A facile and efficient synthesis of bis(oxazoline)s

Article abstract of DOI:10.1002/jhet.477

Thiophene-2,5-dicarboxylic acid, benzene-1,3-dicarboxylic acid, or furan-2,5-di-carboxylic acid, respectively, reacted with various β-amino alcohols in toluene under reflux within 24 h, to form nine bis(oxazoline)s (1-3) in good yields through water deprivation via a one-pot reaction. The synthetic method is facile and efficient and deserves great application potentials in the research and development in the area of bis(oxazoline)s.

Full text of DOI:10.1002/jhet.477

1340
A Facile and Efficient Synthesis of Bis(oxazoline)s
Vol 47
Wei Jie Li* and Sheng Xiang Qiu
Program for Natural Product Chemical Biology and Drug Discovery, South China Botanical
Garden, Chinese Academy of Sciences, Guangzhou 510650, People’s Republic of China
*E-mail: weijieli1688@yahoo.com.cn
Received November 11, 2009
DOI 10.1002/jhet.477
Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Thiophene-2,5-dicarboxylic acid, benzene-1,3-dicarboxylic acid, or furan-2,5-di-carboxylic acid,
respectively, reacted with various b-amino alcohols in toluene under reflux within 24 h, to form nine
bis(oxazoline)s (1–3) in good yields through water deprivation via a one-pot reaction. The synthetic
method is facile and efficient and deserves great application potentials in the research and development
in the area of bis(oxazoline)s.
J. Heterocyclic Chem., 47, 1340 (2010).
INTRODUCTION
approach should be explored to meet the needs of
bis(oxazoline) ligands.
Since Butula et al. prepared the first optically active
bis(oxazoline) in 1976, the design and development of
effective chiral bis(oxazoline) ligands have played a sig-
nificant role in advancement of asymmetric catalysis
and have attracted a great deal of attention because they
hold special structural characters and provide high enan-
tioselectivities in a variety of asymmetric catalytic
reactions [1–6]. Chiral bis(oxazoline) ligands have wide-
spread uses in asymmetric hydrosilylation [7], cyclopro-
pantion reaction [8], Friedel-Crafts reaction [9], Diels-
Alder reaction [10], Aldol addition [11], Michael reac-
tion [12], Henry reaction [13], allylic oxidation [14],
1,3-dipolar cycloaddition [15], and so on.
In this article, we report the results of the reaction of
dicarboxylic acids with b-amino alcohols under reflux
through water deprivation to obtain chrial bis(oxazo-
line)s 1a–1e, 2a–2c, and a novel achiral bisoxazoline 3
(Fig. 1 and Scheme 1–3) via a one-pot reaction. This
method afforded high yields with simple workup
procedure.
RESULTS AND DISCUSSION
Gao et al. reported that chiral bis(oxazoline)s 1a–1e
were synthesized from thiophene-2,5-dicarboxylic acid
by sequential amidation with a chiral ethanolamine, con-
version of hydroxyl to chloro group, and base-promoted
oxazoline ring formation [17,18]. Kanazawa et al.
described the synthetic procedure of chiral 1,3-bis[40-
substitutedoxazolin-20-yl]benzene including bis(oxazo-
line)s 2a–2c, which isophthaloyl dichloride reacted with
chiral b-amino alcohols at 0ꢀC to form the correspond-
ing diamide-dialcohols as the successive intermediates
and then cyclized to obtain the target compounds in the
presence of methanesulfonyl chloride at 0ꢀC [19]. As
described above, the syntheses of chiral bis(oxazoline)s
involve multistep reactions, which result in more side
reactions and low yields.
Chiral bis(oxazoline)s have various structures, which
determine the diversity of their synthetic methods. At
present, two general synthetic routes are summarized
from various synthesis [2,3,16]: (a) Reaction of dintriles
with chiral amino alcohol or diols afford the target com-
pound via a one or multiple-step reaction in the pres-
ence of Lewis acid or base. (b) Dicarboxylic acids or
their derivatives (diacyl halide, diacylamide or diesters)
react with chiral amino alcohol, via the corresponding
bis(b-hydroxylamide)s as the successive intermediates,
that cyclize to produce the target compounds. The latter
method requires activating agents, with thionyl chloride,
also cyclizing agent being the most commonly used,
which results in more side reactions and low yields.
