Efficient one-step synthesis of chiral bidentate oxazoline-alcohol ligands via a cyclic imidate ester rearrangement

Article abstract of DOI:10.1016/j.tetasy.2009.07.038

Various chiral bidentate oxazoline-alcohol ligands were obtained in a straightforward one-step synthesis via a cyclic imidate ester rearrangement. These chiral ligands were tested and compared in asymmetric diethylzinc additions to aldehydes resulting in

Full text of DOI:10.1016/j.tetasy.2009.07.038

Tetrahedron: Asymmetry 20 (2009) 1962–1968
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Tetrahedron: Asymmetry
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Efficient one-step synthesis of chiral bidentate oxazoline-alcohol ligands
via a cyclic imidate ester rearrangement
Timothy Noël a, Koen Robeyns b, Luc Van Meervelt b, Erik Van der Eycken c, Johan Van der Eycken a,
*
a Laboratory for Organic and Bioorganic Synthesis, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S.4), B-9000 Ghent, Belgium
b Biomolecular Architecture, Department of Chemistry, K.U. Leuven, Celestijnenlaan 200 F, B-3001 Leuven (Heverlee), Belgium
c Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Various chiral bidentate oxazoline-alcohol ligands were obtained in a straightforward one-step synthesis
via a cyclic imidate ester rearrangement. These chiral ligands were tested and compared in asymmetric
diethylzinc additions to aldehydes resulting in selectivities of up to 87% ee. An interesting chirality switch
was observed when a CPh2-tether instead of a CH2 was present, offering the opportunity for dual
stereocontrol.
Received 4 June 2009
Accepted 28 July 2009
Available online 14 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
result, substituents at C-2 of the oxazoline moiety can be readily
incorporated.6 Very recently, we discovered a method to synthe-
The key to successful asymmetric catalysis lies in the careful
combination of a suitable ligand with an appropriate metal.1 The
factors determining the success of a ligand are the availability
and price of the starting materials, the ease of synthesis, and the
possibility to obtain structural variation.2 A large variety of chiral
amino acids are readily available in sufficient quantities from the
chiral pool and have been used for the synthesis of chiral oxazoline
ligands.3
Chiral oxazolines bearing a hydroxyl substituent show excellent
catalytic activity in the asymmetric addition of diethylzinc to alde-
hydes.4 Bolm et al. studied the role of planar chirality versus cen-
tral chirality in ferrocene ligands (Fig. 1).5 The combination of
the proper planar chirality and central chirality resulted in a highly
active ligand 1. Remarkably, ligand 2 containing only the central
chirality also displays high enantioselectivity and catalytic
activity.5a
size chiral imidate ligands starting from cyclic imidate ester 3A.7
In the present paper, we describe the use of this imidate in an
efficient one-step reaction to synthesize analogues of 2 bearing a
CH2– instead of a CPh2-tether. The newly synthesized ligands were
tested and compared in the asymmetric diethylzinc addition to
benzaldehydes.
2. Results and discussion
Condensation of imidate esters 3A–C with several aminoalco-
hols 4a–f resulted in the corresponding oxazoline ligands 6 or imi-
date ligands 5 (Table 1) (Fig. 2). No formation of the imidate
alcohols was observed for (1S,2R)-cis-1-amino-2-indanol 4a,
(S)-tert-leucinol 4b, and (S)-valinol 4c: the oxazoline-alcohol was
obtained in quantitative yield (Table 1, entries 1–3). However, with
(S)-phenylglycinol 4d and (S)-phenylalaninol 4e a mixture of imi-
date alcohol and oxazoline-alcohol was formed, indicating only a
small free energy difference between both products (entries 4
and 5).8 Separation of the two components via preparative HPLC
was not possible, suggesting a rapid equilibration. With (1R,2R)-
trans-1-amino-2-indanol 4f, it was possible to selectively form
the imidate alcohol (entry 6).7 The condensation of the substituted
imidate esters 3B–C with aminoalcohol 4a similarly resulted in the
corresponding oxazoline ligands 6aB–6aC in good yield (entries
7 and 8).
O
O
t-Bu
N
t-Bu
N
OH
Fe
OH
Ph
Ph
(S,Rp)-1
Ph Ph
(S)-2
Figure 1. Examples of bidentate oxazoline-alcohol ligands.
It is known that the synthesis of oxazolines can be efficiently
performed via reaction of an aminoalcohol and an imidate. As a
Introduction of substituents on the imidate ester starts from the
commercially available substituted 2-methylbenzonitriles (Scheme
1). A Wohl–Ziegler reaction with NBS (1.1 equiv) afforded the
desired monobromide 8B–C. However, formation of a certain
amount (up to 24%) of dibromide 9B–C could not be prevented. This
* Corresponding author. Tel.: +32 9 264 44 80; fax: +32 9 264 49 98.
E-mail address: Johan.Vandereycken@UGent.be (J.V.d. Eycken).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.038

T. Noël et al. / Tetrahedron: Asymmetry 20 (2009) 1962–1968
1963
Table 1
CN
CN
Br
CN
Wohl-Ziegler
Synthesis of imidates 5 and oxazolines 6
+
R
R
R
Br
8
For : 1.1 eq NBS
R1
N
R2
9
R1
R2
For : 3 eq NBS
7B-C
8B-C
Br
*
*
9B-C
NH
* *
R= 2-Cl B,
4-Cl C
OH
H2N
OH
O
4a-f
.HCl
O
AgNO3,
CH3CN/H2O
83-90%
Me3NO,
DMSO, CH2Cl2
53 - 67%
Et3N, CH2Cl2
5
R
3A-C
R
NH2Cl
O
R = H 3A, 2-Cl 3B,
4-Cl 3C
1. NaBH4, EtOH
CN
2. HCl in dry Et2O
R
R
R2
H
94-96%
*
*
O
N
O
10B-C
3B-C
R1
Scheme 1. Synthesis of substituted imidate esters 3B–C.
OH
R
6
NaBH4 resulted in immediate formation of the imidate which was
isolated as a crystalline HCl salt.
R1
R2
OH
OH
*
*
:
H2N
OH
The synthesized ligands were tested and compared in the asym-
NH2
NH2
metric diethylzinc addition to benzaldehyde 11 (Table 2).9
4a
R
Table 2
H2N
OH
Asymmetric addition of diethylzinc to benzaldehyde in the presence of N,O-ligands
R = t.Bu 4b, i-Pr 4c
Ph 4d, PhCH2 4e
4f
O
OH
Et2Zn (1.5 equiv)
Ligand (10 mol%)
Entry Imidate Aminoalcohol 4
Yield
Yield
H
toluene, T = 0°C
ester
oxazoline 6a
imidate
(%)
5a (%)
11
Ligand
(S)-12
b
1
3A
(1S,2R)-cis-1-Amino-2-
indanol 4a
(S)-tert-Leucinol 4b
(S)-Valinol 4c
(S)-2-Phenylglycinol 4d
(S)-Phenylalaninol 4e
(1R,2R)-trans-1-Amino-2-
indanol 4f
Quant. 6aA
Entry
Time (h)
Yielda (%)
% eeb
Configurationc
b
b
2
3
3A
3A
3A
3A
3A
Quant. 6bA
Quant. 6cA
51.7 6dA
1
2
6aA
6bA
6cA
5fA
6aB
6aC
48
48
48
24
48
48
69
31
60
14
25
66
85
55
44
36
15
79
S-(ꢀ)
S-(ꢀ)
S-(ꢀ)
S-(ꢀ)
S-(ꢀ)
S-(ꢀ)
4c
5c
6
48.3 5dA
30.9 5eA
91 5fA
69.1 6eA
3
b
4d
5
b
b
7
8
3B
3C
4a
4a
83 6aB
66 6aC
6
a
Isolated yield.
a
b
c
b
Isolated yield.
