Synthesis of novel chiral C2-symmetric bisoxazoline ligands containing 2,5-di(m-substituted)phenyl-1,3,4-oxadiazole

Article abstract of DOI:10.1081/SCC-120021848

Seven novel chiral C₂-symmetric substituted bisoxazoline ligands containing 2,5-di(m-substituted)phenyl-1,3,4(m-substituted)phenyl-1,3,4-oxadiazole have been synthesized from 2,5-di-(m-carboxylphenyl)-1,3,4-oxadiazole and aminoalcohol by NaOH o

Full text of DOI:10.1081/SCC-120021848

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Synthesis of Novel Chiral C2-Symmetric
Bisoxazoline Ligands Containing 2,5-Di( m -
substituted)phenyl-1,3,4-oxadiazole
Dong-Cheng Xu a , Da-Ming Du a , Nan Ji a , Zhan-Yue Wang a & Wen-Ting Hua a
a Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education , College of Chemistry and Molecular Engineering , Peking University , Beijing,
P.R. China
Published online: 20 Aug 2006.
To cite this article: Dong-Cheng Xu , Da-Ming Du , Nan Ji , Zhan-Yue Wang & Wen-Ting Hua (2003) Synthesis of Novel Chiral
C2-Symmetric Bisoxazoline Ligands Containing 2,5-Di( m -substituted)phenyl-1,3,4-oxadiazole, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:14, 2563-2574, DOI: 10.1081/
SCC-120021848
To link to this article: http://dx.doi.org/10.1081/SCC-120021848
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 14, pp. 2563–2574, 2003
Synthesis of Novel Chiral
C2-Symmetric Bisoxazoline Ligands Containing
2,5-Di(m-substituted)phenyl-1,3,4-oxadiazole
*
Dong-Cheng Xu, Da-Ming Du, Nan Ji, Zhan-Yue Wang,
*
and Wen-Ting Hua
Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering,
Peking University, Beijing, P.R. China
ABSTRACT
Seven novel chiral C2-symmetric substituted bisoxazoline ligands
containing 2,5-di(m-substituted)phenyl-1,3,4-oxadiazole have been
synthesized from 2,5-di-(m-carboxylphenyl)-1,3,4-oxadiazole and
aminoalcohol by NaOH or Et3N cyclization method via halogenated
amide intermediate.
Key Words: Bisoxazoline; Oxadiazole; Synthesis.
*Correspondence: Da-Ming Du, Wenzhou Medical College, Wenzhou, 325003,
Zhejiang, China and Wen-Ting Hua, Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College of Chemistry
and Molecular Engineering, Peking University, Beijing, 100871, P.R. China;
Fax: 86-10-62751708; E-mail: dudm@pku.edu.cn; E-mail: huawt@pku.edu.cn.
2563
DOI: 10.1081/SCC-120021848
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2564
Xu et al.
INTRODUCTION
The 2,5-diaryl-oxadiazole is one class of very rigid and almost planar
molecule possessing many ꢀ-conjugated system.[1–3] Recently, much
attention has been focused on the use of aromatic 1,3,4-oxadiazole unit
in development of new photoelectric materials, such as conductor and
electroluminescent owing to their special structure unit and proper-
ties.[4–6] Moreover, the structural factors may be advantageous to the
molecular stereo-recognition in the host-guest inclusion when they were
involved in this system. For this reason, a series of chiral macrocycles
containing 2,5-diphenyl-1,3,4-oxadiazole have been synthesized as host,
which showed remarkable chiral recognition to D- or L-amino acids,
peptides, and some activity molecules in our previous report.[7]
In recent years, the bisoxazoline ligands and their metal complexes
have been used extensively in varied asymmetric catalytic reaction as
C2-symmetric chiral catalysts.[8–14] It is a new idea that make up a novel
chiral catalyst system employing the two special structural units. In this
article, we designed and synthesized the new chiral C2-symmetric ligands
containing both a rigid 2,5-di(m-substituted)phenyl-1,3,4-oxadiazole and
two 4-substituted chiral oxazoline rings. Here, we reported the synthesis
of these novel chiral bisoxazoline ligands containing 2,5-di(m-substitu-
ted)phenyl-1,3,4-oxadiazole units.
