Salicylaldehyde based oxazolidines as catalysts for the asymmetric addition of diethylzinc to aldehydes

Article abstract of DOI:10.1002/jhet.5570450336

(Chemical Equation Presented) A series of oxazolidines have been prepared by condensation of N-isopropyl norephedrine with a variety of salicylaldehyde derivatives. Despite the stereochemical relationship of (1R,2S)-norephedrine with (1R,2S)-ephedrine, th

Full text of DOI:10.1002/jhet.5570450336

May-Jun 2008
873
Salicylaldehyde Based Oxazolidines as Catalysts for the
Asymmetric Addition of Diethylzinc to Aldehydes
Raleigh W. Parrott II, Christopher G. Hamaker, and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160
Received December 11, 2007
Ph
Et
H
Et
O
Zn
Ph
H
Et
Zn
O
addition followed
by quench
Ph
Me
O
N
OH
(S)-configured product
H
A series of oxazolidines have been prepared by condensation of N-isopropyl norephedrine with a variety
of salicylaldehyde derivatives. Despite the stereochemical relationship of (1R,2S)-norephedrine with
(1R,2S)-ephedrine, the resultant oxazolidines 12-14 were determined to have a stronger stereochemical
relationship with (1S,2S)-pseudoephedrine based oxazolidines. The resultant oxazolidines were used as
catalytic ligands in the addition of diethylzinc to several aldehydes. It was determined that the oxazolidine
derivative 12 gave the highest yield and a moderate enantioselectivity.
J. Heterocyclic Chem., 45, 873 (2008).
INTRODUCTION
ephedrine or pseudoephedrine as the nitrogen substituent
is a methyl group. However, the Ephedra based β-amino-
alcohol norephedrine would be an excellent tool for
There have been many different β-aminoalcohol
structural motifs that have been employed in the catalytic
asymmetric addition of diorganozinc compounds to
Chart 1. Oxazolidine catalysts.
aldehydes [1,2].
Oxazolidines that contain the β-
aminoalcohol moiety have been used to this end. The
oxazolidines that have been prepared are structurally
diverse and vary in terms of their effectiveness as chiral
ligands (Chart 1), [3-7]. Recently, we became interested
in the development of new oxazolidine catalysts for
asymmetric synthetic applications [8]. In this context, we
prepared (1R,2S)-ephedrine based oxazolidine catalyst 6
and (1S,2S)-pseudoephedrine based oxazolidine catalyst 7
(Figure 1). These chiral catalysts were employed in the
asymmetric 1,2-addition of diethylzinc with aldehydes
and gave fair to moderate enantioselectivities (Scheme 1).
The use of the (1R,2S)-ephedrine based oxazolidine
catalyst gave the (R)-configured product, while the
(1S,2S)-pseudoephedrine based catalyst gave the (S)-
configured product. The origin of this enantioselectivity
is believed to be based, in part, on the relative
stereochemistry of the substituents on the oxazolidine
ring. Specifically, the stereochemical positioning of the
phenolic unit is potentially the primary controlling
mechanism responsible for which enantiomer of the
product is formed. In addition to this, it is proposed that
the N-methyl group also plays a role in the magnitude of
enantioselection that is observed. Thus, we became
interested in determining if the magnitude of the
asymmetric induction could be influenced further by
increasing the steric demand of the alkyl group attached to
the nitrogen. This is not directly possible with either
Ph
S
Ph
Ph
Ph
CH3
Bn
S
HO
O
N
CH3
H3C
35 (Braga et al.)
CH3
Et
N
O
N
O
H
H
O
N
13 (Falorni et al.)
24 (Wang et al.)
H
Ph
Ph
O
H
N
N
O
H
H
HO
HO
46 (Nakano et al.)
57 (Ge et al.)
creating new derivatives. Herein, we report on the
synthesis of (1R,2S)-norephedrine based oxazolidine
catalyst with a more sterically demanding nitrogen
substituent and its use in the asymmetric addition of
diethylzinc to carbonyl compounds.
