Synthesis of non-symmetric bisoxazoline compounds. An easy way to reach tailored chiral ligands

Article abstract of DOI:10.1016/j.tetasy.2006.07.031

Bisoxazoline compounds have been used as chiral catalyst ligands in a wide variety of reactions. A great deal of effort has been aimed at the synthesis of C₂-symmetric bisoxazolines but very few references exist for non-symmetric ones. As part of our studies into the possible usefulness of non-symmetric bisoxazolines, we report an easy method for the synthesis of bisoxazoline compounds bearing different substituents in each oxazoline ring.

Full text of DOI:10.1016/j.tetasy.2006.07.031

Tetrahedron: Asymmetry 17 (2006) 2270–2275
Synthesis of non-symmetric bisoxazoline compounds. An easy way
to reach tailored chiral ligands
*
*
´
´
´
Jose I. Garcıa, Jose A. Mayoral, Elisabet Pires and Isabel Villalba
Dep. Quı´mica Orga´nica, Instituto de Ciencia de Materiales de Arago´n, Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 7 July 2006; accepted 25 July 2006
Available online 23 August 2006
Abstract—Bisoxazoline compounds have been used as chiral catalyst ligands in a wide variety of reactions. A great deal of effort has been
aimed at the synthesis of C2-symmetric bisoxazolines but very few references exist for non-symmetric ones. As part of our studies into the
possible usefulness of non-symmetric bisoxazolines, we report an easy method for the synthesis of bisoxazoline compounds bearing dif-
ferent substituents in each oxazoline ring.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ligand. Initial attempts to achieve this were made using pyri-
dineoxazoline (Pyox) ligands18 (Fig. 1). Promising results
were obtained in that a cis-preference was observed in
cyclopropanation reactions when using clay-immobilized
pyox–Cu complexes with styrene as a solvent, although
reversal of the enantioselectivity was not observed.
Bisoxazoline compounds have become increasingly impor-
tant as chiral ligands in the asymmetric catalysis of a wide
variety of organic reactions.1,2 Several synthetic methods
have been described for the synthesis of these types of
ligands3–13 but they are all dedicated to C2-symmetric
bisoxazolines.
Our group has worked on the modification of bisoxazoline
compounds in order to make them suitable for immobiliza-
tion onto different supports such as silica,14 polymers,15
and clays,16 as well as on the use of such catalysts in cyclo-
propanation reactions.
O
N
N
R = Ph, iPr
R
Figure 1. Pyridineoxazoline used as a ligand for the immobilization of
copper complexes on clays.
These studies have shown that the surface has a significant
effect when using clay-immobilized bisoxazoline complexes
in solvents with low dielectric constants. Reversal of
enantioselectivity with respect to homogeneous phase
reactions and a preference for cis cyclopropanes were
observed.17 These results were rationalized on the basis
of an increased steric interaction between the clay surface
with the Cu–carbene intermediate and the incoming
styrene.
These results encouraged us to design new bisoxazoline
ligands with the same structural pattern. In order to achieve
this goal we needed to establish a new synthetic method for
bisoxazoline compounds bearing one unsubstituted oxazo-
line (R = H) (Fig. 2) to minimize the distance between the
clay and the copper complex.
The above effect could be improved if it were possible to
make the clay play the role of a bulky substituent of the
Based on our previous experience in the synthesis of bisox-
azoline compounds,19 we herein report the use of a similar
synthetic pathway to obtain non-symmetric (C1-symmetric)
bisoxazoline ligands. This approach gave a wide variety of
new bisoxazoline compounds that could prove very inter-
esting as clay-immobilized chiral ligands.
*
Corresponding authors. Tel.: +34 976762271; fax: +34 976762077
(J.I.G.); e-mail: jig@unizar.es
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.031

J. I. Garcı´a et al. / Tetrahedron: Asymmetry 17 (2006) 2270–2275
2271
The reaction of equimolecular amounts of 2,2-dimethyl-
malononitrile and amino alcohol with ZnCl2 or Zn(OTf)2
led to C2-symmetric bisoxazolines 3 as the major reaction
products, regardless of the starting amino alcohol (Table
1).
O
O
N
N
R
Figure 2. Non-symmetric bisoxazoline compounds.
Table 1. Results of the reaction of equimolecular amounts of 2,2-
dimethylmalononitrile and amino alcohols 1a–f using Zn(OAc)2 (20%)
in toluene at 110 ꢁC
2. Results and discussion
2
Time (h)
Yield (%) 2a
Yield (%) 3
Yield (%) 4
The synthesis of non-symmetric bisoxazolines is based on
the separate synthesis of each oxazoline ring (Fig. 3).