Results and Discussion
The ligands 4a–d were synthesized from 2,5-di-(m-carboxylphenyl)-
1,3,4-oxadiazole 1 with corresponding b-amino alcohols by two methods
respectively as shown in Sch. 1. The b-amino alcohols have been prepared
from corresponding chiral amino acids by reduction with LiAlH4 or
NaBH4 according to the reported methods.[15] First is multistep
method. The 2,5-di-(m-carboxylphenyl)-1,3,4-oxadiazoles 1 were reacted
with SOCl2, condensation of the resulting diacyl dichloride intermediates
with b-amino alcohols afforded the corresponding dihydroxy diamide
intermediates 2a–d in 84.7–81.5% yield. The following is replacement
of 2a–d with SOCl2 in dichloromethane (2a–c) or DMF (2d) and furn-
ished the 3a–d in 64.5–79% yield. Owing to the low solubility of 2d in
dichloromethane, very low yield was obtained. When DMF was used
alternatively for 2d, good yield for 3d was obtained (64.5%). Finally,
the chiral bisoxazoline ligands 4a–c were obtained via intramolecular
cyclization of 3a–c in the presence of NaOH (method a). 4d cannot use
this method for cyclization. Fortunately, 4d was obtained in 72.8% yield

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C2-Symmetric Bisoxazoline Ligands
2565
Scheme 1. Preparation of chiral ligands 4a–d.
Scheme 2. Preparation of chiral ligands 6a–c.
via cyclization with Et3N in refluxing toluene and DMF (method b). It is
advantageous in this three step method that the higher yields and more
pure products could be obtained in the every steps, except for reaction
process is longer.
Diamide 5 was synthesized according to the same procedure of dihy-
droxy diamides 2a–d from 2,5-di-(m-carboxylphenyl)-1,3,4-oxadiazole 1
and (1R,2S)-(-)-2-amino-1-phenyl-1,3-propanediol, but with longer reac-
tion time for fluxing 36 h. However, diamide 5 cannot be treated with

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2566
Xu et al.
SOCl2 and subsequent with NaOH for cyclization to obtain the corre-
sponding bisoxazoline 6a, owing to it has two hydroxy groups.
Fortunately, treatment of diamide 5 with p-TsCl and triethylamine in
refluxing dichloromethane,[16] activation of the primary OH group by
formation of the tosylate can give the desired bisoxazoline 6a in 59%
yield. The bisoxazoline 6a can be further converted to acetate 6b and
methyl ether 6c in 78.3% and 58.3% yield respectively. The structures
1
of these new ligands were identified by H NMR, MS, IR, and elemental
analysis.
Second is one pot method, which was developed by Vorbruggen.[17]
This method is applicable for synthesis of varied ligands containing mono
oxazoline and bisoxazolines from corresponding aromatic acid or hetero-
cyclic acid.[17,18] But, there is also trouble in the one pot method that the
large triphenyl phosphine oxide was produced at the same time as by
product, this add to the difficulties in purification of product. The 2,5-di-
(m-carboxylphenyl)-1,3,4-oxadiazole 1 can also were transformed into
ligands 4 directly in one step with corresponding b-amino alcohols in
the presence of triphenyl phosphine. This method is simple and conve-
nient, however the yield is lower. In this article, we have used crystallize-
able method in steps in preliminary separation of the large triphenyl
phosphine oxide, the crude product was further purified via column
chromatography on silica gel.
In conclusion, we have found efficent synthetic procedure for synth-
esis of a new series of chiral diphenyl oxdiazole bisoxazoline ligands.
These novel diphenyloxadiazole bisoxazolines may have potential as
chiral ligands for catalytic asymmetric reaction. Further application of
this series new chiral ligands in catalytic enantioselective reaction are
under research in our laboratory.
EXPERIMENTAL SECTION
Melting points were uncorrected. 1H NMR spectra were recorded on
a Bruker ARX 400 MHz spectrometer, tetramethylsilane (TMS) serving
as internal standard. Infrared spectra were obtained on a Bruker Vector
22 spectrometer. Mass spectra were obtained on a VG-ZAB-HS mass
spectrometer. Optical rotations were measured on a Perkin-Elmer 241
MC spectrometer. Elemental analyses were carried out on an
Elementar Vario ELinstrument. Solvents used were purified and dried
by standard procedures. All reactions were carried out under an
atmosphere of nitrogen. 2,5-di(m-carboxyphenyl)-1,3,4-oxadizole was
synthesized according to literature produre.[19]

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C2-Symmetric Bisoxazoline Ligands
2567
2,5-bis[m-[N-(10S)-(10 -isobutyl-20-hydroxyethyl)amido]phenyl]-1,3,4-
oxadiazole 2a. General Procedure I. A solution of 2,5-di-(m-carboxy-
phenyl)-1,3,4-oxadiazole 1 (1.17 g, 3.76 mmol) and SOCl2 (20 mL) was
refluxed for 10 h. The excess SOCl2 was removed under reduced pressure,
benzene (20 mL) was added and the solvent was removed again to dry-
ness to afford the diacyl dichloride. The above diacyl dichloride in
CH2Cl2 (50 mL) was added dropwise to a solution of S-leucinol (0.88 g,
7.52 mmol) and Et3N (2.82 mL) in CH2Cl2 (30 mL) at 0ꢀC and stirring at
room temperature for 24 h. The precipitate was filtered and washed with
diethyl ether to afford the colorless solid powder 2a 1.51 g (79.2% yield).