Determined by HPLC analysis with a chiral stationary phase column (Chiralcel
n.d.: not detected.
An inseparable mixture of imidate and oxazoline is formed.
OD–H).
c
Assigned by the sign of the specific rotation.
d
Reaction performed at room temperature.
O
O
O
The best result was obtained with 6aA as a chiral ligand (69%
N
HO
N
N
HO
yield, 85% ee) (Table 2, entry 1). Less bulky groups on the oxazoline
ring result in a lower selectivity (Table 2, entries 2 and 3). When
performed with the imidate alcohol 5fA as a chiral ligand, the
reaction was sluggish and a low enantioselectivity was observed
(Table 2, entry 4). Surprisingly, when the reaction was performed
with ligand 6aB, containing a chlorine substituent in the ortho-
position, 12 was obtained in a low yield and an enantioselectivity
(Table 2, entry 5). In contrast, ligand 6aC, bearing a chlorine in the
para-position of the oxazoline substituent, afforded a yield and a
selectivity which were only slightly lower than those with 6aA
(Table 2, entry 6).
HO
6aA
6bA
6cA
OH
O
O
Cl
N
O
N
N
HO
HO
Cl
6aB
6aC
5fA
With 6aA as our best ligand, we tried to optimize the reaction
parameters (Table 3). Addition of Ti(iOPr)4 resulted in a higher
yield but a lower selectivity (Table 3, entry 1). In the presence of
Ti(iOPr)4 and n-BuLi, the reaction was rather unselective (Table 3,
entry 2). When the reaction was performed with only n-BuLi to
deprotonate the ligand, the yield and the selectivity did not im-
prove (Table 3, entry 3). Varying the solvent had no beneficial ef-
fect as compared to our initial experiment (Table 3, entries 4–7).
Next, a variety of substituted arylaldehydes were submitted
(Table 4) to the optimized conditions of Table 2 (entry 1). In gen-
eral, lower yields and selectivities were obtained in comparison
Figure 2. Oxazoline and imidate ligands synthesized.
resulted in lower yields (57–82%) and a difficult separation. More-
over, low yields were obtained in the oxidation of the monobromide
with Me3NO. In contrast, reaction of 7 with 3 equiv of NBS resulted
selectively in the dibrominated product 9 in excellent yield (94–
98%). Hydrolysis of 9 with AgNO3 in CH3CN/H2O afforded 10 in very
high yields. The formation of imidate ester 3B–C occurred nicely via
our recently optimized method:7 treatment of aldehyde 10 with

1964
T. Noël et al. / Tetrahedron: Asymmetry 20 (2009) 1962–1968
Table 3
2-bromobenzonitrile,
ZnCl2, chlorobenzene,
Treflux
Asymmetric addition of diethylzinc to benzaldehyde in the presence of 6aA as a chiral
ligand
O
OH
N
30%
O
OH
Et2Zn (1.5 equiv)
4a
13
NH2
6aA (10 mol%)
Br
H
solvent, T = 0°C, 48h
1. n.BuLi, Et2O, T = -78ºC
2. benzophenone,
T = -40ºC to RT
11
(S)-12
O
65%
N
Entry
Solvent
Additivea
Yieldb (%)
% eec
HO
1
2
3
4
5
6
7
Toluene
Toluene
Toluene
n-Hexane
CH2Cl2
THF
Ti(iOPr)4
82
57
46
13
36
9
55
9
Ti(iOPr)4/n-BuLi
Ph
Ph
n-BuLi
63
29
73
81
84
14
/
/
/
/
Scheme 2. Synthesis of the analogue 14 of 6aA with a CPh2-tether.
Et2O
58
a
b
c
The additives were added in an equimolar amount relative to the ligand.
Isolated yield.
Determined by HPLC analysis with a chiral stationary phase column (Chiralcel
gand remained unchanged. Similar effects have been reported in
other papers and are known as ‘dual stereocontrol’.10,11 Further-
more, in the case of the indane-fused oxazolines 6aA and 14,
increasing the steric bulk of the tether resulted in a lower enanti-
oselectivity. In contrast, when the chiral substituent on the oxaz-
oline moiety was a t-butyl-substituent, higher enantioselectivities
were obtained with a bulky phenyl-substituted tether.5a This ef-
fect, together with the dual stereocontrol, suggests that the intro-
duction of the phenyl substituents modifies the catalytic
mechanism or the structure of the catalytic site.10,11
OD–H).
with those of unsubstituted benzaldehyde. The best result was ob-
tained with 2-naphthaldehyde (Table 4, entry 4).
Table 4
Asymmetric addition of diethylzinc to several arylaldehydes in the presence of 6aA as
chiral ligand
Entry
Arylaldehyde
Yielda (%)
% eeb
Configurationc
1
2
3
4
5
2-Cl-Benzaldehyde
3-Cl-Benzaldehyde
4-Cl-Benzaldehyde
2-Naphthaldehyde
trans-Cinnamaldehyde
57
46
24
52
32
55
74
62
87
61
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
3. Conclusion
In conclusion, we have successfully developed a one-step synthe-
sis of chiral bidentate CH2-tethered oxazoline-alcohol ligands via a
cyclic imidate ester rearrangement. Application of the ligands in
the diethylzinc addition to arylaldehydes resulted in good enanti-
oselectivities (up to 87% ee). We have also shown that the presence
of a CPh2-tether causes a chirality switch, offering the opportunity
for tuning the enantioselectivity via dual stereocontrol.
a
Isolated yield.
b
Determined by HPLC analysis with a chiral stationary phase column (Chiralcel
AD–H, OB–H, and OD–H), see Section 4.
c
Assigned by the sign of the specific rotations.
Suitable crystals for X-ray diffraction analysis were grown from
a solution of 6aA in isooctane/Et2O. An X-ray structure was ob-
tained, and is shown in Figure 3. The hydroxyl proton forms a
hydrogen bond with the nitrogen of the oxazoline moiety. As a re-
sult, a stable seven-membered ring chelate is formed.
4. Experimental
4.1. General
All reactions were carried out under argon atmosphere in dry
solvents under anhydrous conditions, unless otherwise stated.