2a
2b
2c
2d
2e
2f
22
6
21
6
24
24
81
84
91
75
61
90
0
4
0
4
5
0
0
8
0
17
0
7
HO
NH2
R1
+
NC
CN
O
a Yields calculated by 1H NMR spectroscopy.
In this case, Zn(OAc)2 was found to be the best catalyst for
obtaining oxazoline 2, although the formation of bisox-
azoline 3 and small amounts of a new by-product identified
as methyl oxazoline 4, was sometimes observed.
CN
O
O
N
N
N
R1
R1
Figure 3. Non-symmetric bisoxazoline formation.
In all cases, good yields of product 2 were obtained. Small
amounts of either bisoxazoline 3 or methyl oxazoline 4
were observed in most cases. The exceptions were when
R1 = tBu and H, in which case only product 2 was
obtained.
The chemistry for synthesising oxazoline compounds start-
ing from dimethylmalononitrile is well known, but the
problem was how to synthesize one oxazoline ring while
leaving a nitrile group untouched.
Problems associated with the solubility of 2-ethanolamine
in toluene and the lower stability of the unsubstituted ox-
azoline ring led to difficulties in scaling up reactions using
2-ethanolamine 1a as the starting material. Other solvents
(e.g., THF and dioxane) were tried in order to improve
the synthetic method. The solubility of 2-ethanolamine
was higher in THF but the reaction temperature was not
sufficiently high enough to give good results. When using
dioxane, we were unable to obtain the desired product.
We therefore decided to synthesize the unsubstituted ring
in the second reaction step.
Our group recently described an efficient method for the
synthesis of C2-symmetric bisoxazolines. Bisoxazolines
were synthesized in a one-step reaction from the corre-
sponding amino alcohol and dimethylmalononitrile using
a variety of Zn catalysts.19 Taking advantage of this infor-
mation we decided to try these catalysts in the synthesis of
oxazoline compound 2 (Fig. 4).
Formation of the second oxazoline ring from compound 2
was carried out without the need for further purification of
product 2. In this case, Zn(OTf)2 (Fig. 5) was used as a cat-
alyst, as we knew that this was the best one for the synthe-
sis of bisoxazoline compounds.19
O
O
R'1
N
N
3
2
R2
R1 R2
R1
HO
NH2
R1
Zn(AcO)2
toluene
O
Surprisingly, the desired product 5 was not the only one
observed. The formation of bisoxazoline 3 was also ob-
served, indicating that oxazoline formation is a reversible
process under the reaction conditions used. A similar
situation was described by Kim et al.20 in the synthesis of
chiral tripodal oxazolines.
CN
+
R'1
CN
1 mmol
NC
N
R'1
R2
R2
R1
1 mmol
1a-e
O
(R'1=H, except 1d)
R'1
N
4
The results for the synthesis of compound 5 are given in
Table 2. We observed that reaction times and conversions
were strongly dependent on the starting oxazoline 2.
Non-symmetric bisoxazolines were obtained in good-to-
moderate yields. Chromatographic purification provided
pure products 5.
R1 R2
Figure 4. Synthesis of oxazoline compounds 2 from starting materials:
(1a) R1 = H, R2 = H; (1b) R1 = Phe, R2 = H; (1c) R1 = tBu, R2 = H; (1d)
R1, R01 ¼ indanyl, R2 = H; (1e) R1 = Me, R2 = H; (1f) R1 = Phe,
R2 = Me.

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J. I. Garcı´a et al. / Tetrahedron: Asymmetry 17 (2006) 2270–2275
O
O
O
O
O
R'1
N
N
NC
1 mmol
N
CN
N
O
CN
+ 1a
a) Zn(AcO)2
20%
toluene
b) Zn(OTf)2
100%
R'1
Zn(OTf)2
toluene
5 b-f
R1 R2
tBu
O
R
N
6 a-d
+
HO
NH2
tBu
HO
NH2
R2
R1
O
2b-f
O
R'1
R'1
R
H
H
N
N
N
N
1 mmol
1.3 mmol
R1
R2
R2
R1
3
R'
3
R'
R'=tBu or R
Figure 5. Formation of non-symmetric bisoxazoline 5 compounds starting
from oxazoline compounds 2b–f and ethanolamine 1a. (b) R1 = Phe,
R2 = H; (c) R1 = tBu, R2 = H; (d) R1, R10 ¼ indanyl, R2 = H; (f)
R1 = Phe, R2 = Me.