M.p. 163–169ꢀC. IR (KBr): 3470, 3320, 2920, 2840, 1640, 1570 cmÀ1
.
EI MS: 508 (Mþ). H NMR (DMSO): ꢁ 0.90 (6H, d, J ¼ 5.2 Hz, CH3),
0.92 (6H, d, J ¼ 5.2 Hz, CH3), 1.37–1.54 (4H, m, CH2), 1.62–1.67 (2H, m,
CH), 3.33–3.50 (4H, m, CH2), 4.09–4.15 (2H, m, CH), 4.75 (2H, t,
J ¼ 5.8Hz, OH), 7.74 (2H, t, J ¼ 7.8 Hz, ArH), 8.12 8.15 (2H, m, ArH),
8.28–8.31 (2H, m, ArH), 8.37 (2H, d, J ¼ 8.6 Hz, NH), 8.63 (2H, t,
J ¼ 1.4 Hz, ArH). Anal. calcd. C28H36N4O5: C, 66.14; H, 7.08; N,
11.02. Found: C, 66.12; H, 7.13; N, 10.93.
1
2,5-bis[m-[N-(10S)-(10-isopropyl-20-hydroxyethyl)amido]phenyl]-1,3,4-
oxadiazole 2b. Following general procedure I, from 2,5-di-(m-carboxy-
phenyl)-1,3,4-oxadiazole 1 (1.68 g, 5.3 mmol) , SOCl2 (30 mL), S-valinol
(1.09 g, 10.5 mmol) and Et3N (4.0 mL) to provide colorless solid 2b in
74.7% yield (1.9g). M.p. 240–242ꢀC. IR (KBr): 3400, 2950, 1650,
1530 cmÀ1. EI MS: 480 (Mþ). 1H NMR (DMSO): ꢁ 0.92 (6H, d,
J ¼ 6.8 Hz, CH3), 0.94 (6H, d, J ¼ 6.8 Hz, CH3), 1.92–2.00 (2H, m,
CH), 3.53–3.59 (4H, m, CH2), 3.83–3.90 (2H, m, CH), 4.63 (2H, t,
J ¼ 5.6, OH), 7.74 (2H, t, J ¼ 7.8 Hz, ArH), 8.15 (2H, d, J ¼ 7.8 Hz,
ArH), 8.28–8.31 (2H, m, ArH), 8.32 (2H, d, J ¼ 8.8 Hz, NH), 8.62 (2H,
s, ArH). Anal. calcd. C26H32N4O5: C, 64.98; H, 6.71; N, 11.67. Found: C,
64.85; H, 6.71; N, 11.52.
2,5-bis[m-[N-(10S)-(10-benzyl-20-hydroxyethyl)amido]phenyl]-1,3,4-oxa-
diazole 2c. Following general procedure I, from 2,5-di-(m-carboxy-
zphenyl)-1,3,4-oxadiazole
1
(0.82 g, 2.65 mmol), SOCl2(20 mL),
S-phenylalaninol (0.8 g, 5.3 mmol) and Et3N (2.0 mL) to give a colorless
solid 2c in 80.8% yield (1.24 g). M.p. 240–242ꢀC. IR (KBr): 3400, 3350,
1
1620, 1550 cmÀ1. FAB-MS: 577 (M þ 1). H NMR (DMSO): ꢁ 2.82 (2H,
dd, J ¼ 8.8, 13.0 Hz, CH2), 2.97 (2H, dd, J ¼ 5.2, 13.4 Hz, CH2), 3.23–3.40
(2H, m, CH2), 3.43–3.56 (2H, m, CH2), 4.15–4.28 (2H, m, NCH), 4.89
(2H, t, J ¼ 5.6 Hz, OH), 7.10–7.34 (10H, m, ArH), 7.72 (2H, t, J ¼ 7.4 Hz,
ArH), 8.05 (2H, dd, J ¼ 1.2, 7.4 Hz, ArH), 8.27 (2H, dd, J ¼ 1.2, 7.4 Hz,
ArH), 8.52 (2H, d, J ¼ 8.0 Hz, NH), 8.55 (2H, s, ArH). Anal. calcd.
C34H32N4O5: C, 70.82; H, 5.59; N, 9.72. Found: C, 70.97; H, 5.59; N, 9.50.

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2568
Xu et al.