Benzaldehyde was passed through basic alumina. All other re-
agents were purchased and used without purification, unless
otherwise noted. Analytical TLC was performed using Macherey-
Nagel SIL G-25 UV254 plates. Flash chromatography was carried
out with Rocc silicagel (0.040–0.063 mm). 1H NMR and 13C NMR
were recorded on a Bruker Avance 300 or a Bruker AM 500 spec-
trometer as indicated, with chemical shifts reported in ppm rela-
tive to TMS, using the residual solvent signal as a standard. 13C
NMR spectra were recorded using the attached proton test. IR-
spectra were recorded on a Perkin–Elmer spectrum 1000 FT-IR
spectrometer with a Pike Miracle HATR module. EI Mass spectra
were recorded with a Hewlett–Packard 5988A mass spectrometer.
LC–MS analysis was performed on an Agilent 1100 series HPLC
with quaternary pump, DAD, and single quadrupole MS detector
Figure 3. X-ray structure of 6aA.
Remarkably, with (S)-6bA as the ligand we obtained (S)-12 with
an ee of 55% (Table 2, entry 2), with the related (S)-2 as a ligand. Bolm
et al. reported formation of the opposite enantiomer (R)-12 with 92%
ee.5a In order to verify if this chirality switch also holds for other li-
gands, we synthesized (1S,2R)-14 as an analogueof (1S,2R)-6aA with
a CPh2-tether (Scheme 2). When the diethylzinc addition was per-
formed in the presence of 14, indeed the opposite enantiomer (R)-
(12) was obtained in 86% yield, but with only 22% ee.
type VL with an API-ES source, using
a
Phenomenex Luna
C18(2) column (250 ꢁ 4.6 mm, particle size 5
lm). Analytical chi-
ral HPLC separations were performed on an Agilent 1100 series
HPLC system with DAD detection. Exact molecular masses were
measured on a Kratos MS50TC mass spectrometer. Melting points
were measured with a Kofler melting point apparatus.
Clearly, this chirality switch is caused by the presence of the
two phenyl substituents, as the absolute configuration of the li-

T. Noël et al. / Tetrahedron: Asymmetry 20 (2009) 1962–1968
1965
4.2. A typical procedure for the preparation of the substituted
2-(bromomethyl)benzonitriles
(300 MHz, CDCl3): d 6.92 (s, 1H), 7.41 (dd, J = 2.0, 8.4 Hz, 1H),
7.55 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.0, 1H). 13C NMR (75.4 MHz,
CDCl3): d 34.3 (CH), 106.9 (C), 115.2 (C), 130.4 (CH), 130.6 (CH),
133.5 (CH), 140.5 (C), 145.9 (C). IR (HATR): 3080, 3058, 3028,
3004, 2359, 2227, 1589, 1556, 1481, 1462, 1404, 1304, 1279,
4.2.1. Synthesis of 2-chloro-6-(bromomethyl)benzonitrile 8B
A solution of 2-chloro-6-methylbenzonitrile 7B (4.83 g, 31.9
mmol), NBS (6.24 g, 35.1 mmol), and benzoylperoxide (232.0 mg,
0.96 mmol) in CCl4 (100 mL) was refluxed for 7 h. Afterwards, the
solids are filtered off and the filtrate was concentrated in vacuo.
The crude product was purified by flash chromatography over
silicagel (pentane/Et2O, 90/10) resulting in pure 8B, 4.35 g (82%).
No formation of the dibromo product 9B was observed. 1H NMR
(300 MHz, CDCl3): d 4.60 (s, 2H), 7.43–7.54 (m, 3H). 13C NMR
(75.4 MHz, CDCl3): d 28.9 (CH2), 113.4 (C), 113.9 (C), 128.5 (CH),
129.7 (CH), 133.7 (CH), 137.7 (C), 143.4 (C). IR (HATR): 3070,
3025, 2227, 1588, 1567, 1455, 1443, 1264, 1219, 1203, 1180,
1155, 1117, 988, 905, 796, 780, 737, 628, 609 cmꢀ1. EI-MS m/z
(rel. intensity%): 231 (M+, 10), 229 (M+, 8), 152 (33), 150 (100),
123 (27), 114 (22), 81 (18), 79 (18), 63 (21), 50 (14). Mp: 83 °C.
HRMS (EI) calcd for C8H5N35Cl79Br: 228.9294; found 228.9307.
1206, 1170, 1138, 1114, 1081, 902, 820, 742, 689, 649, 622 cmꢀ1
.
EI-MS m/z (rel. intensity%): 309 (M+, 2), 232 (25), 230 (100), 228
(73), 149 (16), 114 (47), 87 (20), 74 (10), 63 (20), 50 (15). Mp:
120 °C. HRMS (EI) calcd for C8H4N35Cl79Br2: 306.8399; found
306.8386.
4.4. A typical procedure for the preparation of the substituted
2-formylbenzonitriles
Compounds 10B and 10C were synthesized according to a liter-
ature procedure.12
4.4.1. Synthesis of 2-chloro-6-formylbenzonitrile 10B
To a solution of 9B (18.0 g, 58.2 mmol) in CH3CN (60 mL) was
added a solution of AgNO3 (39.5 g, 233 mmol) in H2O (32 mL).
The resulting yellow suspension was refluxed for 20 min. The sol-
ids were filtered off and washed with CH2Cl2 (150 mL). The com-
bined filtrate was washed with H2O (25 mL), dried over Na2SO4,
and concentrated in vacuo. The crude product was purified by flash
chromatography over silicagel (hexane/EtOAc, 2/1) resulting in
pure 10B, 8.67 g (90%). 1H NMR (300 MHz, CDCl3): d 7.72 (t,
J = 7.9 Hz, 1H), 7.79 (dd, J = 1.2, 7.9 Hz, 1H), 7.94 (dd, J = 1.2,
7.9 Hz, 1H), 10.31 (s, 1H). 13C NMR (75.4 MHz, CDCl3): d 112.9
(C), 114.4 (C), 127.5 (CH), 133.8 (CH), 134.9 (CH), 138.5 (C), 139.0
(C), 187.6 (CH). IR (HATR): 3069, 2865, 2221, 1697, 1584, 1566,
1443, 1395, 1291, 1224, 1195, 1182, 1155, 922, 798, 781, 726,
675 cmꢀ1. EI-MS m/z (rel. intensity%): 167 (5); 165 (15), 139
(33), 137 (100), 110 (24), 101 (44), 84 (13), 75 (79), 61 (23), 50
(45). Mp: 140 °C. HRMS (EI) calcd for C8H4NO35Cl: 164.9981; found
164.9969.