Figure 6. Formation of non-symmetric bisoxazoline 6 compounds starting
from dimethylmalononitrile and the corresponding amino alcohols 1 in a
two-step one-pot procedure. (a) R = Phe, (b) R = Bn, (c) R = Me, (d)
R = Bn–O–CH2.
Table 2. Results in the reaction of equimolecular amounts of 2b–f and
ethanolamine 1a using Zn(OTf)2 in toluene at 110 ꢁC
Table 3. Results of the one-pot synthesis of non-symmetric bisoxazolines
6 after three days of reaction
Product
Time (days)
Yield 5 (%)a
5/3a
Product
Yield 6 (%)a
6/3a
5b
5c
5d
5f
2
7
2
3
62
71
50
64
6
12
4
7a
7b
7c
7d
50
76
70
72
2.3
15
3.6
3
8.6
a Calculated by 1H NMR spectroscopy.
a Calculated by 1H NMR spectroscopy.
In order to prove the versatility of this method we decided
to use amino alcohols other than ethanolamine in order to
obtain new bisoxazoline compounds with different substit-
uents at the 4- and 40-positions. We fixed the presence of a
tert-butyl group in one of the oxazoline rings due to the
better enantioselectivity that is usually associated with the
presence of this bulky substituent.
to increase the molecular diversity of chiral bisoxazolines
for catalytic applications.
4. Experimental
4.1. General
We also tried to improve the synthetic methodology by
working with a one-pot process, that is, adding Zn(OTf)2
and the second amino alcohol to the initial reaction mix-
ture and carrying out the work up only after bisoxazoline
formation (Fig. 6).
1H and 13C NMR spectra (CDCl3, d ppm, J Hz) were ob-
tained using a Bruker AV-400 instrument with TMS as the
standard. Quantitative elemental analyses were performed
on a Perkin–Elmer 2400 instrument. Polarimetry was
carried out using a Jasco P-1020 instrument.
In all cases, we obtained a mixture of C2-symmetric bisox-
azolines 3 and the desired product 6, which could be puri-
fied by column chromatography. Once again, conversions
and product ratios were found to be dependent on the
starting amino alcohol but, in most cases, fairly good yields
of the target compound were obtained (Table 3).
Enantiomerically pure amino alcohols were commercially
available except for (S)-2-methylphenylglycinol and (R)-
2-amino-3-(benzyloxy)-1-propanol, which were obtained
from the corresponding amino acids by Meyers’ method.21
4.2. General procedure for the synthesis of products 2a–f
3. Conclusions
The synthesis of 2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-ox-
azol-2-yl]-2-methylpropanenitrile 2c is representative.
We have designed a simple, general, and convenient meth-
od for the synthesis of non-symmetric bisoxazolines. In
two-step one-pot reactions using dimethylmalononitrile,
two different amino alcohols and Zn(OAc)2 and Zn(OTf)2
as catalysts, we were able to obtain a wide variety of new
bisoxazoline compounds. Fourteen new products, consid-
ering bisoxazolines and their precursors, have been synthe-
sized and fully characterized. This method opens the way
A 250-mL two-necked round-bottomed flask fitted with a
reflux condenser was charged with 2,2-dimethylmalono-
nitrile (941.1 mg, 10 mmol), zinc acetate (20% 367 mg) and
toluene (80 ml). The solution was stirred for 5 min and a
solution of L-tert-leucinol 1c (1.172 g, 10 mmol) in toluene
(20 ml) was added. The solution was then heated at reflux.
The reaction mixture was allowed to cool and then washed

J. I. Garcı´a et al. / Tetrahedron: Asymmetry 17 (2006) 2270–2275
2273
with brine (1 · 100 ml) and NaHCO3 (2 · 100 ml), dried
4.3. General stepwise procedure for the synthesis of bisox-
azolines 5 from oxazolines 2b–e
over MgSO4 and the solvent evaporated to give 1.765 g
(9.1 mmol, 91%) of pure 2c. 1H NMR: 4.21 (dd,
J = 10.09, 8.80 Hz, 1H), 4.11 (dd, J = 8.80, 7.50 Hz, 1H),
3.83 (dd, J = 10.09, 7.50 Hz, 1H), 1.58 (s, 3H), 1.57 (s,
3H), 0.82 (s, 9H). 13C NMR: 24.37, 24.57, 32.29, 32.82,
68.91, 74.59, 120.33, 163.77. Anal. Calcd for C11H18N2O:
C, 68.01; H, 9.34; N, 14.42. Found C, 67.87; H, 9.33; N,
14.52.