2,5-bis[m-[N-(10S)-(10-phenyl-20-hydroxyethyl)amido]phenyl]-1,3,4-
oxadiazole 2d. Following general procedure I, from 2,5-di-(m-carboxy-
phenyl)-1,3,4-oxadiazole 1 (1.9 g, 6.1 mmol), SOCl2 (34 mL), R-phenyl-
glycinol (1.65 g, 12.0 mmol) and Et3N (6.9 mL) to give a colorless solid 2d
in 81.5% yield (2.68 g). M.p. 278–280ꢀC. H NMR (DMSO): ꢁ 3.67–3.82
1
(4H, m, OCH2), 5.09 (4H, J ¼ 6.0 Hz, CH and OH), 7.19–7.46 (10H, m,
ArH), 7.45 (2H, t, J ¼ 8.0 Hz, ArH), 8.21 (2H, d, J ¼ 7.8 Hz, ArH), 8.33
(2H, d, J ¼ 7.8 Hz, ArH), 8.81 (2H, s, ArH), 9.20 (2H, d, J ¼ 7.8 Hz, NH).
IR (KBr): 3311, 1640, 1543, 1320 cmÀ1. FAB MS: 549 (M þ 1,7), 475 (24).
Anal. calcd. C32H28N4O5: C, 70.06; H, 5.14; N, 10.20. Found: C, 69.90;
H, 5.25; N, 10.32.
2,5-bis[m-[N-(10S)-(10-isobutyl-20-chloroethyl)amido]phenyl]-1,3,4-oxa-
diazole 3a. General Procedure II. To the suspension of compound 2a
(508 mg, 1 mmol) in the CH2Cl2 (10 mL) was added SOCl2 (4 mL) and
the mixture refluxing for 5 h. The reaction mixture was cooled and
poured into the ice-water, the organic phase (CH2Cl2) was separated
from mixtures. The aqueous layer was extracted with CH2Cl2
(5 Â 5 mL). The extracts were combined and washed to neutral with
5% NaHCO3 and brine respectively, dried over Na2SO4 and filtered.
The filtrate was concentrated in vacuo to afford the product 3a in 79%
yield (430 mg). M.p. 125–128ꢀC. IR (KBr): 3350, 2990, 1640, 1520 cmÀ1
.
MS (FAB): 545 (M þ 1), ꢁ 1.00 (12H, m, 4CH3), 1.42–1.48 (1H, m,
CH2), 1.55–1.62 (1H, m, CH2), 1.65–1.88 (4H, m, CH2, CH), 3.70–
3.74 (1H, m, CH2Cl), 3.86–3.91 (1H, m, CH2Cl), 4.05–4.10 (1H, m,
CH2Cl), 4.35–4.45 (1H, m, CH2Cl), 4.56–4.62 (2H, m, NCH), 6.40
(2H, d, J ¼ 8.6 Hz, NH), 7.55–7.66 (2H, m, ArH), 8.01 (1H, t, J ¼ 8.2 Hz,
ArH), 8.15 (1H, dd, J ¼ 1.2, 7.8 Hz, ArH), 8.28–8.32 (2H, m, ArH), 8.52
(1H, d, J ¼ 1.4 Hz, ArH), 8.68 (1H, s, ArH). Anal. calcd. C28H34Cl2N4O3:
C, 61.65; H, 6.28; N, 10.27. Found: C, 61.54; H, 6.12; N, 10.23.
2,5-bis[m-[N-(10S)-(10 -isopropyl-20 -chloroethyl)amido]phenyl]-1,3,4-
oxadiazole 3b. Following general procedure II, from compound 2b
(480 mg, 1 mmol), SOCl2 (4 mL) to afford the product 3b in 76% yield
(393 mg). M.p. 138–143ꢀC. IR (KBr): 3400, 3350, 1680, 1550 cmÀ1. MS
(FAB): 517 (M þ 1). 1H NMR (CDCl3): ꢁ 1.08 (12H, d, J ¼ 6.7 Hz,
4CH3), 1.88–1.96 (1H, m, CH), 2.04–2.16 (1H, m, CH), 3.82–3.90 (3H,
m, CH2), 4.15–4.28 (3H, m, CH2, CH), 4.52 (1H, s, NH), 6.48 (2H, d,
J ¼ 9.0 Hz, NH), 7.59–7.67 (2H, m, ArH), 8.07 (1H, t, J ¼ 8.2 Hz, ArH),
8.17 (1H, d, J ¼ 7.8 Hz, ArH), 8.31 (2H, t, J ¼ 7.6 Hz, ArH), 8.53 (1H, s,
ArH), 8.56 (1H, s, ArH). Anal. calcd. C26H30Cl2N4O3: C, 60.35; H, 5.84;
N, 10.83. Found: C, 60.58; H, 5.86; N, 11.04.
2,5-bis[m-[N-(10S)-(10-benzyl-20-chloroethyl)amido]phenyl]-1,3,4-oxa-
diazole 3c. Following general procedure II, from compound 2c (576 mg,

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C2-Symmetric Bisoxazoline Ligands
2569
1 mmol), SOCl2 (5 mL) to afford the product 3c in 69% yield (417 mg).