4.2.2. Synthesis of 2-(bromomethyl)-4-chlorobenzonitrile 8C
The reaction was performed on 4-chloro-2-methylbenzonitrile
7C (2.0 g, 13.2 mmol) according to the typical procedure. The crude
product was purified by flash chromatography over silicagel
(pentane/Et2O, 96/4) resulting in pure 8C, 1.74 g (57%). Formation
of the dibromo product 9C was also observed, 0.97 g (24%). For
8C: 1H NMR (300 MHz, CDCl3): d 4.57 (s, 2H), 7.39 (dd, J = 2.0,
8.3 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H). 13C
NMR (75.4 MHz, CDCl3): d 28.2 (CH2), 110.8 (C), 116.0 (C), 129.4
(CH), 130.8 (CH), 134.2 (CH), 139.7 (C), 142.8 (C). IR (HATR):
3080, 3035, 2224, 1592, 1564, 1480, 1438, 1404, 1284, 1230,
1222, 1180, 1105, 1080, 900, 882, 827, 742, 726, 630, 618 cmꢀ1
.
EI-MS m/z (rel. intensity%): 233 (M+, 25), 231 (M+, 100), 229 (M+,
77), 203 (9), 152 (6), 150 (18), 114 (66), 87 (31), 63 (35). Mp:
78 °C. HRMS (EI) calcd for C8H5N35Cl79Br: 228.9294; found
228.9287.
4.4.2. Synthesis of 4-chloro-2-formyl-benzonitrile 10C
The reaction was performed on 9C (18.07 g, 58.4 mmol) accord-
ing to the typical procedure. The crude product was purified by
flash chromatography over silicagel (hexane/EtOAc, 9/1) resulting
in pure 10C, 8.04 g (83%). 1H NMR (300 MHz, CDCl3): d 7.71 (dd,
J = 2.0, 8.3 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H),
10.31 (s, 1H). 13C NMR (75.4 MHz, C6D6): d 111.9 (C), 115.2 (C),
129.2 (CH), 133.3 (CH), 134.6 (CH), 138.0 (C), 139.3 (C), 186.2
(CH). IR (HATR): 3101, 3069, 2871, 2226, 1698, 1584, 1558, 1485,
1376, 1294, 1203, 1119, 1099, 897, 839, 744, 702, 620 cmꢀ1. EI-
MS m/z (rel. intensity%): 167 (10); 165 (29), 139 (33), 137 (100),
110 (26), 102 (44), 100 (33), 75 (55), 61 (16), 50 (39). Mp:
119 °C. HRMS (EI) calcd for C8H4NO35Cl: 164.9981; found
164.9988.
4.3. A typical procedure for the preparation of the substituted
2-(dibromomethyl)benzonitriles
Compounds 9B and 9C were synthesized according to a litera-
ture procedure.12
4.3.1. Synthesis of 2-chloro-6-(dibromomethyl)benzonitrile 9B
A
solution of 2-chloro-6-methylbenzonitrile 7B (9.91 g,
65.4 mmol), NBS (35.22 g, 197.9 mmol), and benzoylperoxide
(534.0 mg, 2.2 mmol) in CCl4 (100 mL) was refluxed overnight.
Afterwards, the solids were filtered off and the filtrate was concen-
trated in vacuo. The crude product was purified by flash chroma-
tography over silicagel (hexane/EtOAc, 95/5) resulting in pure 9B,
19.04 g (94%). 1H NMR (300 MHz, CDCl3): d 6.96 (s, 1H), 7.49 (dd,
J = 0.8, 8.1 Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.94 (dd, J = 0.8, 8.1 Hz,
1H). 13C NMR (75.4 MHz, CDCl3): d 35.0 (CH), 109.5 (C), 113.1
(C), 128.0 (CH), 130.6 (CH), 134.1 (CH), 136.9 (C), 146.3 (C). IR
(HATR): 3076, 3008, 2232, 1589, 1567, 1454, 1439, 1292, 1251,
1238, 1174, 1140, 1134, 891, 796, 779, 735, 651, 633 cmꢀ1. EI-
MS m/z (rel. intensity%): 309 (M+, 2), 232 (25), 230 (100), 228
(74), 149 (14), 114 (39), 87 (17), 74 (9), 63 (16), 50 (13). Mp:
120 °C. HRMS (EI) calcd for C8H4N35Cl79Br2: 306.8399; found
306.8386.
4.5. A typical procedure for the preparation of imidate esters
4.5.1. Synthesis of 1,3-dihydro-iminoisobenzofuran
hydrochloride 3A
2-Formylbenzonitrile (7.0 g, 53.4 mmol) was dissolved in abso-
lute ethanol (420 mL) and cooled to ꢀ78 °C. NaBH4 (2.02 g,
53.4 mmol) was added and the reaction mixture was allowed to
warm to 0 °C over 30 min. The reaction mixture was poured into
H2O and extracted with CH2Cl2 (3 ꢁ 1000 mL). The organic phases
were dried over Na2SO4 and concentrated in vacuo. The resulting
orange oil was dissolved in dry CH2Cl2 (165 mL) and dry HCl in
Et2O (65 mL) was added. The resulting suspension was filtrated
and the white crystals were washed with dry THF. This resulted
in 8.3 g (92%) of imidate ester hydrochloride 3A. 1H NMR
(300 MHz, CD3OD) d 5.99 (s, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.84 (d,
4.3.2. Synthesis of 4-chloro-2-(dibromomethyl)-benzonitrile 9C
The reaction was performed on 4-chloro-2-methylbenzonitrile
(9.80 g, 64.6 mmol) according to the typical procedure. The crude
product was purified by flash chromatography over silicagel (hex-
ane/EtOAc, 95/5) resulting in pure 9B, 19.55 g (98%). 1H NMR

1966
T. Noël et al. / Tetrahedron: Asymmetry 20 (2009) 1962–1968
J = 7.8 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H). 13C
NMR (75.4 MHz, CD3OD): d 81.0 (CH2), 123.9 (CH), 124.6 (C),
126.5 (CH), 131.1 (CH), 138.1 (CH), 148.9 (C), 178.4 (C). IR (HATR):
3422, 3357, 3062, 3036, 2924, 2806, 2717, 2628, 1676, 1617, 1592,
1560, 1486, 1446, 1330, 1318, 1222, 1080, 938, 794, 739 cmꢀ1. EI-
MS m/z (rel. intensity%): 133 ((M+ꢀHCl), 50), 104 (100), 89 (15), 77
(44), 63 (14), 51 (20), 43 (7). ES-MS: 134 [MꢀClꢀ]+. Mp: decompo-
sition. HRMS (EI) calcd for C8H7NO: 133.0528; found 133.0533.
CHCl3). Mp: 162 °C. HRMS (EI) calcd for C17H15NO2: 265.1103;
found 265.1104.