RESULTS AND DISCUSSION
The oxazolidine catalysts used in this work were
prepared by first reductively alkylating enantiomerically
pure norephedrine with acetone, benzaldehyde, or
cyclohexanone in the presence of sodium borohydride

874
R. W. Parrott II, C. G. Hamaker, S. R. Hitchcock
Vol 45
oxazolidines reported in the chemical literature
(Table 2) [11].
Scheme 1
Ph
CH3
Scheme 2
O
N
CH3
Ph
Et2Zn, RCHO
toluene, rt
HO
OH
OH
6
+
OH
(CH3)2CO, MgSO4, EtOH;
NaBH4
CH2CH3
NH2
NHR
H
Ph
Ph
(R)-enantiomer
C(CH3)3
CH3
CH3
6
8
9: R = -CH(CH3)2
10: R = -cyclo-C6H11
11: R = -CH2Ph
Ph
CH3
O
N
CH3
OH
H
Et2Zn, RCHO
toluene, rt
HO
7
+
Ph
CH3
CH2CH3
4
Ph
5
R'
O
N
3
2
(S)-enantiomer
C(CH3)3
OH
CH(CH3)2
OH
1
7
R'
CHO
9
Na2SO4, MeOH
(Scheme 2) [9]. These derivatives were then reacted with
a variety of salicylaldehyde derivatives. The N-isopropyl-
norephedrine derivative 9 was reacted with salicyl-
aldehyde and 3,5-di-tert-butyl-2-hydroxybenz aldehyde to
yield oxazolidines 12 and 13, respectively (Scheme 1).
Oxazolidine 12 was obtained in 40% isolated yield.
Unfortunately, oxazolidine 13 could only be obtained in
11% yield and was isolated as a mixture of diastereomers
[10]. The preparation of N-benzyl- and N-cyclohexyl-
norephedrine derivatives, 10 and 11, respectively, proved
R'
R'
12: R' = -H (40%)
13: R' = -C(CH3)3 (11%)
The substituents on C2, C4, and C5 positions share a
cis-relationship in their orientation as inferred from NOE
experiments. Additionally, the crystal structure also
suggests that the isopropyl group on the N3-nitrogen has a
trans-relationship to the substituents on the ring carbons
due to the intermolecular hydrogen bonding interaction
between N3-nitrogen and the hydroxyl group. The relative
conformation of the nitrogen substituent in the solid state
was determined to be a trans-relationship with the C2, C4
and C5-positon. Based on these collected results and the
1
to be complicated. The crude H NMR spectra of these
compounds suggested that the target oxazolidines had
formed based on the presence of the characteristic C2-
methine proton (~5.1 ppm). However, these compounds
were minor components (<5%) of product mixtures that
were primarily the corresponding starting materials. The
oxazolidines could not be recovered by flash
chromatography, presumably due to the hydrolysis of the
oxazolidines in the presence of silica. Oxazoldines 10
and 11 were ultimately abandoned in lieu of the other
derivatives.
1
similarity of the H NMR spectra of 12 and 13, it is
proposed that oxazolidine 13 also has the same relative
configuration about the oxazolidine ring system.
With oxazolidines 12 and 13 in hand, efforts were made
to determine the stereochemical orientation of the methine
carbon (C2) bearing the aromatic residue of the
salicylaldehyde component. This was accomplished by
obtaining an NOE difference spectrum of oxazolidine 12.
The methine proton H2 was irradiated and the resultant
NOE difference spectrum showed positive enhancements
for the protons H4 and H5.
Oxazolidine 12 was also subjected to X-ray crystal-
lographic analysis to determine the absolute
configuration of the oxazolidine ring system (Figure 1,
Table 1). The ring system (O1/C2/N3/C4/C5) adopts an
envelope conformation and all of the bond distances and
angles are within normal ranges and are similar to other
Figure 1. Crystal structure of 12. Displacement ellipsoids are drawn at
the 30% probability level and hydrogen atoms are shown as spheres of
arbitrary size. The dashed line indicates the intramolecular hydrogen
bond.