The synthesis of (4S)-4-tert-butyl-2-[1-(4,5-dihydro-1,3-
oxazol-2-yl)-1-methylethyl]-4,5-dihydro-1,3-oxazole 5c is
representative. A 250-mL two-necked round-bottomed
flask fitted with a reflux condenser was charged with 2-
[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-2-methylpro-
panenitrile 2c (1.941 g, 10 mmol) in anhydrous toluene
(10 ml) and zinc triflate (4 g, 11 mmol). The system was
purged with argon and anhydrous toluene (90 ml) was
added. The solution was stirred for 5 min and ethanol-
amine (794 mg, 13 mmol) was added. The solution was
heated at reflux for 7 days. The reaction mixture was
allowed to cool and was then washed with brine
(1 · 100 ml) and NaHCO3 (2 · 100 ml), dried over MgSO4
and the solvent evaporated to give 71% of the target com-
pound 5c. The crude product was purified by column chro-
matography (Al2O3; hexane/ethyl acetate, 6:4, 0.4% NEt3).
4.2.1. 2-(4,5-Dihydro-1,3-oxazol-2-yl)-2-methylpropane nitrile
2a. 2-(4,5-Dihydro-1,3-oxazol-2-yl)-2-methyl propanenit-
rile was prepared analogously to 2c in 81% yield. 1H
NMR: 4.36 (t, J = 9.52 Hz, 2H), 3.89 (t, J = 9.52 Hz,
2H), 1.63 (s, 6H). 13C NMR: 24.03, 37.91, 41.77, 60.36,
121.43, 168.46. Anal. Calcd for C7H10N2O: C, 60.85; H,
7.30; N, 20.28. Found C, 60.91; H, 7.35; N, 20.20.
4.2.2. 2-Methyl-2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxa-zol-2-
yl]propanenitrile 2b. 2-Methyl-2-[(4S)-phenyl-4,5-dihydro-
1,3-oxazol-2-yl]propanenitrile was prepared analogously
to 2c to give 84% of the target compound. Purification of
4.3.1. (4S)-4-tert-Butyl-2-[1-(4,5-dihydro-1,3-oxazol-2-yl)-1-
methylethyl]-4,5-dihydro-1,3-oxazole 5c. [a]D = ꢀ44.6 (c
1
1, CH2Cl2). H NMR: 4.18 (m, 2H), 4.09 (m, 1H), 4.02
1
(m, 1H), 3.77 (m, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 0.79 (s,
9H) 13C NMR: 170.19, 168.49, 75.27, 69.11, 67.95, 54.32,
38.58, 33.91, 25.62, 24.40, 24.35. Anal. Calcd for
C13H22N2O2: C, 65.51; H, 9.30; N, 11.75. Found C,
65.34; H, 9.32; N, 11.78.
the crude product was not necessary. H NMR: 7.26 (m,
2H), 7.15 (m, 3H) 5.18 (dd, J = 10.16, 8.18 Hz, 1H), 4.68
(dd, J = 10.16, 8.56 Hz, 1H), 4.17 (dd, J = 8.56, 8.18 Hz,
1H), 1.68 (s, 6H). 13C NMR: 24.40, 32.39, 68.50, 73.6,
120.10, 125.45, 126.89, 127.86, 140.33, 165.49.
4.3.2.
(4S)-2-[1-(4,5-Dihydro-1,3-oxazol-2-yl)-1-methyl
4.2.3.
oxazol-2-yl}-2-methylpropanenitrile
2-{(3aS,8aR)-8,8a-dihydro-3aH-indeno[1,2-d][1,3]-
2d. 2-{(3aS,8aR)-
ethyl]-4-phenyl-4,5-dihydro-1,3-oxazole 5b. (4S)-2-[1-(4,5-
Dihydro-1,3-oxazol-2-yl)-1-methylethyl]-4-phenyl-4,5-di-
hydro-1,3-oxazole was prepared analogously to 5c from 2,2-
dimethylmalononitrile, (S)-(+)-2-phenylglycinol, and etha-
nolamine 2b to give 62% of the target compound in a reac-
tion time of 48 h. The crude product was purified by
column chromatography (Al2O3; hexane/ethyl acetate,
8,8a-Dihydro-3aH-indeno[1,2-d][1,3]oxazol-2-yl}-2-methyl-
propanenitrile was prepared analogously to 2c to give 75%
of the target compound. Purification of the crude product
was not necessary. 1H NMR: 7.46–7.40 (m, 1H), 7.24–
7.14 (m, 3H), 5.53 (d, J = 7.94 Hz, 1H), 5.37 (ddd,
J = 7.94, 7.07, 1.64 Hz, 1H), 3.39 (dd, J = 18.04, 7.07 Hz,
1H), 3.20 (dd, J = 18.04, 1.64 Hz, 1H), 1.55 (s, 3H), 1.51
(s, 3H). 13C NMR: 165.53, 141.00, 139.49, 128.79, 127.58,
125.66, 125.37, 121.19, 84.53, 76.76, 39.62, 33.33, 25.32,
25.28.