To address above issues, we successfully developed a
new, facile, and efficient method for the synthesis of
Therefore,
a
simpler and more efficient synthesis
C
V
2010 HeteroCorporation

November 2010
A Facile and Efficient Synthesis of Bis(oxazoline)s
1341
Figure 1. Chemical structures of bis(oxazoline)s.
on a Varian UNITY INOVI-500 NMR spectrometer, a Bruker
Avance DPX300 NMR spectrometer or a Bruker DRX-400
NMR spectrometer, using TMS as internal standard. Mass
spectra were taken on a MDS Sciex API 2000 LC/GC/MS
instrument. Elemental analyses were carried out on a Perkin-
Elmer 240C elemental analyzer. Optical rotation values were
measured on a POLARTRONIC HNQW 5 polarimeter.
All solvents used for the synthesis were of analytical grade
and were dried and freshly distilled under a nitrogen atmos-
phere prior to use. Chiral b-amino alcohols, furan-2,5-dicar-
boxylic acid, and benzene-1,3-dicarboxylic acid were pur-
chased from Fluka Chemical Co. Thiophene-2,5-dicarboxylic
acid was synthesized in our own laboratory. Other reagents
were all of analytical grade.
General procedure for the synthesis of 2,5-bis[40(S)-substi-
tuted-oxazolin-20-yl]thiophene (1a–1e). Thio-phene-2,5-dicar-
boxylic acid (100.0 mg, 0.58 mmol), chiral b-amino alcohol
(1.16 mmol), and toluene (20 mL) were added to a three-neck
flask with a water segregator, a reflux condenser, and a mag-
netic stirring bar. The mixture was refluxed and dehydrated
for 24 h. After cooling to room temperature, the solvent
was removed under reduced pressure, and the residue was
purified by silica gel column chromatography with dichloro-
methane and ethanol (50:1) as eluent to give the pure title
compound.
bis(oxazoline)s starting from dicarboxylic acids. With
this convenient method, bis(oxazoline)s 1 or 2 were read-
ily synthesized in high yields from thiophene-2,5-dicar-
boxylic acid (TDA) or benzene-1,3-dicarboxylic acid
(BDA) and b-amino alcohols (Scheme 1 and 2). Briefly, a
mixture of dicarboxylic acid and b-amino alcohol was
refluxed in toluene through water deprivation for 24 h.
After cooling to ambient temperature, the solvent was
removed under reduced pressure, and the residue was
purified by silica gel column chromatography to give the
desired product in high yield. The conditions and results
of reaction of carboxylic acids with b-amino alcohols
have been listed in Table 1 (entries 1–8).
Instead of thiophene-2,5-dicarboxylic acid (TDA) or
benzene-1,3-dicarboxylic acid (BDA), furan-2,5-dicarbox-
ylic acid (FDA) reacted with 2-aminoethanol to afford a
new achiral bis(oxazoline) 3 in high yield under the same
reaction condition (Scheme 3 and Table 1, entry 9).
In conclusion, a facile one-pot synthetic method of
bis(oxazoline)s (1–3) was described, which is simple
and efficient, deserving great application potentials in
the research and development in the area of
bis(oxazoline)s.
(ꢁ)-2,5-Bis[40(S)-ethyloxazolin-20-yl]thiophene(1a). This com-
pound was obtained as colorless solid; yield 96%; mp 90–
91ꢀC ([18] 89–90ꢀC); [a]D20 ¼ ꢁ95.3 (c 1.0, CH2Cl2); 1H-
NMR (300 MHz, CDCl3): d 0.99 (t, J ¼ 7.4Hz, 6H, CH3),
1.58–1.65 (m, 2H, CH2), 1.67–1.74 (m, 2H, CH2), 4.06 (dd,
J ¼ 7.4, 10.2 Hz, 2H, OCH2), 4.19–4.28 (m, 2H, NCH), 4.50
(dd, J ¼ 8.4, 10.2 Hz, 2H, OCH2), 7.56 (s, 2H, thiophene-H).
EXPERIMENTAL
General. Melting points were determined by the capillary
method and are uncorrected. 1H-NMR spectra were measured
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1342
W. J. Li and S. X. Qiu
Vol 47
General procedure for the synthesis of 1,3-bis[40(S)-sub-
stitutedoxazolin-20-yl]benzene
(2a–2c). Benzene-1,3-dicar-
Scheme 3
boxylic acid (100.0 mg, 0.60 mmol), chiral b-amino alcohol
(1.20 mmol), and toluene (20 mL) were added to a three-neck
flask with a water segregator, a reflux condenser, and a mag-
netic stirring bar. The mixture was refluxed and dehydrated for
24 h. After cooling to room temperature, the solvent was
removed under reduced pressure and the residue was purified
by silica gel column chromatography with dichloromethane
and ethanol (50:1) as eluent to give the pure title compound.