May-Jun 2008
Salicylaldehyde Based Oxazolidines
875
Table 1. Crystal data, data collection, and structure refinement data for 12.
Based on the similarity between the structures of the
pseudoephedrine based oxazolidine
7
and the
Empirical formula
Formula weight
Crystal dimensions (mm)
Crystal system
Space group
Unit cell parameters
a (Å)
C19H23NO2
297.38
0.32 × 0.18 × 0.18
orthorhombic
P212121 (No. 19)
norephedrine oxazolidines 12 and 13, the expected
stereochemical outcome of the catalytic asymmetric
addition to benzaldehyde was predicted to give similar
results. Thus, the enantioselective diethylzinc process
with ligands 12 and 13 was pursued.
This was
6.2585 (6)
b (Å)
c (Å)
14.8448 (19)
17.2254 (14)
1600.3 (3)
4
1.234
0.079
R1 = 0.0351, wR2 = 0.0726
R1 = 0.0746, wR2 = 0.0844
1.009
accomplished using 10% mol catalyst loading and three
equivalents of diethylzinc. The results of the catalytic
addition diethylzinc to benzaldehyde revealed moderate
enantioselectivities (Table 3).
V (Å3)
Z
ρcalc (g cm-1)
µ (mm-1)
As predicted, the norephedrine based catalysts 12 and
13 afforded the same absolute stereochemistry of the
alcohol product as the pseudoephedrine based catalyst 7.
This suggested that the stereochemistry in the region of
the C2/N3/C4 tandem was the determinant of the
stereochemical outcome of the catalysis. In this regard,
oxazolidine 13 gave a higher level of enantioselection but
proved to be difficult to prepare in sufficient quantities to
R indices (F2 > 2σ(F2))
R indices (all data)
GOF
Largest peak and hole (e·Å-3)
0.152 and – 0.178
With the stereochemistry about the oxazolidine ring
system of 12 established, a structural comparison was
made with Ephedra based oxazolidines 6 and 7 that were
previously prepared [8]. It was determined that the
relative configurations of the C2- and C4-positions around
the N3-nitrogen of 12 more closely resembled the
configuration of the pseudoephedrine based oxazolidine 7
than the ephedrine based oxazolidine 6 (Figure 2). The
stereochemical relationship between 7 and 12 would
suggest that the stereochemical outcome in the
asymmetric addition of diethylzinc to benzaldehyde
would lead to would lead to the same resultant product
with the (S)-configuration.
1
allow for further testing. In addition to this, the H and
13C NMR spectra suggested the presence of the C2-epimer.
Attempts to remove the C2-epimer by either
recrystallization or chromatography were not successful.
In contrast oxazolidine 12 could be readily obtained as a
single diastereomer by recrystallization as determined by
1H NMR spectroscopy.
Table 3. Enantioselective addition of diethylzinc to benzaldehyde with
oxazolidines 7 and 12-13.
OH
O
Table 2. Selected bond lengths and angles for 12.
oxazolidne catalyst
Et2Zn, toluene
Ph
H
Ph
H
Bond lengths (Å)
Bond angles (°)
C2-N3-C31
C4-N3-C31
C4-N3-C2
N3-C4-C5
O1-C5-C4
C2-O1-C5
O1-C2-N3
Et
C31-N3
C4-N3
C2-N3
C2-C21
C2-O1
C5-O1
C4-C5
1.492 (3)
112.72 (19)
117.9 (2)
er (|S-R|)b
74.5:25.5 (49)
69.0:31.0 (38)
77.5:22.5 (55)
1.481 (3)
1.482 (3)
1.509 (3)
1.420 (3)
1.442 (3)
1.565 (4)
entry
ligand
7d
12
%completiona
config.c
106.12 (19)
102.39 (19)
105.28 (19)
105.83 (18)
102.87 (19)
1
2
3
99
94
92
S
S
S
13
aThe degree of completion was determined by 1H NMR
spectroscopy. bThe enantiomeric ratios were determined via
CSP HPLC using a Chiralcel-OD column. cThe absolute
configuration of the product was determined by comparison of
optical activities and retention times in the literature values [12].
dThe enantioselectivity derived from ligand 7 was previously
determined [8].
Torsion angles (°)
C21-C2-
N3-C4
156.8 (2)
C21-C2-
N3-C31
– 72.8 (3)
Thus, catalyst 12 was utilized in the asymmetric 1,2-
addition of diethylzinc to various aldehydes to test the
capabilities of this structural family of catalysts. The
addition occurred readily with both aromatic and aliphatic
aldehydes and the stereochemical outcome was greater on
average for aromatic aldehydes, although the
enantioselectivities were modest at best. The result
obtained from the use of n-hexanal was anomalous as
compared to the other entries. The enantiomeric ratio
seemed to suggest that the aldehyde could be attacked
Ph
R
CH3
S
Ph
S
CH3
S
Ph
R
CH3
S
O
N
CH3
O
N
CH3
O
N
S
CH(CH3)2
OH
R
S
OH
OH
C(CH3)3
C(CH3)3
6
12
7
Ephedrine based
Norephedrine based
Pseudoephedrine based
Figure 2

876
R. W. Parrott II, C. G. Hamaker, S. R. Hitchcock
Vol 45
from either the Re- or Si-face with little discrimination for
the steric volume of the n-hexanal side chain.
Nonetheless, there was significant discrimination in the
case of the aromatic aldehydes.
EXPERIMENTAL
General Remarks. Toluene was purchased as an anhydrous
reagent and used without further purification. All reactions were
run under a nitrogen atmosphere. Unless otherwise noted, all 1H
and 13C NMR spectra were recorded in CDCl3 using an NMR
spectrometer operating at 400 MHz and 100 MHz, respectively.
Chemical shifts are reported in parts per million (δ scale), and
coupling constants (J values) are listed in hertz (Hz).
Tetramethylsilane (TMS) was used as the internal standard (δ =
0 ppm). Infrared spectra are reported in reciprocal centimeters
(cm-1) and are measured either as a nujol mull, a neat liquid, or
in CHCl3. Melting points were recorded on a Mel-Temp
apparatus and are uncorrected. Mass spectral analyses were
conducted by the mass spectrometry analytical laboratories of
Table 4. Enantioselective additions of diethylzinc to aldehydes via
oxazolidine 12.
entry
aldehyde
C6H5-
p-CH3OC6H4-
p-ClC6H4-
t-PhCH=CH-
C5H11-
%completiona
er (|S:R|)b
config.c
1
2
3
4
5
94
28
95
86
92
69.0:31.0 (38)
73.5: 26.5 (47)
71.0:29.0 (42)
65.0:35.0 (30)
45.5:54.5 (9)
S
S
S
S
R
1
aThe percent completion was determined by evaluating the H NMR
spectra. bThe enantiomeric ratios were determined via CSP HPLC
using a Chiralcel-OD column. cThe configuration was determined by
comparison with retention times and optical activities in the chemical
literature [12].
the University of Illinois at Urbana-Champaign using
a
quadrapole time of flight mass spectrometer hybrid with MS/MS
capability.
Crystal Structure Determination. Colorless crystals of
C19H23NO2 (12) were isolated by crystallization from
a
hexane/ether solution at low temperature. Data for 12 were
collected on a Bruker-Nonius CAD4/Mach3 diffractometer
equipped with an Oxford Cryostreams Cobra cryostat using Mo
Kα radiation at –100 ºC. Data collection and cell refinement
was performed using CAD4 express [14]. Data reduction was
carried out using XCAD4 [15]. Unit cell parameters were
obtained from a least-squares refinement of 25 centered
reflections. See Table 1 for a summary of crystal data and X-ray
collection information. The structure of 12 was solved using the
direct methods program SIR-92 [16] and refinement was
completed using the program SHELXL-97 [17]. Carbon C41
was found to be disordered over two positions, with both
positions having 50% occupancy. Carbon 41a was modeled
anisotropically, while carbon 41b was modeled isotropically.