1
6:4, 0.4% NEt3). [a]D = ꢀ124.6 (c 1, CH2Cl2). H NMR:
7.30–7.24 (m, 2H), 7.22–7.14 (m, 3H), 5.13 (dd,
J = 10.12, 7.74 Hz, 1H), 4.57 (dd, J = 10.12, 8.33 Hz,
1H), 4.25 (dd, J = 9.63, 9.63 Hz, 2H), 4.05 (dd, J = 8.33,
7.74 Hz, 1H), 3.83 (dd, J = 9.63, 9.63 Hz, 2H), 1.53 (s,
3H), 1.52 (s, 3H). 13C NMR: 170.43, 170.01, 142.39,
128.69, 127.50, 126.65, 75.57, 69.46, 68.02, 54.40, 38.82,
24.47, 24.36. Anal. Calcd for C15H18N2O2: C, 69.74; H,
7.02; N, 10.84. Found C, 69.81; H, 7.07; N, 10.82.
4.2.4. 2-Methyl-2-[(4S)-4-methyl-4,5-dihydro-1,3-oxazol-2-
yl]propanenitrile
2e. 2-Methyl-2-[(4S)-4-methyl-4,5-di-
hydro-1,3-oxazol-2-yl]propanenitrile was prepared analo-
gously to 2c to give 61% of the target compound.
1
Purification of the crude product was not necessary. H
4.3.3. (3aS,8aR)-2-[1-(4,5-Dihydro-1,3-oxazol-2-yl)-1-meth-
ylethyl]-8,8a-dihydro-3aH-indeno[1,2-d][1,3] oxazole 5d.
(3aS,8aR)-2-[1-(4,5-Dihydro-1,3-oxazol-2-yl)-1-methyleth-
yl]-8,8a-dihydro-3aH-indeno[1,2-d][1,3] oxazole was pre-
pared analogously to 5c from 2,2-dimethylmalononitrile,
(1S)-amino-(2R)-indanol, and ethanolamine to give 50%
of the target compound in a reaction time of 48 h. The
crude product was purified by column chromatography
(Al2O3; hexane/ethyl acetate, 2:8, 0.4% NEt3). [a]D =
NMR: 4.39 (dd, J = 9.35, 8.24 Hz, 1H), 4.22–4.11 (m,
1H), 3.83 (dd, J = 8.24, 7.70 Hz, 1H), 1.58 (s, 6H), 1.21
(d, J = 6.65 Hz, 3H). 13C NMR: 18.78, 22.92, 30.87,
59.44, 72.84, 118.87, 162.65.
4.2.5. 2-Methyl-2-[(4S)-4-methyl-4-phenyl-4,5-dihydro-1,3-
oxazol-2-yl]propanenitrile 2f. 2-Methyl-2-[(4S)-4-methyl-
4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]propanenitrile
was
1
prepared analogously to 2c to give 90% of the target com-
pound. Purification of the crude product was not neces-
sary. H NMR: 7.32–7.14 (m, 5H), 4.34 (d, J = 8.24 Hz,
1H), 4.28 (d, J = 8.24 Hz, 1H), 1.65 (s, 6H), 1.54 (s, 3H).
13C NMR: 25.45, 29.38, 33.42, 73.16, 81.30, 121.26,
125.11, 127.19, 128.64, 146.14, 164.49.