(ꢁ)-1,3-Bis[40(S)-isopropyloxazolin-20-yl]benzene(2a). This
compound was obtained as colorless solid; yield 93%; mp 58–
ESI-MS: m/z (MH+) 279. Anal. Calcd. for C14H18N2O2S: C,
60.41; H, 6.52; N, 10.06. Found: C, 60.23; H, 6.54; N, 10.02.
(ꢁ)-2,5-Bis[40(S)-isopropyloxazolin-20-yl]thiophene(1b). This
compound was obtained as colorless solid; yield 91; mp 66–
1
67ꢀC ([18] 66–68ꢀC); [a]D20 ¼ ꢁ29.7 (c 0.5, CH3COCH3); H-
1
60ꢀC; [a]D20 ¼ ꢁ141.5 (c 0.3, CHCl3); H-NMR (500 MHz,
NMR (500 MHz, CDCl3): d 0.91 (d, J ¼ 7.0 Hz, 6H, CH3),
1.15 (d, J ¼ 7.0 Hz, 6H, CH3), 1.84–1.91 (m, 2H, CH), 4.08–
4.15 (m, 4H, OCH2), 4.39 (dd, J ¼ 8.0, 9.0 Hz, 2H, NCH),
7.57 (s, 2H, thiophene-H). ESI-MS: m/z (MH+) 307. Anal.
Calcd. for C16H22N2O2S: C, 62.71; H, 7.24; N, 9.14. Found:
C, 62.55; H, 7.26; N, 9.11.
CDCl3): d 0.94 (d, J ¼ 7.0 Hz, 6H, CH3), 1.06 (d, J ¼ 7.0
Hz, 6H, CH3), 1.87–1.94 (m, 2H, CH), 4.11–4.19 (m, 4H,
OCH2), 4.38–4.45 (m, 2H, NCH), 7.45–8.51 (m, 4H, benzene-
H). ESI-MS: m/z (MH+) 301. Anal. Calcd. for C18H24N2O2: C,
71.97; H, 8.05; N, 9.33. Found: C, 71.75; H, 8.08; N, 9.31.
(ꢁ)-1,3-Bis[40(S)-phenyloxazolin-20-yl]benzene(2b). This com-
pound was obtained as colorless solid; yield 94%; mp 122–
(+)-2,5-Bis[40(S)-tert-butyloxazolin-20-yl]thiophene(1c). This
compound was obtained as colorless solid; yield 89%; mp
119–120ꢀC ([17] 120–121ꢀC); [a]2D0
¼
+5.9 (c 0.6,
1
124ꢀC ([19] 120–124ꢀC); [a]D20 ¼ ꢁ73.1 (c 0.3, CH2Cl2); H-
1
CH3COCH3); H-NMR (500 MHz, CDCl3): d 0.98 (s, 18H,
CH3), 4.02 (dd, J ¼ 7.5, 10.0 Hz, 2H, OCH2), 4.24 (dd, J ¼
8.0, 8.5 Hz, 2H, NCH), 4.35 (dd, J ¼ 8.5, 10.0 Hz, 2H,
OCH2), 7.53 (s, 2H, thiophene-H). ESI-MS: m/z (MH+) 335.
Anal. Calcd. for C18H24N2O2S: C, 64.64; H, 7.84; N, 8.38.
Found: C, 64.41; H, 7.86; N, 8.35.
NMR (500 MHz, CDCl3): d 4.42 (dd, J ¼ 8.0, 8.5 Hz, 2H,
OCH2), 4.92 (dd, J ¼ 8.0, 10.0 Hz, 2H, OCH2), 5.48 (dd, J ¼
7.0, 10.0 Hz, NCH), 7.27–7.41 (m, 10H, Ph-H), 7.57 (t, J ¼
7.5 Hz, 1H, benzene-H), 8.39 (dd, J ¼ 1.5, 7.5 Hz, 2H, ben-
zene-H), 8.76 (t, J ¼ 1.5 Hz, 1H, benzene-H). ESI-MS: m/z
(MH+) 369. Anal. Calcd. for C24H20N2O2: C, 78.24; H, 5.47;
N, 7.60. Found: C, 78.01; H, 5.49; N, 7.58.