Hydrogen atoms attached to carbon were assigned positions
based on the geometries of their attached carbons and were
refined as riding with C-H distances between 0.95Å and 1.00 Å
and with Uiso(H) = 1.2Ueq(C) The hydrogen attached to oxygen
was assigned its position based on the Fourier difference map.
Crystallographic data for compound 12 have been deposited
with the Cambridge Crystallographic Data Centre (CCDC),
CCDC No. 662535. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033; email:
deposit@ccdc.cam.ac.uk.
Procedure for the Reductive Alkylation of Norephedrine.
To a flame dried, nitrogen purged flask was added (1R,2S)-
norephedrine 8a (10.1 g, 66.8 mmol), ethanol (100 mL), and
acetone (7.4 mL, 100 mmol). The mixture was allowed to stir at
room temperature for 24 hours. At that time, the solution was
cooled to 0 ºC and sodium borohydride (5.07 g, 134 mmol) was
added and allowed to stir for 2 hours. The ethanol was removed
under reduced pressure and the reaction quenched with sodium
hydroxide (1M, 100 mL). The product was extracted with ethyl
acetate (100 mL x 2), washed with brine, dried with magnesium
sulfate, gravity filtered, and concentrated under reduced
pressure. The amino alcohol was purified via recrystallization
with hexanes: ethyl acetate (2:1) to afford 9 as a white solid in
70% yield.
The proposed transition state for asymmetric addition
of diethylzinc to benzaldehyde catalyzed by oxazolidine
12 is illustrated in Scheme 3. This proposed mechanism
is derived from the structure obtained from X-ray
crystallography of 12 in conjunction with literature
examples of proposed mechanisms [13].
CONCLUSION
The introduction of a more sterically demanding N3-
isopropyl substituent in oxazolidine 12 had only a limited
impact in the catalytic enantioselective addition of
diethylzinc to aldehydes. It is apparent that alternate
strategies must be applied with oxazolidines in order to
exploit their full potential as ligands in this catalytic
process. Research is underway to address alternative
means of enhancing the efficacy of oxazolidines as
asymmetric catalysts.
Scheme 3
Ph
Et
H
Et
O
Zn
Ph
H
Et
Zn
O
addition followed
by quench
Ph
Me
O
N
OH
(S)-configured product
H
Proposed favored transition state for 12
H
Et
Ph
Et
O
Zn
Zn
O
H
Et
addition followed
by quench
Ph
Me
O
N
Ph
OH
(R)-configured product
H
unfavored transition state for 12

May-Jun 2008
Salicylaldehyde Based Oxazolidines
877
25
(1R,2S)-2-Isopropylamino-1-phenyl-1-propanol (9). [α]D
= -10.3 (c 1.28, CHCl3). Mp = 99-101 oC. 1H NMR: δ 0.80 (d,
J = 6.6 Hz, 3H), 1.10 (t, J = 7.2 Hz, 6H), 2.97 (m, 1H), 3.05 (dq,
J = 4.0, 6.6 Hz, 1H), 4.70 (d, J = 4.0 Hz, 1H), 7.23-7.35 (m,
5H). Characterization data for this compound matched the
identical compound found in the literature [9b].
