ ¼ )108, ½aꢂ ¼ )125, ½aꢂ ¼ )222 (c 1.6, CHCl3);
578 546
C11H12N4O2 (232.24).
€
fur Organische Chemie in Erlangen on a MICROMASS
ZAB-Spectrometer (8 kV). Spectral parameters of
Figure 1 (Jeol Alpha 500 spectrometer): B0 ¼ 11:7 T
(1H ¼ 500 MHz). Inverse gradient probehead, CDCl3,
4.3. General method for the synthesis of oxazoline esters
10a and b
1
+24 ꢁC, inverse gradient enhanced H,15N-HMBC, 512
data points in f2, spectral width in f2 5200 Hz, 64 scans
per t1-increment, acquisition time 0.1 s, relaxation delay
2.0 s, spectral width in f1 25,250 Hz, 256 t1-increments,
90ꢁ-pulses ¼ 6.2 ls (1H) and 32.0 ls (15N), delay in
HMBC sequence ¼ 62.5 ms, equivalent to a J-coupling
of 8 Hz, exponential window in t2 and Gaussian window
in t1. Single crystal X-ray structure analysis: Details for
crystal data, data collection and refinement are given in
Table 1. X-ray data for 10a were collected on a Nonius
Kappa CCD area detector, using Mo-Ka radiation
To a solution of alcohol 6 (0.093 g, 0.40 mmol), NEt3
(0.11 mL, 0.80 mmol) and a cat. amount of DMAP
(0.002–0.004 g) in CH2Cl2 (1.6 mL) was added at 0 ꢁC a
solution of p-nitrobenzoyl chloride (0.104 g, 0.56 mmol;
for 10b: p-bromobenzoyl chloride: 0.123 g, 0.56 mmol) in
CH2Cl2 (1.0 mL). After removal of the ice bath, the
reaction mixture was stirred for a further 18 h at ca.
25 ꢁC. After addition of H2O (1 mL) and phase separa-
tion, the aqueous phase was extracted with EtOAc
(3 · 5 mL), and the collected organic layers dried over
Na2SO4 and concentrated. The crude reaction product
was purified by silica gel chromatography.
ꢂ
(k ¼ 0:71073 A). Scalepack absorption correction was
employed. The structure was solved by direct methods
with SHELXS-9713 and refined with full-matrix least-
squares against F 2 with SHELXL-97.13
4.4. Spectroscopic data for p-nitro-benzoic acid (2S)-
azido-2-[2-phenyl-4,5-dihydro-oxazol-(4S)-yl]-ethyl
ester,19 10a
4.2. Synthesis of (2S)-azido-2-[2-phenyl-4,5-dihydro-oxa-
zol-(4S)-yl]-ethanol,19
6
Solvent gradient from CH2Cl2 to CH2Cl2/MeOH 98/2.
Yellow crystals, 0.116 g, 76%, Rf ¼ 0:45 (CH2Cl2/MeOH
A suspension of diazidodiol 320 (0.172 g, 1.00 mmol) and
benzaldehyde (0.203 mL, 2.00 mmol) in CH2Cl2 (20 mL)
was cooled to 0 ꢁC. After addition of 5–10 drops of the
BF3ÆOEt2-complex (0.503 mL, ca. 48% BF3, 4.00 mmol)
a clear solution was obtained. Further addition of
BF3ÆOEt2-complex was accompanied by gas evolution,
99/1), mp 116–118 ꢁC; IR (Nujol):
~m 3113, 3081, 3057,
2173, 2148, 2121, 2097, 1721, 1642, 1607, 1527, 1456,
1371, 1348, 1295, 1274, 1086, 1024, 981, 877, 824,
719 cmꢀ1
;
1H NMR: d 8.31 (pseudo dt, 2H, J ¼ 9:0,
2.1 Hz, p-NO2C6H4–CH), 8.24 (pseudo dt, 2H, J ¼ 9:0,

A. Scheurer et al. / Tetrahedron: Asymmetry 15 (2004) 867–872
871
2.1 Hz, p-NO2C6H4–CH), 7.97–7.92 (m, 2H, Ar–
CHortho), 7.51 (ddt, 1H, J ¼ 8:2, 6.6, 1.4 Hz, Ar–CHpara),
7.42 (m, 2H, Ar–CHmeta), 4.79 (dd, 1H, J ¼ 11:8, 4.1 Hz,
CH2CH–N3), 4.73 (dd, 1H, J ¼ 11:8, 8.2 Hz, CH2CH–
N3), 4.61 (ddd, 1H, J ¼ 9:9, 7.0, 3.9 Hz, OCH2CH), 4.54
(dd, 1H, J ¼ 9:9, 8.4 Hz, OCH2CH), 4.41 (dd, 1H,
J ¼ 8:4, 7.0 Hz, OCH2CH), 3.94 (ddd, 1H, J ¼ 8:2, 4.1,
3.9 Hz, CH2CH–N3); 13C NMR: d 166.03 (1C, O–
C@N), 164.37 (1C, CO2), 150.74 (1C, Cipso a to NO2),
134.78 (1C, Cipso a to CO2), 131.91 (1C, Ar–CHpara),
130.94 (2C, p-NO2C6H4–CH), 128.52 and 128.44 (4C,
Ar–CHortho and meta), 126.91 (1C, Cipso a to O–C@N),
123.69 (2C, p-NO2C6H4–CH), 69.32 (1C, OCH2CH,
correlates with protons at 4.54 and 4.41 ppm), 67.39 (1C,
OCH2CH, correlates with proton at 4.61 ppm), 65.77
(1C, CH2CH–N3, correlates with protons at 4.79 and
4.73 ppm), 62.61 (1C, CH2CH–N3, correlates with pro-
ton at 3.94 ppm); MS (FAB, m-NBA) m=z (%): calcd for
C18H16N5O5 382.12 [M+H]þ, found 393 (52), 382 (43)
[M+H]þ, 322 (100), 250 (34); HRMS (ESI, MeCN, 4 kV)
m=z (%): calcd for C18H16N5O5 389.1151 [M+H]þ,
(100), calcd for C18H16N4O379Br 415.0406 [M+H]þ,
20 20
found 415.0404 (10); ½aꢂ ¼ )14.5, ½aꢂ ¼ )15.3,
D
578
20
546
½aꢂ ¼ )17.4 (c 2.5, CHCl3); C18H15N4O3Br (415.24).
Acknowledgements
Financial support by the CNRS-DFG BILATERAL
P
ROJECT SA 276/27-1 (grants to A.S. and Ch.S.) and by
the Fonds der Chemischen Industrie is gratefully
acknowledged. Furthermore, we would like to thank the
Centre Rꢁegional de Mesures Physiques de l’Ouest for
high-resolution mass spectra.
References and notes
1. Witte, H.; Seeliger, W. Liebigs Ann. Chem. 1974, 996–
1009.
20
20
found 389.1149 (100); ½aꢂ ¼ )12.6, ½aꢂ ¼ )13.3,
2. See for example: (a) Fritschi, H.; Leutenegger, U.;
Pfaltz, A. Angew. Chem. 1986, 98, 1028–1029; Angew.
Chem., Int. Ed. Engl. 1986, 25, 1005–1006; (b) Lowen-
thal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005–6008; (c) Evans, D. A.; Woerpel, K. A.;
Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991,
113, 726–728; (d) Pfaltz, A. Acc. Chem. Res. 1993, 26,
339–345; (e) Pfaltz, A. Adv. Catal. Processes 1995, 1,
61–94.
D
578
20
546
½aꢂ ¼ )14.9 (c 1.0, CHCl3); C18H15N5O5 (381.34).
Crystals suitable for X-ray analysis were obtained by
slow CDCl3 evaporation of the NMR sample (Table 1).
4.5. Spectroscopic data for p-bromo-benzoic acid (2S)-
azido-2-[2-phenyl-4,5-dihydro-oxazol-(4S)-yl]-ethyl
ester,19 10b
€
3. See for example: (a) Muller, D.; Umbricht, G.; Weber, B.;
Pfaltz, A. Helv. Chim. Acta 1991, 74, 232–240; (b) Corey,
E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807–6810;
(c) Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T.
Chem. Ber. 1991, 124, 1173–1180; (d) Harm, A. M.;
Knight, J. G.; Stemp, G. Synlett 1996, 677–678; (e) Davies,
I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J.
J. Org. Chem. 1996, 61, 9629–9630; (f) Davies, I. W.;
Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. Tetrahedron Lett. 1996, 37, 813–814.
Solvent gradient from CH2Cl2 to CH2Cl2/MeOH 99/1.
White crystals, 0.115 g, 69%, Rf ¼ 0:62 (CH2Cl2), mp
~
100–101 ꢁC; IR (Nujol): m 3099, 3066, 2169, 2125, 2097,
1718, 1646, 1589, 1456, 1370, 1349, 1329, 1292, 1271,
1179, 1132, 1116, 1105, 1086, 1070, 1026, 1011, 977, 849,
1
831, 755, 700, 689 cmꢀ1; H NMR: d 7.98–7.90 (m, 4H,
p-BrC6H4–CH and Ar–CHortho), 7.60 (pseudo dt, 2H,
J ¼ 8:9, 2.1 Hz, p-BrC6H4–CH), 7.50 (ddt, 1H, J ¼ 8:3,
6.5, 1.3 Hz, Ar–CHpara), 7.45–7.38 (m, 2H, Ar–CHmeta),
4.73 (dd, 1H, J ¼ 11:8, 4.0 Hz, CH2CH–N3), 4.65 (dd,
1H, J ¼ 11:8, 8.3 Hz, CH2CH–N3), 4.59 (ddd, 1H,
J ¼ 9:9, 7.0, 4.1 Hz, OCH2CH), 4.52 (dd, 1H, J ¼ 9:9,
8.2 Hz, OCH2CH), 4.39 (dd, 1H, J ¼ 8:2, 7.0 Hz,
OCH2CH), 3.90 (ddd, 1H, J ¼ 8:3, 4.1, 4.0 Hz,
CH2CH–N3); 13C NMR: d 165.93 (1C, O–C@N), 165.52
(1C, CO2), 131.90 (2C, p-BrC6H4–CH), 131.84 (1C, Ar–
CHpara), 131.30 (2C, p-BrC6H4–CH), 128.61 (1C,
p-BrC6H4–Cipso), 128.53 and 128.41 (4C, Ar–
CHortho and meta), 128.33 (1C, p-BrC6H4–Cipso), 126.97
(1C, Cipso a to O–C@N), 69.36 (1C, OCH2CH, corre-
lates with protons at 4.52 and 4.39 ppm), 67.42 (1C,
OCH2CH, correlates with proton at 4.59 ppm), 65.12
(1C, CH2CH–N3, correlates with protons at 4.73 and
4.65 ppm), 62.77 (1C, CH2CH–N3, correlates with pro-
ton at 3.90 ppm); MS (FAB, m-NBA) m=z (%): calcd for
C18H16N4O379Br 415.04 [M+H]þ, gef.: 417 (100)
[M(81Br)+H]þ, 415 (99) [M(79Br)+H]þ, 337 (11)
[M)C6H5]þ; HRMS (ESI, MeOH, 4 kV) m=z (%): calcd
for C19H19N4O479BrNa 469.0487 [M+CH3OH+Na]þ,
found 469.0531 (5), calcd for C18H15N4O379BrK
452.9965 [M+K]þ, found 452.9992 (12), calcd for
C18H15N4O379BrNa 437.0225 [M+Na]þ, found 437.0223
4. (a) Scheurer, A.; Mosset, P.; Saalfrank, R. W. Tetrahe-
dron: Asymmetry 1997, 8, 1243–1251, and 3161; (b)
Scheurer, A.; Mosset, P.; Saalfrank, R. W. Tetrahedron:
Asymmetry 1999, 10, 3559–3570.
€
5. Scheurer, A. Ph.D. Dissertation, FA-Universitat Erlan-
€
gen-Nurnberg, 2001.
6. Boulch, R.; Scheurer, A.; Mosset, P.; Saalfrank, R. W.
Tetrahedron Lett. 2000, 41, 1023–1026.