(+)-2,5-Bis[40(S)-phenyloxazolin-20-yl]thiophene(1d). This
compound was obtained as colorless solid; yield 93%; mp
(ꢁ)-1,3-Bis[40(S)-benzyloxazolin-20-yl]benzene(2c). This com-
1
127–128ꢀC; [a]D20 ¼ +59.5 (c 0.4, CH2Cl2); H-NMR (500
pound was obtained as colorless solid; yield 94%; mp 105–
1
107ꢀC ([19] 106–107ꢀC); [a]D20 ¼ ꢁ4.1 (c 0.5, CHCl3); H-
MHz, CDCl3): d 4.32 (dd, J ¼ 8.0, 16.0 Hz, 2H, NCH), 4.78
(dd, J ¼ 8.5, 10.0 Hz, 2H, OCH2), 5.39 (dd, J ¼ 8.0, 10.0 Hz,
2H, OCH2), 7.27–7.36 (m, 10H, Ph-H), 7.68 (s, 2H, thiophene-
H). ESI-MS: m/z (MH+) 375. Anal. Calcd. for C22H18N2O2S:
C, 70.57; H, 4.85; N, 7.48. Found: C, 70.46; H, 4.84; N, 7.46.
(+)-2,5-Bis[40(S)-benzyloxazolin-20-yl]thiophene(1e). This
compound was obtained as colorless solid; yield 93%; mp
NMR (300 MHz, CDCl3): d 2.73–3.28 (m, 4H, CH2Ph), 4.17
(dd, J ¼ 7.5, 8.5Hz, 2H, OCH2), 4.37–4.41 (m, 2H, OCH2),
4.58–4.63 (m, 2H, NCH), 7.10–7.36 (m, 10H, Ph-H), 7.50–
8.49 (m, 4H, benzene-H). ESI-MS: m/z (MH+) 397. Anal.
Calcd. for C26H24N2O2: C, 78.76; H, 6.10; N, 7.07. Found: C,
78.52; H, 6.12; N, 7.05.
108–110ꢀC ([18] 107–109ꢀC); [a]2D0
¼
+91.5 (c 0.3,
Synthesis of 2,5-bis(oxazolin-20-yl) furan (3). Furan-2,5-
dicarboxylic acid (100.0 mg, 0.64 mmol), 2-aminoethanol
(78.3 mg, 1.28 mmol), and toluene (20 mL) were added to a
three-neck flask with a water segregator, a reflux condenser,
and a magnetic stirring bar. The mixture was refluxed and
dehydrated for 24 h. After cooling to room temperature, the
solvent was removed under reduced pressure, and the residue
was purified by silica gel column chromatography with
1
CH3COCH3); H-NMR (500 MHz, CDCl3): d 2.74 (dd, J ¼
8.5, 13.5 Hz, 2H, CH2-Ph), 3.21 (dd, J ¼ 5.0, 13.5 Hz, 2H,
CH2-Ph), 4.14 (dd, J ¼ 7.0, 9.0 Hz, 2H, OCH2), 4.37 (dd, J ¼
8.5, 9.0 Hz, 2H, OCH2), 4.58–4.61 (m, 2H, NCH), 7.22–7.31
(m, 10H, Ph-H), 7.52 (s, 2H, thiophene-H). ESI-MS: m/z
(MH+) 403. Anal. Calcd. for C24H22N2O2S: C, 71.62; H, 5.51;
N, 6.96. Found: C, 71.34; H, 5.53; N, 6.94.
Table 1
The conditions and results of dicarboxylic acid reacted with b-amino alcohol in toluene through water deprivation.a
Entry
Dicarboxylic acid
b-Amino alcohol
Bis(oxazoline)
Yield (%)
1
2
3
4
5
6
7
8
9
TDA
TDA
TDA
TDA
TDA
BDA
BDA
BDA
FDA
(S)-2-aminobutan-1-ol
L-leucinol
1a
1b
1c
1d
1e
2a
2b
2c
3
96
91
89
93
93
93
94
94
88
L-tert-leucinol
L-phenylglycinol
L-phenylalaninol
L-leucinol
L-phenylglycinol
L-phenylalaninol
2-aminoethanol
a Dicarboxylic acid/b-amino alcohol ¼ 1/2 (mole ratio). Reaction time: 24 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
A Facile and Efficient Synthesis of Bis(oxazoline)s
1343
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title compound as colorless liquid; yield 88%; H-NMR (400
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet