A simple synthesis of 2-substituted oxazolines and oxazines

Article abstract of DOI:10.1016/S0040-4039(02)00723-2

β-Aminoalcohols react with carboxylic acids in the presence of a zeolite, Ersorb-4, resulting in the formation of oxazoline derivatives in good yields. Similarly, 3-aminopropanol and benzoic acid gave the corresponding 2-phenyloxazine.

Full text of DOI:10.1016/S0040-4039(02)00723-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3985–3987
A simple synthesis of 2-substituted oxazolines and oxazines
Agnieszka Cwik,a Zolta´n Hell,a,* Adrienn Hegedu¨s,a Zolta´n Fintaa and Zolta´n Horva´thb
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, Budapest H-1521, Hungary
bErdo
3 ke´mia-ker Ltd, Gyo¨mro3 i u´t 132-136, Budapest H-1108, Hungary
Received 26 February 2002; revised 11 April 2002; accepted 12 April 2002
Abstract—b-Aminoalcohols react with carboxylic acids in the presence of a zeolite, Ersorb-4, resulting in the formation of
oxazoline derivatives in good yields. Similarly, 3-aminopropanol and benzoic acid gave the corresponding 2-phenyloxazine.
© 2002 Elsevier Science Ltd. All rights reserved.
The oxazoline group is an important functionality in
synthetic organic chemistry. The racemic 2-substituted
oxazoline ring can be considered as a protected car-
boxylic acid group.1 If this carboxylate group is incor-
porated in a pharmacologically active compound, this
modification could change the absorption characteris-
tics and pharmacokinetic properties of these drugs.
Under physiological conditions the oxazoline ring will
slowly hydrolyze liberating the free carboxylic acid
moiety.2 Some optically active oxazoline derivatives are
valuable auxiliaries in asymmetric syntheses.3
reaction parameters with occasional low yields of the
reaction products.
The application of natural or artificial acidic or basic
inorganic solid materials as efficient catalysts in organic
synthesis has been studied.9 Natural clays have several
advantages as they are environmentally-friendly, non-
toxic, recoverable, reusable and are inexpensive but
efficient mild catalysts. Recently a detailed method was
described for the preparation of 2-substituted oxazoli-
nes from nitriles in the presence of kaolinitic clay.10
Numerous methods have been developed for the prepa-
ration of 2-substituted oxazolines from carboxylic acids
using high temperatures of up to 200–220°C,4 repeated
use of SOCl2,5 phosphines together with harmful halo-
genated hydrocarbons such as CCl4 or hex-
achloroethane,2 or under other drastic reaction
conditions. Some other methods using carboxylic
esters,6 nitriles7 or aldehydes8 as starting materials have
also been described but most of them utilize complex
reagents, strongly acidic conditions or other stringent
Ersorb-4 is a weakly acidic zeolite-type adsorbent with
4 A pore size. It can adsorb small molecules such as
,
water, hydrochloric acid, ammonia, etc. Its use in the
acylation of amines with carboxylic acids has been
reported.11 Based on the good results obtained in that
acylation reaction, we examined the selective N-
acylation of aminoalcohols with carboxylic acids. When
2-aminoethanol was reacted with benzoic acid in the
presence of Ersorb-4 (E-4) in hot toluene or xylene the
ring-closed oxazoline was obtained in good yield within
Figure 1.
* Corresponding author. Tel.: +36-1-463-1414; fax: +36-1-463-3648; e-mail: hell.oct@chem.bme.hu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00723-2

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A. Cwik et al. / Tetrahedron Letters 43 (2002) 3985–3987
5 h (Fig. 1). Neither benzoic acid 2-hydroxyethyl amide—
the known precursor of 2-phenyloxazoline12—nor ben-
zoic acid 2-aminoethyl ester as the result of an
O-acylation could be detected in the reaction mixture.
(−)-2-aminobutanol and p-chlorobenzoic acid (entry 9)
the oxazoline was formed stereospecifically. Similarly,
the optically active carboxylic acid Naproxen gave the
oxazoline in 56% yield with no change in the stereochem-
istry (Fig. 2). Treatment of 3-aminopropanol with ben-
zoic acid under similar reaction conditions gave the
2-phenyloxazine in 66% yield (Fig. 3).
Examination of some aliphatic and aromatic carboxylic
acids with different b-aminoalcohols gave the following
results. The small aliphatic carboxylic acids, acetic and
propionic acid, failed to give any product and completely
destroyed the structure of E-4. Aromatic carboxylic acids
gave good results.13 The results are summarized in Table
1.14
The workup of the reaction mixture was very simple,
After the evaporation of the solvent, the residue was
triturated with acetone, E-4 was filtered off, the filtrate
was evaporated and the residue characterized. The cata-
lyst filtered out from the reaction mixture was reusable
after 2 h thermal treatment at 120°C without significant
loss of activity (Table 1, entry 2). Being a non-aggressive
agent, E-4 can be used safely in the reaction of substances
with different functional groups. (In other experiments
we found that other functional groups, e.g. amines,
nitriles, etc. remained intact even after heating for a long
time in the presence of E-4.) In this way, a simple, cheap
and environmentally-friendly synthesis of 2-substituted
oxazolines was developed.
In some cases (entries 4, 8 and 11) a small amount of the
appropriate acid amide was identified but the formation
of other byproducts was not observed. In these cases the
product was purified by column chromatography. ortho-
Substituted carboxylic acids gave poorer yields, probably
due to steric hindrance. This is supported by the fact that
the yield obtained with salicylic acid (entry 11) was better
than that with both phthalic acid monoester (entry 12)
and acetylsalicylic acid (entry 13). In the reaction of
Table 1. Reaction of b-aminoalcohols with aromatic carboxylic acids
Entry
R
R%
R%%
R%%%
Yielda (%)
Mp (°C) (lit.)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
CH3
Cl
(CH3)3C
H
Cl
Cl
CH3O
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
90
138–139 (135–13615
138–139 (135–13615
138–139 (135–13615
144–145
)
)
)
79b
52c
35d
88
118–119
75
153–154
e
C2H5 (9)
C2H5 (9)
C2H5 (S)
H
H
H
H
H
H
73
–
–
55d
88
(2516
)
e
9
H
H
OH
COOCH3
OCOCH3
H
101–102
10
11
12
13
14
15
78
104–105 (122–12317
)
30d
32
40 (42–4318
124
)
30
85
45
104
COOCH3
CH2Cl
134 (130–1328)
89–90
OH
a Isolated yield.
b Recycled E-4.
c 0.5 g E-4/mmol acid, see Ref. 13.
d Product purified by column chromatography (Kieselgel, acetone eluent).
e Oil.
Figure 2.
Figure 3.

A. Cwik et al. / Tetrahedron Letters 43 (2002) 3985–3987
3987
Acknowledgements
9. (a) Laszlo, P. Science 1987, 235, 1473; (b) Laszlo, P. Pure
Appl. Chem. 1990, 62, 2027.
10. Jnaneswara, G. K.; Deshpande, V. H.; Lalithambika, M.;
Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett.
1998, 39, 459.
11. Hell, Z.; Cwik, A.; Finta, Z.; Horva´th, Z. J. Mol. Catal.
A (Chem.) 2002, 184, 191.
This work was supported by the Hungarian Research
Fund Programs (OTKA Grant Nos. F-029382 and
T-029193).
12. Seeliger, W.; Thier, W. Liebigs Ann. Chem. 1966, 698,
158.
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