4.6.2. Synthesis of (S)-2-(20-hydroxymethyl)phenyl-4-tert-
butyloxazoline 6bA
The reaction was performed on (S)-tert-leucinol (95.0 mg,
0.81 mmol) according to the typical procedure. The crude product
was purified by flash chromatography over silicagel (CH2Cl2/
MeOH, 98/2) resulting in pure 6bA, 189.0 mg (quant.). 1H NMR
(300 MHz, CDCl3): d 0.97 (s, 9H), 4.15 (dd, J = 8.0, 10.1 Hz, 1H),
4.25 (dd, J = 8.0, 8.5 Hz, 1H), 4.39 (dd, J = 8.5, 10.1 Hz, 1H), 4.60
(d, J = 12.3 Hz, 1H), 4.73 (d, J = 12.3 Hz, 1H), 6.82 (br s, 1H), 7.32–
7.47 (m, 3H), 7.85 (m, 1H). 13C NMR (75.4 MHz, CDCl3): d 25.8
(CH3), 33.7 (C), 64.7 (CH2), 68.4 (CH2), 76.1 (CH), 126.6 (C), 127.6
(CH), 130.0 (CH), 130.3 (CH), 131.4 (CH), 142.2 (C), 163.7 (C). IR
(HATR): 3236, 2960, 2905, 2868, 1638, 1573, 1478, 1449, 1396,
1364, 1342, 1312, 1304, 1262, 1214, 1201, 1138, 1076, 1050,
1024, 971, 948, 785, 746, 700 cmꢀ1. EI-MS m/z (rel. intensity%):
233 (M+, 44), 204 (12), 176 (72), 158 (50), 146 (15), 133 (100),
130 (20), 119 (32), 105 (58), 91 (36), 77 (62), 69 (26), 57 (41), 41
4.5.2. Synthesis of 7-chloro-1,3-dihydro-imino-isobenzofuran
hydrochloride 3B
The reaction was performed on 2-chloro-6-formylbenzonitrile
10B (2.0 g, 12.1 mmol) according to the typical procedure resulting
in 2.32 g (94%) of imidate ester hydrochloride 3B. 1H NMR
(300 MHz, DMSO-d6) d 5.93 (s, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.80
(d, J = 7.8 Hz, 1H), 7.94 (t, J = 7.8 Hz, 1H). 13C NMR (75.4 MHz,
DMSO-d6): d 78.0 (CH2), 121.1 (C), 121.8 (CH), 130.3 (CH), 130.5
(C), 137.9 (CH), 150.3 (C), 173.6 (C). IR (HATR): 3053, 2936, 2861,
2706, 2628, 2545, 2436, 1662, 1610, 1582, 1524, 1474, 1430,
1408, 1322, 1306, 1228, 1196, 1156, 1132, 1060, 1042, 919, 857,
792, 763, 727, 654 cmꢀ1. EI-MS m/z (rel. intensity%): 169 (M+,11),
167 (M+, 33), 140 (33), 138 (100), 111 (10), 102 (47), 89 (74), 75
(69), 63 (42), 50 (50), 43 (19). ES-MS: 168 [MꢀClꢀ]+. Mp: decompo-
sition. HRMS (EI) calcd for C8H6NO35Cl: 167.0138; found 167.0153.
(80). ES-MS: 234 [M+H]+. ½a D20
¼ ꢀ26:6 (c 0.94, CHCl3). Mp:
ꢂ
<50 °C. HRMS (EI) calcd for C14H19N2O2: 233.1416; found
233.1414.
4.6.3. Synthesis of (S)-2-(20-hydroxymethyl)phenyl-4-i-
propyloxazoline 6cA
4.5.3. Synthesis of 5-chloro-1,3-dihydro-imino-isobenzofuran
hydrochloride 3C
The reaction was performed on L-valinol (116.8 mg, 1.13 mmol)
according to the typical procedure. The crude product was purified
by flash chromatography over silicagel (hexane/EtOAc, 70/30)
resulting in pure 6cA, 248.0 mg (quant.). 1H NMR (300 MHz,
CDCl3): d 0.96 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H), 1.83 (sept,
J = 6.7 Hz, 1H), 4.11–4.21 (m, 2H), 4.41–4.50 (m, 1H), 4.62 (dd,
J = 6.0, 12.3 Hz, 1H), 4.69 (dd, J = 4.8, 12.3 Hz, 1H), 6.78 (dd,
J = 4.8, 6.0 Hz, 1H), 7.32–7.46 (m, 3H), 7.86 (m, 1H). 13C NMR
(75.4 MHz, CDCl3): d 18.6 (CH3), 18.7 (CH3), 33.0 (CH), 64.7 (CH2),
70.2 (CH2), 72.6 (CH), 126.7 (C), 127.7 (CH), 130.1 (CH), 130.4
(CH), 131.5 (CH), 142.2 (C), 163.8 (C). IR (HATR): 3221, 2960,
2900, 2868, 1637, 1598, 1573, 1466, 1446, 1349, 1322, 1310,
1254, 1198, 1061, 1047, 1024, 963, 946, 781, 750, 711 cmꢀ1. EI-
MS m/z (rel. intensity%): 219 (M+, 40), 190 (10), 188 (6), 176
(32), 158 (21), 146 (9), 133 (100), 119 (19), 105 (54), 91 (26), 77
The reaction was performed on 2-formyl-5-chlorobenzonitrile
10C (2.0 g, 12.1 mmol) according to the typical procedure resulting
in 2.38 g (96%) of imidate ester hydrochloride 3C. 1H NMR
(300 MHz, CD3OD) d 5.94 (s, 2H), 7.79 (dd, J = 0.9, 8.5 Hz, 1H),
7.88 (d, J = 0.9 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H). 13C NMR
(75.4 MHz, CD3OD): d 80.5 (CH2), 123.7 (C), 124.4 (CH), 127.8
(CH), 131.8 (CH), 144.7 (C), 150.7 (C), 177.6 (C). IR (HATR): 2801,
1671, 1643, 1613, 1586, 1545, 1464, 1447, 1417, 1310, 1290,
1212, 1173, 1119, 1082, 1067, 943, 894, 864, 855, 834, 790, 774,
752, 660 cmꢀ1. EI-MS m/z (rel. intensity%): 169 (M+, 16), 167 (M+,
48), 140 (33), 138 (100), 132 (20), 111 (20), 102 (44), 89 (21), 75
(60), 63 (36), 50 (86), 43 (21). ES-MS: 168 [MꢀClꢀ]+. Mp: decompo-
sition. HRMS (EI) calcd for C8H6NO35Cl: 167.0138; found 167.0143.
(47), 65 (6), 51 (16), 41 (39). ES-MS: 220 [M+H]+. ½a D20
¼ ꢀ42:9 (c
ꢂ
4.6. A typical procedure for the preparation of oxazoline-
alcohol ligands 6
0.99, CHCl3). Mp: <50 °C. HRMS (EI) calcd for C13H17NO2:
219.1259; found 219.1259.
4.6.1. Synthesis of 2-(20-hydroxymethyl)phenyl-(3aS,8aR)-3a,8a-
dihydro-8H-indeno[1,2-d]oxazoline 6aA
4.6.4. Synthesis of 2-(20-hydroxymethyl-60-chloro)phenyl-(3aS,8aR)-
3a,8a-dihydro-8H-indeno[1,2-d]oxazoline 6aB
A suspension of (1S,2R)-(ꢀ)-cis-1-amino-2-indanol (788.0 mg,
5.28 mmol) and imidate ester 3A (1.0 g, 5.90 mmol) in CH2Cl2
(40 mL) was cooled in an ice bath. Et3N (2.24 mL, 16.1 mmol)
was added and the reaction mixture was stirred for 48 h at room
temperature. Evaporation in vacuo, purification by flash chroma-
tography over silicagel (hexane/EtOAc, 2/1), and finally recrystalli-
zation from hexane/CH2Cl2 resulted in 6aA as a white solid, 1.40 g
(quant.). 1H NMR (300 MHz, CDCl3) d 3.42 (d, J = 17.8 Hz, 1H), 3.56
(dd, J = 6.6, 17.8 Hz, 1H), 4.61 (d, J = 5.0 Hz, 1H), 4.64 (d, J = 5.0 Hz,
1H), 5.52 (m, 1H), 5.83 (d, J = 7.8 Hz, 1H), 6.56 (m, 1H), 7.27–7.47
(m, 6H), 7.51–7.57 (m, 1H), 7.86–7.92 (m, 1H). 13C NMR
(75.4 MHz, CDCl3): d 39.6 (CH2), 64.6 (CH2) 76.6 (CH), 83.0 (CH),
125.3 (CH), 125.4 (CH), 126.5 (C), 127.6 (CH), 127.7 (CH), 128.7
(CH), 130.2 (CH), 130.5 (CH), 131.6 (CH), 139.4 (C), 141.7 (C),
142.2 (C), 164.2 (C). IR (HATR): 3202, 2931, 1633, 1599, 1577,
1461, 1445, 1421, 1353, 1293, 1237, 1205, 1169, 1137, 1061,
1018, 998, 968, 956, 858, 785, 778, 755, 709, 691 cmꢀ1. EI-MS m/
z (rel. intensity%): 265 (M+, 11), 133 (27), 116 (100), 115 (46), 89
A suspension of (1S,2R)-(ꢀ)-cis-1-amino-2-indanol (100.0 mg,
0.67 mmol) and imidate ester 3B (150.0 mg, 0.74 mmol) in CH2Cl2
(5 mL) was cooled in an ice bath. Et3N (0.28 mL, 2.0 mmol) was
added and the reaction mixture was stirred for 48 h at room
temperature. Evaporation in vacuo, purification by flash chroma-
tography over silicagel (CH2Cl2/MeOH, 98/2), and finally recrystal-
lization from hexane/CH2Cl2 resulted in 6aB as a white solid,
165.1 mg (83%). 1H NMR (300 MHz, CDCl3): d 3.41–3.49 (dd,
J = 1.8, 17.9 Hz, 1H), 3.50–3.60 (dd, J = 6.1, 17.9 Hz, 1H), 4.14–4.20
(dd, J = 6.2, 12.5 Hz, 1H), 4.25–4.33 (dd, J = 8.1, 12.5 Hz, 1H), 4.69
(dd, J = 6.2, 8.1 Hz, 1H), 5.60 (ddd, J = 1.8, 6.1, 7.7 Hz, 1H), 5.77 (d,
J = 7.7 Hz, 1H), 7.23–7.37 (m, 6H), 7.52–7.57 (m, 1H). 13C NMR
(75.4 MHz, CDCl3): d 39.3 (CH2), 63.5 (CH2), 76.1 (CH), 84.2 (CH),
125.2 (CH), 125.3 (CH), 127.3 (C), 127.7 (CH), 128.7 (CH), 129.4
(CH), 131.4 (CH), 133.8 (C), 139.3 (C), 141.3 (C), 143.3 (C), 163.1
(C). IR (HATR): 3179, 1652, 1478, 1458, 1444, 1420, 1358, 1328,
1292, 1240, 1176, 1150, 1098, 1078, 1049, 991, 853, 777, 758,
730, 714, 642 cmꢀ1. EI-MS m/z (rel. intensity%): 301 (M+, 2), 299
(M+, 7), 167 (12), 131 (10), 116 (100), 104 (19), 77 (32), 63 (11).
(13), 77 (36), 51 (12). ES-MS: 266 [M+H]+. ½a D20
¼ ꢀ178:5 (c 1.02,
ꢂ

T. Noël et al. / Tetrahedron: Asymmetry 20 (2009) 1962–1968
1967
ES-MS: 300 [M+H]+. ½a D20
ꢂ
¼ ꢀ209:5 (c 0.93, CHCl3). Mp: 158 °C.
17.9 Hz, 1H), 3.51 (dd, J = 6.4, 17.9 Hz, 1H), 5.52 (ddd, J = 1.9, 6.4,
8.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 7.21–7.31 (m, 5H), 7.54–7.64
(m, 3H). 13C NMR (75.4 MHz, CDCl3): d 39.7 (CH2), 77.2 (CH), 83.6
(CH), 121.8 (C), 125.3 (CH), 125.7 (CH), 127.0 (CH), 127.5 (CH),
128.5 (CH), 129.8 (C), 131.5 (CH), 131.6 (CH), 133.7 (CH), 139.7
(C), 141.7 (C), 163.5 (C). IR (HATR): 3065, 3024, 2951, 2918,
2851, 1630, 1619, 1588, 1476, 1458, 1425, 1353, 1316, 1295,
1234, 1212, 1166, 1097, 1081, 1023, 992, 749, 726, 707, 684,
HRMS (EI) calcd for C17H14NO235Cl: 299.0713; found 299.0719.
4.6.5. Synthesis of 2-(20-hydroxymethyl-40-chloro)phenyl-(3aS,8aR)-
3a,8a-dihydro-8H-indeno[1,2-d]oxazoline 6aC
A suspension of (1S,2R)-(ꢀ)-cis-1-amino-2-indanol (100.0 mg,
0.67 mmol) and imidate ester 3C (150.0 mg, 0.74 mmol) in CH2Cl2
(5 mL) was cooled in an ice bath. Et3N (0.28 mL, 2.0 mmol) was
added and the reaction mixture was stirred for 48 h at room
temperature. Evaporation in vacuo, purification by flash chroma-
tography over silicagel (CH2Cl2/MeOH, 99/1), and finally recrystal-
lization from hexane/CH2Cl2 resulted in 6aB as white needles,
131.2 mg (66%). 1H NMR (300 MHz, CDCl3): d 3.38 (dd, J = 1.3,
17.9 Hz, 1H), 3.53 (dd, J = 6.5, 17.9 Hz, 1H), 4.53 (dd, J = 7.3,
12.5 Hz, 1H), 4.58 (dd, J = 7.4, 12.5 Hz, 1H), 5.49 (ddd, J = 1.3, 6.5,
7.9 Hz, 1H), 5.79 (d, J = 7.9 Hz, 1H), 6.47 (dd, J = 7.3, 7.5 Hz, 1H),
7.27–7.33 (m, 5H), 7.47–7.51 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H). 13C
NMR (75.4 MHz, CDCl3): d 39.6 (CH2), 64.2 (CH2), 76.6 (CH), 83.1
(CH), 124.9 (C), 125.4 (2x CH), 127.7 (CH), 127.8 (CH), 128.8
(CH), 130.5 (CH), 131.6 (CH), 137.5 (C), 139.4 (C), 141.5 (C), 143.9
(C), 163.5 (C). IR (HATR): 3340, 1621, 1595, 1564, 1482, 1456,
1444, 1428, 1400, 1348, 1306, 1292, 1278, 1246, 1229, 1199,
1142, 1103, 1040, 1031, 992, 895, 862, 824, 764, 754, 742, 712,
677 cmꢀ1. EI-MS m/z (rel. intensity%): 301 (M+, 2), 299 (M+, 6),
167 (8), 139 (9), 116 (100), 103 (11), 89 (8), 77 (20), 63 (4). ES-
676, 641 cmꢀ1 EI-MS m/z (rel. intensity%): 315 (M+,7), 313
.