M.p. 197–200ꢀC. IR (KBr): 3360, 1650, 1530 cmÀ1. MS (FAB): 613
1
(M þ 1). H NMR (CDCl3): ꢁ 3.10 (4H, dd, J ¼ 4.2, 8.4 Hz, CH2), 3.65
(2H, dd, J ¼ 3.4, 11.2 Hz, CH2Cl), 3.82 (2H, dd, J ¼ 4.0, 11.2 Hz, CH2Cl),
4.63–4.78 (2H, m, NCH), 6.49 (2H, d, J ¼ 8.4 Hz, NH), 7.20–7.39 (10H,
m, ArH), 7.65 (2H, t, J ¼ 7.8 Hz, ArH), 7.95 (2H, d, J ¼ 7.6 Hz, ArH),
8.30 (2H, d, J ¼ 7.6 Hz, ArH). Anal. calcd. C34H30Cl2N4O3: C, 66.56; H,
4.93; N, 9.13. Found: C, 66.63; H, 4.81; N, 8.91.
2,5-bis[m-[N-(10R)-(10-phenyl-20-chloroethyl)amido]phenyl]-1,3,4-oxa-
diazole 3d. To the solution of dihydroxy diamide 2d (1.49 g, 2.71 mmol) in
the DMF (25 mL) was added dropwise a solution of thionyl chloride
(1.5 mL, 20 mmol) in DMF (5 mL) via syringe. The mixture was kept
stirring at room temperature for 24 h. The reaction mixture was poured
into the ice-water (100 mL), the precipitate was filtered and dried to give
1.32 g (83.3% yield) of the crude product. The crude product was recrys-
tallized from methanol to afford colorless solid 1.03 g (64.5%). M.p.
188–190ꢀC. H NMR (CDCl3): ꢁ 4.00 (4H, d, J ¼ 7.6 Hz, CH2Cl), 5.30–
1
5.42 (2H, m, NCH), 7.30–7.53 (10H, m, ArH), 7.78 (2H, t, J ¼ 7.6 Hz,
ArH), 8.16 (2H, d, J ¼ 7.8 Hz, ArH), 8.33 (2H, d, J ¼ 7.8 Hz, ArH), 8.66
(2H, s, ArH), 9.37 (2H, d, J ¼ 8.2 Hz, NH). IR (KBr): 3430, 3280, 1643,
1537, 1312 cmÀ1. MS (FAB): 585 (M þ 1, 14). Anal. calcd. C32H26Cl2N4O3:
C, 65.64; H, 4.48; N, 9.57. Found: C, 65.69; H, 4.47; N, 9.71.
2,5-bis[m-[(40S)-40-isobutyloxazolin-20-yl]phenyl-1,3,4-oxadiazole 4a.
General procedure III. To a solution of compounds 3a (625 mg,
1.14 mmol) in MeOH (20 mL) was added the solution of NaOH (2.5 g)
in water (10 mL) and stirring for 72 h at room temperature. The mixture
was extracted with ethyl acetate (5 Â 10 mL). The extracts were combined
and washed with brine, dried over anhydrous NaSO4 and filtered. The
filtrate was concentrated in vacuo and the residue was separated by
column chromatography on silica gel elution with CH2Cl2-MeOH (9:1)
to afford crude product, which was recrystallized from ethyl acetate and
20
hexane to give colorless solid 4a 341 mg (63%). M.p. 138–140ꢀC. ½ꢂꢁD
¼ À43.8ꢀ (c ¼ 1, MeOH). IR (KBr): 1680 cmÀ1. MS (EI): 472 (Mþ).
1H NMR (CDCl3): ꢁ 0.95–0.98 (12H, t, J ¼ 7.0 Hz, CH3), 1.35–1.40 (2H,
m, CH), 1.65–1.72 (2H, m, CH2), 1.78–1.83 (2H, m, CH2), 3.95–3.99 (2H,
t, J ¼ 8.0 Hz, CH2), 4.29–4.33 (2H, J ¼ 7.8 Hz, CH), 4.47–4.51 (2H, t,
J ¼ 8.6 Hz, CH2), 7.44–7.48 (2H, t, J ¼ 7.7 Hz, ArH), 7.99–8.00 (2H, d,
J ¼ 7.6 Hz, ArH), 8.06–8.08 (2H, d, J ¼ 7.6 Hz, ArH), 8.44 (2H, s, ArH).
Anal. calcd. C28H32N4O3: C, 71.16; H, 6.82; N, 11.86. Found: C, 71.31;
H, 6.99; N, 11.63.
2,5-bis[m-[(40S)-40-isopropyloxazolin-20-yl]phenyl] -1,3,4-oxadiazole 4b.
Compound 4b was synthesized according to the general precedure III

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2570
Xu et al.
employing the 3b (400 mg, 0.77 mmol) and NaOH (2 g) to give the
20
colorless solid 243 mg (71%), M.p. 143–145ꢀC. ½ꢂꢁD ¼ À57.2ꢀ (c ¼ 1,
MeOH). IR (KBr): 1680 cmÀ1
;
MS (EI): 444 (Mþ). 1H NMR
(CDCl3): ꢁ 0.97 (6H, d, J ¼ 6.8 Hz, CH3), 1.07 (6H, d, J ¼ 6.6 Hz,
CH3), 1.82–1.98 (2H, m, CH), 4.10–4.25 (4H, m, CH2), 4.43–4.55
(2H, m, NCH), 7.60 (2H, t, J ¼ 7.8 Hz, ArH), 8.16 (2H, dd, J ¼ 1.4,
7.8 Hz, ArH), 8.31 (2H, dd, J ¼ 1.4, 7.8 Hz, ArH), 8.69 (2H, s, ArH).
Anal. calcd. C26H28N4O3: C, 70.25; H, 6.35; N, 12.60. Found: C, 70.20.
H, 6.30; N, 12.40.
2,5-bis[m-[(40S)-40-benzyloxazolin-20-yl]phenyl]-1,3,4-oxadiazole 4c.
Compound 4c was synthesized according to the general procedure III
employing the 3c (600 mg, 0.98 mmol) and NaOH (2 g) to afford the
20
colorless solid in 67% yield (355 mg). M.p. 178–178.5ꢀC. ½ꢂꢁD ¼ 53.6ꢀ
(c ¼ 1, MeOH). IR (KBr): 1680 cmÀ1; EIMS: 540 (Mþ). 1H NMR
(CDCl3): ꢁ 2.76–2.82 (2H, dd, J ¼ 8.8, 13.8 Hz, CH2), 3.26–3.31 (2H,
dd, J ¼ 5.1, 13.8 Hz, CH2), 4.20–4.24 (2H, dd, J ¼ 7.6, 8.2 Hz, CH2),
4.40–4.45 (2H, t, J ¼ 8.7 Hz, CH2), 4.61–4.69 (2H, m, CH), 7.22–7.34
(10H, m, ArH), 7.59–7.63 (2H, t, J ¼ 7.8 Hz, ArH), 8.15–8.17 (2H, t,
J ¼ 7.8 Hz, ArH), 8.32–8.34 (2H, t, J ¼ 6.4 Hz, ArH), 8.68–8.69 (2H, t,
J ¼ 1.6 Hz, ArH). Anal. calcd. C34H28N4O3: C, 75.54; H, 5.22; N, 10.36.
Found: C, 75.34; H, 5.23; N, 10.26.
2,5-bis[m-[(40R)-40-phenyloxazolin-20-yl]phenyl]-1,3,4-oxadiazole 4d.
A round 100 mLround-bottom flask with a magnetic stir bar was
charged with compound 3d (0.8 g, 1.36 mmol), DMF (10 mL) and
toluene (30 mL). Et3N (1.9 mL, 13.6 mmol) was added to the reaction
mixture. The solution was stirred under reflux for 12 h. After cooling to
room temperature, ethyl acetate (50 mL) was added and the resulting
mixture was washed saturated NaHCO3. The aqueous layer was
extracted with ethyl acetate (3 Â 30 mL). The combined organic layers
was washed with water (50 mL) and brine (50 mL), dried over
anhydrous Na2SO4 and filtered. The solvent was removed under
reduced pressure. Purification of the residue by column chromatog-
raphy on silica gel (ethyl acetate–petroleum ether1:3) to afford the
20
pure colorless solid 4d 0.51 g (72.8%). M.p. 121–122ꢀC; ½ꢂꢁD ¼ þ 16.3ꢀ.
1H NMR (CDCl3): ꢁ 4.35(2H, t, J ¼ 8.4 Hz, CH), 4.87 (2H, dd, J ¼ 8.4,
9.8 Hz, CH2), 5.45 (2H, dd, J ¼ 8.2, 9.8 Hz, CH2), 7.30–7.42(10H,
m, ArH), 7.63 (2H, t, J ¼ 7.8 Hz, ArH), 8.25 (2H, d, J ¼ 7.8 Hz,
ArH), 8.35 (2H, d, J ¼ 7.8 Hz, ArH), 8.78 (2H, s, ArH). IR (KBr):
3029, 2996, 2876, 1644, 1602, 15441475, 1451, 1363, 1315, 1260,
1070 cmÀ1. FAB MS: 513 (M þ 1, 100), 394 (49), 367 (7). Anal. calcd.
C32H24N4O3: C, 74.98; H, 4.72; N, 10.93. Found: C, 74.99; H, 4.76;
N, 10.96.

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C2-Symmetric Bisoxazoline Ligands
2571
2,5-bis[m-[N-(20S,30R)-(10,30-dihydroxy-30-phenylpropyl)amido]phenyl]-
1,3,4-oxadiazole 5. A solution of 2,5-di-(m-carboxyphenyl)-1,3,4-oxadia-
zole 1 (3.1 g, 10.0 mmol) and SOCl2 (40 mL) was refluxed for 12 h. The
excess SOCl2 was removed under reduced pressure, benzene (20 mL) was
added and the solvent was removed again to dryness to afford the diacyl
dichloride. A solution of the above diacyl dichloride in CH2Cl2 (100 mL)
was added dropwise to the suspension of (1R, 2S)-(-)-2-amino-1-phenyl-
1,3-propanediol (3.26 g, 19.5 mmol) and Et3N (7.5 mL) in CH2Cl2
(100 mL) at 0ꢀC and then stirring at room temperature for 36 h. The
precipitate was filtered and washed with dichloromethane and diethyl
ether to afford the colorless solid 3.89 g (65.6% yield). The mother solu-
tion was washed with water, dried over Na2SO4 and concentrated to give
0.32 g of the starting material amino alcohol. Based on recovered starting
20
material, the total yield of was 69%. m.p. 240–242ꢀC. ½ꢂꢁD ¼ þ 110.9ꢀ
(c ¼ 0.1, MeOH). 1H NMR (DMSO): ꢁ 3.38–3.46 (2H, m, OH), 3.58–3.69
(2H, m, OH), 4.23 (2H, m, CHN), 4.77 (2H, t, J ¼ 5.4 Hz, HOCHACHB),
4.94 (2H, t, J ¼ 4.8 Hz, HOCHACHB), 5.51 (2H, d, J ¼ 5.2 Hz, CHPh),
7.16–7.40 (10H, m, ArH), 7.71 (2H, t, J ¼ 8.0 Hz, ArH), 8.04 (2H, d,
J ¼ 8.2 Hz, ArH), 8.20 (2H, d, J ¼ 9.0 Hz, NH), 8.26 (2H, d, J ¼ 7.8 Hz,
ArH), 8.51 (2H, s, ArH). IR (KBr): ꢃ 3333, 3062, 3032, 1624, 1606, 1550,
1490, 1042 cmÀ1. FAB MS: m/z 609(M þ 1, 6), 181 (100). Anal.
calcd. C34H32N4O7: C, 67.09; H, 5.30; N, 9.21. Found: C, 66.94; H,
5.13; N, 9.01.
2,5-bis[m-[(40S)-40-((1R)-1-phenyl-1-hydroxymethyl)oxazolin-20-yl]phe-
nyl]-1,3,4-oxadiazole 6a. To a solution of diamide 5 (3.09 g, 5.08 mmol)
and dry Et3N (9.8 mL, 70.7 mmol) in CHCl2 (70 mL) was added p-methyl
benzenesulfonyl chloride p-TsCl (2.94 g, 15.4 mmol) at room temperature
under nitrogen. The reaction mixture was kept at reflux for 12 h. After
addition of 4 mLof water the solution was heated to reflux for 1 h. The
cold reaction mixture was then extracted with water (3 Â 30 mL). The
organic layer was dried over anhydrous NaSO4, and filtered. The filtrate
was concentrated in vacuo to afford the crude product 2.64 g (90.8%).
The crude product was purified by column chromatography on silica gel
(chloroform–ethyl acetate 1:1) to afford colorless solid 1.72 g (59.2%).
20
1
M.p. 189–189.5ꢀC. ½ꢂꢁD ¼ þ 113.0ꢀ (c ¼ 0.1, MeOH). H NMR (CDCl3):
ꢁ 3.59 (2H, s, OH), 4.16–4.37 (4H, m, CH2O), 4.55–4.65 (4H, m,
CHN þ HPh), 7.31–7.47 (10H, m, ArH), 7.59 (2H, t, J ¼ 7.8 Hz, ArH),
8.15 (2H, d, J ¼ 8.0 Hz, ArH), 8.29 (2H, d, J ¼ 7.8 Hz, ArH), 8.68 (2H, s,
ArH). IR (KBr): ꢃ 3250, 3088, 3027, 1640, 1602, 1543, 1479, 1381, 1081,
967 cmÀ1. FAB MS: m/z 573 (M þ 1, 43), 217 (10), 91 (100). Anal.
calcd. C34H28N4O5: C, 71.31; H, 4.93; N, 9.78. Found: C, 71.22; H,
4.86; N, 9.57.

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2572
Xu et al.
2,5-bis[m-[(40S)-40-((1R)-1-methylcarboxy-1-phenylmethyl)oxazolin-20-
yl]-phenyl]-1,3,4-oxadiazole 6b. To a suspension of bisoxazoline 6a
(202.5 mg, 0.43 mmol), triethylamine (0.28 mL, 1.5 mmol) and 4-dimethy-
laminopyridine (2 mg) in dichloromethane (15 mL) was added dropwise
acetic anhydride (143 mL, 1.5 mmol) at 0ꢀC. The mixture was stirred for
3 h at 0ꢀC. After warming to room temperature, water (10 mL) was added
and the organic layer was separated. The aqueous layer was extracted
with dichloromethane (3 Â 10 mL). The combined organic layers was
washed with water (10 mL) and brine (10 mL), dried over anhydrous
Na2SO4 and filtered. The solvent was removed under reduced pressure.