ꢀ206.3 (c 1, EtOH). H NMR: 7.48–7.40 (m, 1H), 7.23–
7.12 (m, 3H), 5.49 (d, J = 8.02 Hz, 1H), 5.29 (ddd,
J = 8.02, 7.15, 1.55 Hz, 1H), 4.18 (dd, J = 9.47, 9.47 Hz,
2H) (m, 2H), 3.79 (dd, J = 9.47, 9.47 Hz, 2H) (m, 2H),
3.34 (dd, J = 17.84, 7.15 Hz, 1H), 3.12 (dd, J = 17.84,
1.55 Hz, 1H), 1.43 (s, 3H), 1.36 (s, 3H). 13C NMR:
1

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J. I. Garcı´a et al. / Tetrahedron: Asymmetry 17 (2006) 2270–2275
170.01, 169.15, 141.75, 139.78, 128.41, 127.36, 125.71,
125.17, 83.35, 76.57, 68.04, 54.38, 39.84, 38.62, 24.41,
24.09. Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N,
10.36. Found C, 71.00; H, 6.72; N, 10.35.
azol-2-yl]-1-methylethyl}-4,5-dihydro-1,3-oxazole was pre-
pared analogously to 6a from 2,2-dimethylmalononitrile,
L-tert-leucinol, and (S)-2-amino-3-phenyl-1-propanol to
give 76% of the target compound in a reaction time of
72 h. The crude product was purified by column chroma-
tography (Al2O3; hexane/ethyl acetate, 7:3, 0.4% NEt3).
4.3.4.
ethyl]-4-methyl-4-phenyl-4,5-dihydro-1,3-oxazole
(4S)-2-[1-(4,5-Dihydro-1,3-oxazol-2-yl)-1-methyl-
(5).
1
[a]D = ꢀ91.1 (c 1, CH2Cl2). H NMR: 7.26–7.18 (m, 2H),
(4S)-2-[1-(4,5-Dihydro-1,3-oxazol-2-yl)-1-methylethyl]-4-
methyl-4-phenyl-4,5-dihydro-1,3-oxazole was prepared
analogously to 5c from 2,2-dimethylmalononitrile, (S)-
(+)-2-methyl-2-phenylglycinol, and ethanolamine to give
64% of the target compound in a reaction time of 72 h.
The crude product was purified by column chromato-
graphy (Al2O3; hexane/ethyl acetate, 7:3, 0.4% NEt3).
[a]D = +4.6 (c 1, EtOH). 1H NMR: 7.32–7.23 (m, 4H),
7.20–7.13 (m, 1H), 4.28–4.18 (m, 3H), 4.15 (d,
J = 8.11 Hz, 1H), 3.82 (dd, J = 9.50, 9.50 Hz, 2H), 1.55
(s, 3H), 1.53 (s, 3H), 1.52 (s, 3H). 13C NMR: 170.13,
168.23, 146.80, 128.45, 126.88, 125.34, 80.85, 72.46,
68.07, 54.42, 38.69, 28.73, 24.46, 24.42. Anal. Calcd for
C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found C,
70.55; H, 7.38; N, 10.28.
7.18–7.10 (m, 3H), 4.33 (m, 1H), 4.13–4.06 (m, 2H), 4.03
(dd, J = 8.63, 6.89 Hz, 1H), 3.93 (dd, J = 8.41, 6.87 Hz,
1H), 3.78 (dd, J = 10.00, 6.89 Hz, 1H), 3.04 (dd,
J = 13.69, 4.63 Hz, 1H), 2.58 (dd, J = 13.69, 8.71 Hz,
1H), 1.44 (s, 3H), 1.41 (s, 3H), 0.80 (s, 9H). 13C NMR:
169.67, 168.50, 137.78, 129.45, 128.44, 126.45, 75.30,
71.96, 69.08, 67.08, 41.36, 38.59, 33.94, 25.64, 24.44,
24.23. Anal. Calcd for C20H28N2O2: C, 73.14; H, 8.59; N,
8.53. Found C, 73.09; H, 8.57; N, 8.55.
4.4.3. (4S)-4-tert-Butyl-2-{1-methyl-1-[(4S)-4-methyl-4,5-di-
hydro-1,3-oxazol-2-yl]ethyl}-4,5-dihydro-1,3-oxazole 6c. (4S)-
4-tert-Butyl-2-{1-methyl-1-[(4S)-4-methyl-4,5-dihydro-1,3-
oxazol-2-yl]ethyl}-4,5-dihydro-1,3-oxazole was prepared
analogously to 6a from 2,2-dimethylmalononitrile, L-tert-
leucinol, and (S)-(+)-2-amino-1-propanol to give 70% of
the target compound in a reaction time of 72 h. The crude
product was purified by column chromatography (Al2O3;
hexane/ethyl acetate, 8:2, 0.4% NEt3). Yield 63%.
[a]D = ꢀ86.9 (c 0.785, CH2Cl2). 1H NMR: 4.30 (dd,
J = 9.17, 8.07 Hz, 1H), 4.17–4.04 (m, 3H), 3.82 (dd,
J = 9.98, 6.92 Hz, 1H), 3.78–3.71 (m, 1H), 1.49 (s, 3H),
1.48 (s, 3H), 1.21 (d, J = 6.58 Hz, 3H), 0.84 (s, 9H). 13C
NMR: 169.02, 168.56, 75.29, 74.37, 69.09, 61.39, 38.50,
33.95, 25.63, 24.45, 24.36, 21.32. Anal. Calcd for
C14H24N2O2: C, 66.63; H, 9.59; N, 11.10. Found C,
66.65; H, 9.60; N, 11.09.
4.4. General one-pot procedure for the synthesis of bisox-
azolines 6
The synthesis of (4S)-4-tert-butyl-2-{1-methyl-1-[(4S)-4-
phenyl-4,5-dihydro-1,3-oxazol-2-yl]ethyl}-4,5-dihydro-1,3-
oxazole 6a is representative.
A 250-mL two-necked round-bottomed flask fitted with a
reflux condenser was charged with 2,2-dimethylmalono-
nitrile (941.1 mg, 10 mmol), zinc acetate (20% 367 mg), and
toluene (80 ml). The solution was stirred for 5 min and a
solution of L-tert-leucinol 1c (1.172 g, 10 mmol) in toluene
(20 ml) was added. The solution was heated at reflux for
one day. The system was then allowed to cool. Zinc triflate
(4 g, 11 mmol) and (S)-(+)-2-phenylglycinol (1.78 g,
13 mmol) were added. The solution was again heated at re-
flux for 3 days. The system was allowed to cool. The reac-
tion was then washed with brine (1 · 100 ml) and NaHCO3
(2 · 100 ml), dried over MgSO4 and the solvent evaporated
to give 50% of the target compound 6a. The crude product
was purified by column chromatography (Al2O3; hexane/
ethyl acetate, 8:2, 0.4% NEt3).
4.4.4.
(4S)-4-[(Benzyloxy)methyl]-2-{1-[(4S)-4-tert-butyl-
4,5-dihydro-1,3-oxazol-2-yl]-1-methylethyl}-4,5-dihydro-1,3-
oxazole 6d. (4S)-4-[(Benzyloxy)methyl]-2-{1-[(4S)-4-tert-
butyl-4,5-dihydro-1,3-oxazol-2-yl]-1-methylethyl}-4,5-dihy-
dro-1,3-oxazole was prepared analogously to 6a from 2,2-
dimethylmalononitrile, L-tert-leucinol, and (R)-2-amino-3-
(benzyloxy)propan-1-ol to give 72% of the target com-
pound in a reaction time of 72 h. The crude product was
purified by column chromatography (Al2O3; hexane/ethyl
acetate, 7:3, 0.4% NEt3). Yield 44%. [a]D = ꢀ96.9 (c 1,
CH2Cl2). 1H NMR: 7.28–7.16 (m, 5H), 4.48 (d,
J = 12.14 Hz, 1H), 4.45 (d, J = 12.14 Hz, 1H), 4.29–4.17
(m, 2H), 4.16–4.07 (m, 1H), 4.07 (dd, J = 10.02, 8.70 Hz,
1H), 4.00 (dd, J = 8.70, 6.89 Hz, 1H), 3.77 (dd, J = 10.02,
6.89 Hz, 1H), 3.64–3.59 (m, 1H), 3.36–3.28 (m, 1H), 1.43
(s, 6H), 0.78 (s, 9H). 13C NMR: 169.99, 167.69, 137.44,
127.63, 126.90, 126.87, 74.54, 72.62, 71.34, 70.39, 68.34,
65.10, 37.92, 33.19, 24.89, 23.71, 23.64. Anal. Calcd for
C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found C, 70.39;
H, 8.47; N, 7.79.
4.4.1.
(4S)-4-tert-Butyl-2-{1-methyl-1-[(4S)-4-phenyl-4,5-
dihydro-1,3-oxazol-2-yl]ethyl}-4,5-dihydro-1,3-oxazole 6a.