ꢁ
7. (a) Badiang, J. G.; Aube, J. J. Org. Chem. 1996, 61, 2484–
2487; for reaction with ketones: (b) Gracias, V.; Milligan,
ꢁ
G. L.; Aube, J. J. Am. Chem. Soc. 1995, 117, 8047–8048;
(c) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube, J.
ꢁ
Tetrahedron 1997, 53, 16241–16252; (d) Forsee, J. E.;
ꢁ
Smith, B. T.; Frank, K. E.; Aube, J. Synlett 1998, 1258–
1260; (e) Smith, B. T.; Gracias, V.; Aube, J. J. Org. Chem.
ꢁ
ꢁ
2000, 65, 3771–3774; (f) Furness, K.; Aube, J. Org. Lett.
1999, 1, 495–497; (g) Sahasrabudhe, K.; Gracias, V.;
Furness, K.; Smith, B. T.; Katz, C. E.; Reddy, D. S.;
ꢁ
Aube, J. J. Am. Chem. Soc. 2003, 125, 7914–7922.
8. (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–220;
(b) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 221–264.
9. Version VAMP 7.5a, Build 16, Clark, T., Alex, A., Beck,
B., Chandrasekhar, J., Gedeck, P., Horn, A., Hutter, M.,
Martin, B., Rauhut, G., Sauer, W., Schindler, T., Steinke,
T., Erlangen, 2000.
10. The reaction was carried out several times under the same
reaction conditions (yields: 86–97% after purification).

872
A. Scheurer et al. / Tetrahedron: Asymmetry 15 (2004) 867–872
Doubling of the reagents compared to
lead to 4 and was accompanied with lower yields of 6.
Reaction of with picolinaldehyde or salicylalde-
hyde instead of 5 failed to give any condensation
product.
3
did not
15. Spek, A. L. PLATON, A Multipurpose Crystallographic
Tool; Utrecht University, Utrecht, The Netherlands, 2000.
16. Zheng, S.-L.; Tong, M.-L.; Fu, R.-W.; Chen, X.-M.; Ng,
S.-W. Inorg. Chem. 2001, 40, 3562–3569.
3
17. (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc.
1990, 112, 5525–5534; (b) Chipot, C.; Jaffe, R.; Maigret,
B.; Pearlman, D. A.; Kollman, P. A. J. Am. Chem. Soc.
1996, 118, 11217–11224; (c) Hobza, P.; Selzle, H. L.;
Schlag, E. W. J. Phys. Chem. 1996, 100, 18790–18794; (d)
Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.;
Tanabe, K. J. Am. Chem. Soc. 2002, 124, 104–112.
18. (a) Desiraju, G. R. Acc. Chem. Res. 1996, 29, 441–449; (b)
Steiner, T. Angew. Chem. 2002, 114, 50–80; Angew. Chem.,
Int. Ed. 2002, 41, 48–76; (c) Glaser, H.; Puchta, R.; van
Eikema Hommes, N. J. R.; Leusser, D.; Murso, A.; Stalke,
D.; Bauer, W.; Saalfrank, R. W. Helv. Chim. Acta 2002,
85, 3828–3841.
11. W. Robien, Institute of Organic Chemistry, University of
Vienna (Austria), ꢀCSEARCH Online Softwareꢁ (http://
mailbox.univie.ac.at/~robienw8/csearch_server_info.html).
€
12. (a) Muller, J. Z. Naturforsch. 1979, 34b, 437–441; (b)
€
Muller, J. Z. Naturforsch. 1979, 34b, 531–535.
13. Sheldrick, G. M. SHELXS-97, Program for the Solution of
€
Crystal Structures; University of Gottingen, Germany,
1997; Sheldrick, G. M. SHELXL-97, Program for the
€
Refinement of Crystal Structures; University of Gottingen,
Germany, 1997.
14. CCDC-220603 (10a) contains the supplementary crystal-
lographic data for this paper. This data can be obtained
free of charge via www.ccdc.cam.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-
336-033; or E-mail: deposit@ccdc.cam.ac.uk).
19. Beilstein, ꢀAutoNom Softwareꢁ, Version 2.02.119.
20. In spite of the high N/C ratio of 3, suggesting a potential
explosive hazard, no problem was encountered. However,
caution is recommended in handling 3.