Purification of the residue by recrystallization from ethyl acetate-petro-
leum ether to afford the pure colorless needles 220 mg (78.3%). M.p.
20
1
175–177ꢀC. ½ꢂꢁD ¼ þ 26.3ꢀ (c ¼ 0.3, CHCl3); H NMR(CDCl3): ꢁ 2.16
(6H, s, CH3), 4.18–4.41 (4H, m, CH2O), 4.80–4.85 (2H, m, CHN), 5.90
(2H, d, J ¼ 6.6 Hz, CHPh), 7.31–7.45 (10H, m, ArH), 7.60 (2H, t,
J ¼ 7.8 Hz, ArH), 8.14 (2H, d, J ¼ 8.2 Hz, ArH), 8.31 (2H, d,
J ¼ 8.2 Hz, ArH), 8.65 (2H, s, ArH). IR (KBr): ꢃ 3070, 3025, 2912,
1728, 1655, 1605, 1546, 1475, 1375, 1235, 1056, 1029, 913, 705 cmÀ1
.
FAB MS: m/z 657(M þ 1). Anal. calcd. C38H32N4O7: C, 69.50; H, 4.91;
N, 8.53. Found: C, 69.31; H, 4.99; N, 8.31.
2,5-bis[m-[(40S)-40-((1R)-1-methoxy-1-phenylmethyl)oxazolin-20-yl]phe-
nyl]-1,3,4-oxadiazole 6c. To a suspension of NaH (46 mg, 52% in
mineral oil, 1 mmol) in THF (15 mL) was added bisoxazoline 6a
(202.5 mg, 0.43 mmol) in portions. The resulting mixture was heated at
36ꢀC for 2 h. After cooling to room temperature, methyl iodide (80 mL,
1.29 mmol) was added dropwise to the above reaction mixture. The
mixture was further stirred overnight. Then the solvent was removed
under reduced pressure and dichloromethane was added (30 mL) to
the residue. The solution was washed with 1 N HCl (10 mL), 5%
NaHCO3 (10 mL) and brine (10 mL), dried over anhydrous Na2SO4
and filtered. The solvent was removed under reduced pressure to give
the crude product. Purification of the crude product by recrystalliza-
tion cfrom ethyl acetate-petroleum ether to afford the pure colorless
20
solid 150 mg (58.3%). M.p. 153–154ꢀC. ½ꢂꢁD ¼ þ 42.5ꢀ (c ¼ 0.3,
MeOH). 1H NMR (CDCl3): ꢁ 3.34 (6H, s, CH3), 4.16–4.28 (4H, m,
CH2O), 4.35 (2H, d, J ¼ 6.8 Hz, CHPh), 4.68–4.75 (2H, m, CHN),
7.32–7.36 (10H, m, ArH), 7.58 (2H, t, J ¼ 7.8 Hz, ArH), 8.15 (2H, d,
J ¼ 7.8 Hz, ArH), 8.30 (2H, d, J ¼ 7.8 Hz, ArH), 8.64 (2H, s, ArH). IR
(KBr): ꢃ 3070, 2898, 2827, 1653, 1548, 1482, 1365, 1109, 1070, 978,
708 cmÀ1. FAB MS: m/z 601(M þ 1, 100), 480 (12), 437 (5). Anal.
calcd. C36H32N4O5: C, 71.98; H, 5.37; N, 9.42. Found: C, 71.83; H,
5.46; N, 9.38.

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C2-Symmetric Bisoxazoline Ligands
2573
Synthesis of 2,5-bis[m-[(40S)-40-isobutyloxazolin-20-yl]phenyl]-1,3,4-
oxadiazole 4a via ‘one pot’ method. To a solution of 2,5-di-(m-carbox-
ylphenyl)-1,3,4-oxadiazole 1 (310 mg, 1 mmol) in CH3CN (50 mL) and
DMF (30 mL) was added the S-leucinol (234 mg, 2 mmol), Ph3P (1 g),
CCl4 (2 mL), Et3N (2 mL), and pyridine (15 mL) respectively and stir-
ring for 12 h at room temperature. The reaction mixture was concen-
trated in vacuo progressively and filter out triphenyl phosphine oxide
step by step. The filtrate was separated further by column chromatog-
rapy on silica gel eluted with CH2Cl2–MeOH (10:1) to give crude pro-
duct, which was recrystallized from ethyl acetate and hexane to afford
colorless solid 4a in 38% yield (179 mg). Compounds 4b–d were
also obtained employed ‘one pot’ method according to the same
procedure.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (Grant No. 20172001).
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Received in the Netherlands November 14, 2002