[a]D = ꢀ173.3 (c 1, CH2Cl2). 1H NMR: 7.28–7.22 (m,
2H), 7.21–7.15 (m, 3H), 5.10 (dd, J = 10.07, 7.52 Hz,
1H), 4.53 (dd, J = 10.07, 8.40 Hz, 1H), 4.12 (dd, J = 9.98,
8.76 Hz, 1H), 4.05 (dd, J = 8.76, 7.00 Hz, 1H) 4.03 (dd,
J = 8.40, 7.52 Hz, 1H), 3.81 (dd, J = 9.98, 7.00 Hz, 1H),
1.52 (s, 3H), 1.49 (s, 3H), 0.82 (s, 9H). 13C NMR: 170.59,
168.52, 142.61, 128.67, 127.53, 126.77, 75.51, 75.44,
69.54, 69.13, 38.84, 33.96, 25.68, 24.65, 24.34. Anal. Calcd
for C19H26N2O2: C, 72.58; H, 8.33; N, 8.91. Found C,
72.61; H, 8.35; N, 8.89.
Acknowledgments
4.4.2. (4S)-4-Benzyl-2-{1-[(4S)-4-tert-butyl-4,5-dihydro-1,3-
oxazol-2-yl]-1-methylethyl}-4,5-dihydro-1,3-oxazole
This work was made possible by the generous financial sup-
port of the CICYT (Project CTQ2005-08016). I.V. wishes
6b.
(4S)-4-Benzyl-2-{1-[(4S)-4-tert-butyl-4,5-dihydro-1,3-ox-

J. I. Garcı´a et al. / Tetrahedron: Asymmetry 17 (2006) 2270–2275
2275
11. Da Palma, E.; Chercheja, S.; Burke, A. J.; Prates, J. P.;
Rodrigues, A. I. J. Mol. Catal. 2005, 236, 38–45.
12. Gao, M. Z.; Wang, B.; Kong, D.; Zingaro, R. A.; Clearfield,
A.; Xu, Z. L. Synth. Commun. 2005, 35, 2665–2673.
13. Barros, M. T.; Maydock, C. D.; Faisca, A. M. Tetrahedron:
Asymmetry 2005, 16, 2946–2953.
to thank the MEC for a grant. We thank DSM-Deretil for
furnishing us with pure (S)-2-methylphenylglycine.
References
1. McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151–
4202.
2. Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1–45.
14. (a) Fraile, J. M.; Garc´ıa, J. I.; Harmer, M. A.; Herrer´ıas, C.
I.; Mayoral, J. A. J. Mol. Catal. A 2001, 165, 211–218; (b)
Fraile, J. M.; Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.;
Harmer, M. A. J. Catal. 2004, 221, 532–540.
3. Muller, D.; Umbricht, G.; Weber, B.; Pfalz, A. Helv. Chim.
Acta 1991, 74, 232–240.
15. Fraile, J. M.; Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.
Chem. Commun. 2005, 37, 4669–4671.
4. Corey, E. J.; Imai, N.; Zhang, H. J. Am. Chem. Soc. 1991,
113, 728–729.
5. Lowental, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005–6008.
6. Evans, D. A.; Peterson, G. S.; Jonson, J. S.; Barnes, D. M.;
Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63,
4541–4544.
7. Hall, J.; Lehn, J. M.; DeCian, A.; Fischer, J. Helv. Chim. Acta
1991, 74, 1–6.
16. Burguete, M. I.; Fraile, J. M.; Garcia, J. I.; Garcia-Verdugo,
E.; Herrerias, C. I.; Luis, S. V.; Mayoral, J. A. J. Org. Chem.
2001, 66, 8893–8901.
17. Ferna´ndez, A. I.; Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.;
Salvatella, L. Catal. Commun. 2001, 2, 165–170.
18. Cornejo, A.; Fraile, J. M.; Garcia, J. I.; Gil, M. J.; Herrerias,
C. I.; Legarreta, G.; Martinez-Merino, V.; Mayoral, J. A.
J. Mol. Catal. A-Chem. 2003, 196, 101–108.
19. Cornejo, A.; Fraile, J. M.; Garcia, J. I.; Gil, M. J.; Martinez,
V.; Mayoral, J. A.; Pires, E.; Villalba, I. Synlett 2005, 2321–
2325.
8. Bolm, C.; Weickhardt, K.; Zehner, M.; Ranff, T. Chem. Ber.
1991, 124, 1173–1180.
9. Bayardon, J.; Sinou, D. Tetrahedron: Asymmetry 2005, 16,
2965–2972.
20. Kim, S.-G.; Seong, H. R.; Kim, J.; Ahn, K. H. Tetrahedron
Lett. 2004, 45, 6835–6838.
10. Makino, K.; Ogawa, I.; Hamada, Y. Heterocycles 2005, 6,
433–440.
21. McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568–3571.