(M+,7), 183 (6), 155 (4), 131 (12), 115 (26), 104 (100), 89 (14), 77
(40), 63 (14), 50 (25). ES-MS: 314 and 316 [M+H]+.
½
a 2D0
ꢂ
¼ ꢀ164:7 (c 1.09, CHCl3). HRMS (EI) calcd for C16H12NO79Br:
313.0102; found 313.0117.
4.9. Synthesis of 2-(20-diphenylhydroxymethyl)phenyl-(3aS,8aR)-
3a,8a-dihydro-8H-indeno[1,2-d]oxazoline 14
Compound 14 was synthesized according to a literature proce-
dure.5a A solution of 13 (101.7 mg, 0.33 mmol) in freshly distilled
Et2O (2.5 mL) was cooled to ꢀ78 °C and treated dropwise with n-
BuLi (0.150 mL, 0.37 mmol, 2.5 M in n-hexane). After being stirred
for 1 h at ꢀ40 °C, benzophenone (71.0 mg, 0.38 mmol) was added
in one portion and stirred overnight at room temperature. The
reaction mixture was poured into H2O (25 mL) and extracted with
EtOAc (3 ꢁ 25 mL). The organic phases were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography over silicagel (hexane/EtOAc, 8/2) resulting in
14 as a white solid, 88.0 mg (65%). 1H NMR (300 MHz, CDCl3): d
3.17 (d, J = 3.8 Hz, 2H), 4.10 (br s, 1H), 4.63 (m, 1H), 5.51 (d,
J = 4.9 Hz, 1H), 6.95–7.05 (m, 2H), 7.16–7.62 (m, 15H), 7.90–7.93
(m, 1H). 13C NMR (75.4 MHz, CDCl3): d 39.7 (CH2), 63.8 (CH), 73.6
(CH), 94.2 (C), 123.8 (CH), 124.1 (CH), 125.2 (2 ꢁ CH), 126.4 (CH),
126.8 (2 ꢁ CH), 127.5 (CH), 127.6 (2 ꢁ CH), 128.2 (CH), 128.3
(2 ꢁ CH), 128.4 (3 ꢁ CH), 129.0 (CH), 130.0 (C), 131.9 (CH), 141.4
(C), 141.6 (C), 142.0 (C), 142.1 (C), 148.6 (C), 159.9 (C). IR (HATR):
3460, 3070, 3021, 2948, 2914, 1690, 1600, 1492, 1466, 1448, 1428,
1379, 1336, 1313, 1298, 1288, 1257, 1218, 1184, 1157, 1120, 1054,
1043, 984, 959, 944, 930, 866, 760, 754, 746, 718, 695, 679, 656,
632 cmꢀ1. EI-MS m/z (rel. intensity%): 417 (M+, 4), 270 (100), 241
(36), 239 (47), 209 (21), 193 (16), 165 (51), 148 (23), 130 (66),
118 (51), 91 (50), 77 (93), 51 (41), 41 (9). ES-MS: 418 [M+H]+.
MS: 300 [M+H]+. ½a D20
¼ ꢀ156:4 (c 0.98, CHCl3). Mp: 147 °C. HRMS
ꢂ
(EI) calcd for C17H14NO235Cl: 299.0713; found 299.0717.
4.7. Synthesis of (1R, 2R)-trans-1-(3H-isobenzofuran-1-
ylideneamino)-indan-2-ol 5fA
A suspension of (1R,2R)-(ꢀ)-trans-1-amino-2-indanol (100.0 mg,
0.67 mmol) and imidate ester 3A (125.0 mg, 0.74 mmol) in CH2Cl2
was cooled in an ice bath. Et3N (0.28 mL, 2.0 mmol) was added and
the reaction mixture was stirred for 48 h at room temperature.
Evaporation in vacuo and recrystallization from CH2Cl2 resulted
in 5fA as a white solid, 161 mg (91%). 1H NMR (300 MHz, DMSO)
d 2.74 (dd, J = 7.0, 15.6 Hz, 1H), 3.18 (dd, J = 7.0, 15.6 Hz, 1H),
4.33 (m, J = 5.6, 7.0 Hz, 1H), 5.12 (d, J = 5.6 Hz, 1H), 5.16 (d,
J = 5.2 Hz, 1H), 5.44 (d, J = 14.9 Hz, 1H), 5.50 (d, J = 14.9 Hz, 1H),
7.05–7.20 (m, 4H), 7.44–7.49 (m, 1H), 7.56–7.63 (m, 2H), 7.70 (d,
J = 7.6 Hz, 1H). 13C NMR + HSQC (75.4 MHz, DMSO): 39.3 (CH2),
68.3 (CH), 72.1 (CH2), 79.5 (CH), 122.2 (CH), 122.8 (CH), 124.3
(CH), 124.5 (CH), 126.4 (CH), 127.1 (CH), 128.4 (CH), 129.7 (C),
131.5 (CH), 140.2 (C), 143.2 (C), 143.8 (C), 160.1 (C). IR (HATR):
3189, 1680, 1467, 1419, 1369, 1298, 1225, 1200, 1084, 1028,
998, 777, 747, 730, 703, 675 cmꢀ1. EI-MS m/z (rel. intensity%):
265 (M+, 20), 247 (4), 237 (17), 218 (5), 146 (15), 134 (23), 118
(100), 104 (50), 90 (97), 63 (19), 49 (43). ES-MS: 266 [M+H]+.
½
a 2D0
ꢂ
¼ þ268:4 (c 0.94, CHCl3). Mp: 210 °C. HRMS (EI) calcd for
C29H23O2N: 417.1729; found 417.1729.
4.10. Typical procedure for the asymmetric Et2Zn addition to
benzaldehyde
Ligand 6aA (13.1 mg, 0.049 mmol) was dissolved in toluene
(2 mL). Then Et2Zn (0.75 mL, 0.75 mmol, 1 M in hexane) was added
and the resulting yellow solution was stirred for 20 min at room
temperature under an argon atmosphere. Next, the reaction was
½
a 2D0
ꢂ
¼ ꢀ304:8 (c 0.81, DMSO). Mp: 236 °C. HRMS (EI) calcd for
C17H15NO2: 265.1103; found 265.1107.
cooled to 0 °C and benzaldehyde was added (50 lL, 0.49 mmol).