(1R,2S)-2-(Benzylamino)-1-phenyl-1-propanol (10). [18]
Using benzaldehyde, the title compound was obtained in 99%
yield as a clear oil. Rf = 0.42 (90:10 hexanes/EtOAc). [α]D25 = -
30.0 (c 0.86, CHCl3). 1H NMR (CDCl3): δ 0.86 (d, J = 6.6 Hz,
3H), 3.01 (dq, J = 6.6, 3.5 Hz, 1H), 3.89 (s, 2H), 4.80 (d, J = 3.5
Hz, 1H), 7.26-7.35 (m, 10H). 13C NMR (CDCl3): δ 14.7, 51.4,
58.1, 73.9, 126.6, 127.4, 127.5, 128.4, 128.5, 128.9, 140.3,
142.2. IR (CHCl3): 3406, 3028, 1603, 1028, 732, 700 cm-1.
HRMS (ESI) calcd for C16H20NO (M + H)+: 242.1535 Found:
242.1545.
(1R,2S)-2-Cyclohexylamino-1-phenyl-1-propanol (11). The
purified product was isolated via recrystallization (ethyl
acetate/hexanes) in 85% yield. Mp: 89-91 °C. [α]D25 = +11.2 (c
1.66, CH2Cl2). 1H NMR (CDCl3): δ, 0.78 (d, J = 6.6 Hz, 3H),
1.00-1.34 (m, 7H), 1.59-1.64 (m, 1H), 1.71-1.75 (m, 1H), 1.85-
1.96 (m, 1H), 2.52-2.59 (m, 1H), 3.05-3.11 (m, 1H), 4.66 (d, J =
4.0 Hz, 1H), 7.21-7.34 (m, 5H). 13C NMR (CDCl3): δ, 12.7,
24.8, 24.9, 25.5, 31.8, 32.5, 54.3, 55.8, 72.4, 126.0, 127.0, 128.0,
140.9. IR (nujol mull): 3278, 1102, 738, 701 cm-1. ESI-HRMS
calcd for C15H23NO (M + H)+: 234.1858. Found: 234.1858.
General Procedure for Oxazolidine Synthesis with 2-
hydroxybenzaldehyde. To a flame dried, nitrogen purged flask
was added 9 (2.05 g, 10.6 mmol), methanol (45 mL), 2-
hydroxybenzaldehyde (1.12 mL, 10.6 mmol), and sodium sulfate
(7.50 g, 53.2 mmol). The mixture was stirred under reflux for
17 hours and filtered through Celite. Excess solvent was
removed under reduced pressure and the product was
recrystallized with ethyl ether and hexanes (1:2).
3411, 1607, 1168, 755, 703 cm-1. ESI-HRMS calcd for
C27H40NO2 (M + H)+: 410.3059. Found: 410.3060.
General Procedure for the Addition of Diethylzinc to
Aldehydes. Oxazolidine 12 (0.088 g, 0.29 mmol) was added
with toluene (4 mL) to a flame dried flask in an inert
atmosphere. A solution of diethylzinc in hexanes (1M, 8.92 mL)
was added and allowed to stir at room temperature for 25
minutes. At that time, benzaldehyde (0.30 mL, 2.97 mmol) was
added and allowed to stir at room temperature for 24 hours. The
reaction was quenched with a saturated ammonium chloride
solution (50 mL) and the corresponding alcohol was extracted
using ethyl acetate (50 mL x 2). The alcohol was washed with
brine, dried with magnesium sulfate, gravity filtered, and
concentrated under reduced pressure.
Chiral Stationary Phase HPLC (CSP HPLC) analysis.
The enantioselectivity of the asymmetric addition of diethylzinc
to the carbonyl compounds was determined after the reactions
were quenched and extracted. The determination was carried
out via chiral stationary phase HPLC. A Chiralcel-OD column
was employed with a UV detector operating at 254 nm. The
solvent system was composed of a mixture of hexanes and
isopropanol (99.5:0.5) and the flow rate was 1 mL/min.
1-Phenyl-1-propanol: tR = 11.8 (R) and 14.8 (S) min.
1-(4-Methoxyphenyl)propan-1-ol: tR = 16.3 (R) and 19.3 (S)
min.