The reaction was stirred for another 48 h. After quenching with
1 mL saturated NH4Cl solution, the reaction mixture was added
to 25 mL H2O and extracted with EtOAc (3 ꢁ 25 mL). The combined
organic phases were dried on Na2SO4 and evaporated in vacuo.
Purification by flash chromatography over silicagel (pentane/
EtOAc, 90/10) resulted in 12, 46.3 mg (69%, 85% ee).
The adducts were fully characterized by comparison of their
spectral data with those reported in the literature.6b The enantio-
meric excess of the product was determined by HPLC analysis with
a chiral stationary phase column and the absolute configuration
was assigned via correlation of its specific rotation with the values
reported in the literature.14
4.8. Synthesis of 2-(20-bromophenyl)-(3aS,8aR)-3a,8a-dihydro-8H-
indeno[1,2-d]oxazoline 13
Compound 13 was synthesized according to a literature proce-
dure.13 A mixture of (1S,2R)-(ꢀ)-cis-1-amino-2-indanol (500.0 mg,
3.35 mmol), 2-bromobenzonitrile (610.0 mg, 3.35 mmol), and
anhydrous ZnCl2 (23.0 mg, 0.17 mmol) in anhydrous chloroben-
zene (2 mL) was refluxed for 24 h. After removal of the solvent in
vacuo, the crude product was purified via flash chromatography
over silicagel (hexane/EtOAc, 8/2) giving 13 as a colorless oil,
314.2 mg (30%). 1H NMR (300 MHz, CDCl3): d 3.41 (dd, J = 1.9,

1968
T. Noël et al. / Tetrahedron: Asymmetry 20 (2009) 1962–1968
Conditions for chiral HPLC:
For 1-phenylpropanol 12: Chiralcel OD–H column (250 ꢁ 4.6
mm, particle size 10 m), solvent: n-hexane/EtOH (97/3), flow
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Seitz, M.; Kaiser, A.; Reiser, O. Org. Lett. 2003, 3, 4259–4262; (f) Imai, Y.;
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W.; Yoshinaga, H.; Imai, Y.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Synlett 2000, 1512–
1514; (h) Deng, W.-P.; Hou, X.-L.; Dai, L.-X. Tetrahedron: Asymmetry 1999, 10,
4689–4693.
5. (a) Bolm, C.; Muñiz-Fernández, K.; Seger, A.; Raabe, G.; Günther, K. J. Org. Chem.
1998, 63, 7860–7867; (b) Bolm, C.; Muñiz, K.; Hildebrand, J. P. Org. Lett. 1999, 1,
491–493.
6. (a) Hall, J.; Lehn, J. M.; DeCian, A.; Fischer, J. Helv. Chim. Acta 1991, 74, 1–6; (b)
Allen, J. V.; Williams, J. M. J. Tetrahedron: Asymmetry 1994, 5, 277–282.
7. Noël, T.; Vandyck, K.; Robeyns, K.; Van Meervelt, L.; Van der Eycken, J.
Tetrahedron 2009, doi:10.1016/j.tet.2009.08.028.
8. Bolm et al. observed that in the solid state 2 can rearrange to the corresponding
imidate form: Muñiz-Fernández, K. Ph.D. Thesis RWTH Aachen, 1998.
9. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
10. For a review about dual stereocontrol: (a) Zanoni, G.; Castronovo, F.; Franzini,
M.; Vidari, G.; Giannini, E. Chem. Soc. Rev. 2003, 32, 115–129; (b) Kim, Y. H. Acc.
Chem. Res. 2001, 34, 955–962.
11. (a) Szakonyi, Z.; Balázs, A.; Martinek, T. A.; Fülöp, F. Tetrahedron: Asymmetry
2006, 17, 199–204; (b) Zhong, Y.-W.; Jiang, C.-S.; Xu, M.-H.; Lin, G.-Q.
Tetrahedron 2004, 60, 8861–8868; (c) Burguete, M. I.; Collado, M.;
Escorihuela, J.; Galindo, F.; Garcia-Verdugo, E.; Luis, S. V.; Vicent, M. J.
Tetrahedron Lett. 2003, 44, 6891–6894; (d) Altava, B.; Burguete, M. I.; Garcia-
Verdugo, E.; Luis, S. V.; Miravet, J. F.; Vicent, M. J. Tetrahedron: Asymmetry 2000,
11, 4885–4893; (e) Kobayashi, S.; Horibe, M. J. Am. Chem. Soc. 1994, 116, 9805–
9806.
l
rate = 1 mL/min, T = 35 °C, retention times: 7.8 min for (R)-(+)-12
and 9.0 min for (S)-(ꢀ)-12.
For 1-(2-chlorophenyl)propanol: Chiralcel AD–H column (250 ꢁ
4.6 mm, particle size 10 lm), solvent: n-hexane/EtOH (97/3), flow
rate = 1 mL/min, T = 35 °C, retention times: 7.7 min for (R)-(+) and
8.5 min for (S)-(ꢀ).
For 1-(3-chlorophenyl)propanol: Chiralcel AD–H column (250 ꢁ
4.6 mm, particle size 10 lm), solvent: n-hexane/EtOH (97/3), flow
rate = 1 mL/min, T = 35 °C, retention times: 8.9 min for (R)-(+) and
10.5 min for (S)-(ꢀ).
For 1-(4-chlorophenyl)propanol: Chiralcel OB–H column (250 ꢁ
4.6 mm, particle size 10 lm), solvent: n-hexane/EtOH (97/3), flow
rate = 1 mL/min, T = 35 °C, retention times: 6.5 min for (S)-(ꢀ) and
7.8 min for (R)-(+).
For (E)-1-phenyl-1-penten-3-ol: Chiralcel OD–H column (250 ꢁ
4.6 mm, particle size 10 lm), solvent: n-hexane/EtOH (90/10), flow
rate = 1 mL/min, T = 35 °C, retention times: 5.75 min for (R)-(+) and
7.36 min for (S)-(ꢀ).
For 1-naphthalen-2-yl-1-propanol: Chiralcel OD–H column (250 ꢁ
4.6 mm, particle size 10 lm), solvent: n-hexane/EtOH (97/3), flow
rate = 1 mL/min, T = 35 °C, retention times: 14.68 min for (S)-(ꢀ) and
16.00 min for (R)-(+).
4.11. Crystallographic data
Crystallographic data (excluding structure factors) for ligand
6aA have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 733211.
Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 lEZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
12. Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361–7364.
13. Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467–4478.
14. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108,
6071–6072; (b) Bauer, T.; Gajewiak, J. Tetrahedron: Asymmetry 2005, 16, 851–
855; (c) Bulut, A.; Aslan, A.; Izgü, E. C.; Dogan, Ö. Tetrahedron: Asymmetry 2007,
18, 1013–1016.
Acknowledgments
T.N. and J.V.D.E. wish to thank Ghent University and COST-Chem-
istry (Action D.40—‘Innovative Catalysis’) for financial support.