1-(4-Chlorophenyl)propan-1-ol: The product of the addition
of diethylzinc with 4-chlorobenzaldehyde was derivatized with
2-naphthoyl chloride. Retention time for 1-(4-chlorophenyl)-
propan-1-ol (as naphthoate): tR = 12.8 (R) and 10.6 (S) min.
1-Phenyl-1-penten-3-ol: tR =22.8 (R) and 43.1 (S) min.
3-Octanol: The product of the diethylzinc addition to
hexanal was derivatized as the 2-naphthoate derivative: tR
20.2 (R) and 18.9 (S) min.
=
Acknowledgements. This research was funded in part by a
Research Enhancement Award from Illinois State University's
College of Arts & Sciences. The authors gratefully acknowledge
support for this work, in part, by the National Science
Foundation (NSF grant# CHE 644950) and the donors of the
Petroleum Research Fund as administered by the American
Chemical Society (PRF grant # B 40777-1).
2-[(2S,4S,5R)-3-Isopropyl-4-methyl-5-phenyloxazolidin-2-
yl] phenol (12). Using 2-hydroxybenzaldehyde and 9, the title
25
compound was obtained as white crystals (40%). [α]D
=
-133.6 (c 0.43, CH2Cl2). Mp = 96-98 ºC. 1H NMR (CDCl3): δ
0.88 (d, J = 7.2 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 1.21 (d, J =
6.6 Hz, 3H), 3.09 (septet, J = 6.6 Hz, 1H), 3.55 (pentet, J = 6.6
Hz, 1H), 5.09 (d, J = 7.2 Hz, 1H), 5.38 (s, 1H), 6.81-6.87 (m,
2H), 7.18-7.31 (m, 7H), 12.29 (br s, 1H). 13C NMR (CDCl3): δ
18.8, 19.3, 21.6, 50.7, 57.6, 81.1, 81.2, 95.2 (epimer), 95.3
(epimer), 117.0, 118.8, 120.8, 126.4, 127.6, 128.1, 130.2
(epimer), 130.3 (epimer), 136.6, 158.7. IR (nujol mull): 1174,
753, 712, 702 cm-1. ESI-HRMS calcd for C19H24NO2 (M + H)+:
298.1807. Found: 298.1817.
REFERENCES AND NOTES
[1] Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757-824.
[2] Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856.
[3] Falorni, M.; Collu, C.; Conti, S.; Giacomelli, G.
Tetrahedron: Asymm. 1996, 7, 293-299.
2,4-Di-tert-butyl-6-((2S,4S,5R)-3-isopropyl-4-methyl-5-
phenyloxazolidin-2-yl)phenol (13). Using 3,5-di-tert-butyl-2-
hydroxybenzaldehyde and 9, the title compound was obtained as
white crystals (11%). [α]D25 = -72.2 (c 0.30, CHCl3). Mp = 94-
96 ºC. 1H NMR (CDCl3): δ 0.88 (epimer, d, J = 7.2 Hz, 3H),
0.90 (d, J = 6,6 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.20 (d, J =
6.6 Hz, 3H), 1.30 (s, 9H), 1.45 (s, 9H), 3.09 (epimer, septet, J =
6.6 Hz, 1H), 3.12 (septet, J = 6.6 Hz, 1H), 3.58 (pentet, J = 6.6
Hz, 1H), 5.09 (d, J = 7.2 Hz, 1H), 5.36 (s, 1H), 7.04 (d, J = 2.0
Hz, 1H), 7.25-7.37 (m, 5H), 12.15 (br s, 1H). 13C NMR
(CDCl3): δ 14.8 (epimer), 18.1, 19.3 (epimer), 21.6 (epimer),
23.1 (epimer), 23.3, 29.5, 31.7, 34.1 (epimer), 35.0, 45.9
(epimer), 49.9, 55.4 (epimer), 56.9, 73.2, 81.4, 96.2, 119.4,
124.6, 125.0, 126.1, 126.7 (epimer), 127.0, 127.6, 128.0
(epimer), 128.1, 136.1, 137.2, 139.9, 155.5. IR (nujol mull):
[4a] Kang, Y.-F.; Liu, L. Synth. Commun. 2005, 35, 1819-1823.
[b] Kang, Y.-F.; Liu, L.; Wang, R.; Zhou, Y.-F.; Yan, W.-J. Adv. Syn.
Cat. 2005, 347, 243-247. [c] Kang, Y.-F.; Wang, R.; Liu, L.; Da, C.-S.;
Yan, W.-J.; Xu, Z.-Q. Tetrahedron Lett. 2005, 46, 863-865.
[5a] (a) Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann,
L. A.; Schneider, P. H. Tetrahedron 2002, 58, 10413-10416. (b) Braga,
A. L.; Rodrigues, O. E. D.; Paixao, M. W.; Appelt, H. R.; Silveira, C. C.;
Bottega, D. P. Synthesis 2002, 16, 2338-2340.
[6a] H Nakano, H.; Okuyama, Y.; Fushimi, K.; Yamakawa, R.;
Kayaoka, D.; Hongo, H. Heterocycles 2002, 56, 457-466. [b] Nakano,
H.; Okuyama, Y.; Iwasa, K.; Hongo, H. Heterocycles 2001, 54, 411-418.
[7] Ge, J. F.; Shen, Z. X.; Zhang, Y. W.; Lu, X. H.; Lu, Z. E.
Chin. J. Chem. 2003, 21, 950-954.
[8] Parrott II, R. W.; Hitchcock, S. R. Tetrahedron: Asymm.
2007, 18, 377-382.
[9a] Baxter, E. W.; Reitz, A. B. “Reductive Aminations of

878
R. W. Parrott II, C. G. Hamaker, S. R. Hitchcock
Vol 45
Carbonyl Compounds with Borohydride and Borane Reducing Agents,”
Overman, L. E., Ed. Org. React. 2002, 59, pp. 3-714. [b] Hitchcock,
S.R.; Casper, D. M.; Vaughn, J. F.; Finefield, J. M.; Ferrence, G. M.;
Esken, J. M. J. Org. Chem. 2004, 69, 714-718.
[10] The 1H NMR spectra of the oxazolidine 13 exhibited extra
peaks in the 1H and 13C NMR spectra. The extra peaks were attributed to
either the presence of C2-epimer or atropisomers. Atropisomers have
been observed in oxazolidines. Please see: Clayden, J.; Lai, L.W.;
Helliwell, M. Tetrahedron 2004, 60, 4399.
[13a] Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem.
Soc. 1998, 120, 9800-9809. [b] Goldfuss, B.; Houk, K. N. J. Org.
Chem. 1998, 63, 8998-9006.
[14] Enraf-Nonius, CAD4 Express Software, Delft, The
Netherlands, 1994.
[15] Harms, K.; Wocadlo, S. XCAD-4: Program for Processing
CAD-4 Diffractometer Data, University of Marburg, Germany, 1995.
[16] Altomare, A.; Cascarano, G.; Giacovazzo; C.; Guagliardi, A.
J. Appl. Crystallogr. 1993, 26, 343.
[11] Duffy, M.; Gallagher, J. F.; Lough, A. J. Acta Cryst. 2004,
E60, o234.
[12a] González-Sabín, J.; Gotor, V.; Rebolledo, F. Tetrahedron:
Asymm. 2006, 17, 449-454. [b] Bauer, T.; Gajewiak, J. Tetrahedron:
Asymm. 2005, 16, 851-855. [c] Dave, R.; Sasaki, A. Tetrahedron:
Asymm. 2006, 17, 388-401.
[17] Sheldrick, G. M. SHELXL-97: Programs for Crystal
Structure Analysis (Release 97-2). G. M. Sheldrick, , Institüt für
Anorganische Chemie der Universität, Tammanstrasse 4, D-3400
Göttingen, Germany, 1998.
[18] Bohe, L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X.
Tetrahedron Lett. 1993, 34, 7271-7274.