Synthesis of 2-oxazolines via boron esters of N-(2-hydroxyethyl) amides

Article abstract of DOI:10.1016/j.tetlet.2010.07.167

A new, convenient, one-pot process is presented for the synthesis of 2-oxazolines in high yields (75-94%) via boron esters of N-(2-hydroxyethyl) amides. The procedure involves thermolysis of the boron esters at 240-260 °C, in the presence of solid CaO as an acid scavenger and allows the preparation of oxazolines from hydroxyethyl amides of aliphatic and aromatic monocarboxylic acids.

Full text of DOI:10.1016/j.tetlet.2010.07.167

Tetrahedron Letters 51 (2010) 5313–5315
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Synthesis of 2-oxazolines via boron esters of N-(2-hydroxyethyl) amides
*
*
Baris Ilkgul, Deniz Gunes, Okan Sirkecioglu , Niyazi Bicak
Istanbul Technical University, Department of Chemistry, Maslak, Istanbul 34469, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, convenient, one-pot process is presented for the synthesis of 2-oxazolines in high yields (75–94%)
via boron esters of N-(2-hydroxyethyl) amides. The procedure involves thermolysis of the boron esters at
240–260 °C, in the presence of solid CaO as an acid scavenger and allows the preparation of oxazolines
from hydroxyethyl amides of aliphatic and aromatic monocarboxylic acids.
Received 25 March 2010
Revised 21 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
1. Introduction
More recently, Kangani and Day reported the use of an indium
catalyst together with cyanuric acid chloride for the cycloconden-
The presence of oxazolines in marine organisms has stimulated
syntheses of these compounds via different methods.1 2-Oxazo-
lines are valuable intermediates in various organic transforma-
tions.2,3 These compounds are known to be resistant to base
hydrolysis and are useful reagents as protecting groups for carbox-
ylic acids.4 Metal complexes of bis-oxazolines derived from chiral
amines are efficient catalysts in asymmetric syntheses.5,6 They
have also found extensive use in polymer chemistry due to their
ability to undergo ring-opening polymerization that allows the
preparation of various macromolecular architectures. Hydrolysis
of their polymers offers an easy pathway to linear polyethylene
imines, which are not attainable by other means.7
Various procedures have been developed for the synthesis of 2-
oxazolines from carboxylic acids,8 esters,9 nitriles,10,11 and N-(2-
hydroxyethyl) amides.12–16 Among these, the procedures based
on dehydrative cyclization of N-(2-hydroxyethyl) amides are pre-
ferred due to their easy access from ethanolamine and carboxylic
acid derivatives.
Li and Xu reported the direct synthesis of 2-oxazolines from 2-
hydroxyethyl amides using a mixture of triphenylphosphine (PPh3)
and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) as the dehy-
drating agent. This procedure gave mono-oxazolines in high yields
at room temperature.12 In a similar study, Williams et al. described
a one-pot procedure using diethylaminosulfur trifluoride (DAST) or
bis-(2-methoxyethyl) aminosulfur trifluoride (Deoxo-Fluor) as the
cyclodehydrating agent for the conversion of 2-hydroxyethyl
amides into oxazolines at low temperature.13 Bandgar and Pandit
reported the syntheses of 2-oxazolines from 2-acyloxy-4,6-dime-
thoxy-1,3,5-triazines with 2-amino-2-methyl-1-propanol at room
temperature.14 In addition, Moyano’s group described the synthe-
ses of alkynyl-substituted chiral oxazolines using PPh3-diethyl azo-
dicarboxylate (DEAD) in boiling dichloromethane.15
sation of carboxylic acids with ethanolamines to prepare 2-
oxazolines.16
Most of these procedures involve tedious work-ups, multistep
reactions, and the use of specialized dehydrating agents or cata-
lysts. The critical issue while dehydrating 2-hydroxy ethyl amides
is to avoid decomposition of the 2-oxazolines already formed in
the reaction.
Herein, we describe a new and simple protocol to provide
2-oxazolines in high yields and high purities. This protocol is based
on the thermolysis of boron esters of N-(2-hydroxyethyl) amides at
240–260 °C. The precursor, N-(2-hydroxyethyl) amides were pre-
pared either by aminolysis of the appropriate carboxylic acid esters
or by dehydration of 2-hydroxyethyl ammonium carboxylates at
180–200 °C. A series of 2-hydroxyethyl amides possessing alkyl
and aromatic groups were prepared and esterified with boric acid
according to the general procedure described in the literature.17,18
The eliminated water was continuously removed using a Dean–
Stark trap over 3–4 h. Except for the cases of hydroxyethyl amides
of 4-nitrobenzoic acid and stearic acid, the resulting boron esters
were liquids or low melting solids.
Differential scanning calorimetry (DSC) traces of the boron es-
ters derived from hydroxyethyl amides of stearic acid, acetic acid,
and 4-nitrobenzoic acid showed sharp endotherms at 240, 255, and
245 °C, respectively. This implies fast decomposition of the boron
esters in the temperature range 240–260 °C to give 2-oxazolines.
The overall process involves formation of boron esters of N-(2-
hydroxyethyl) amides and subsequent thermolysis in the presence
of CaO as an acid scavenger (Fig. 1).
The experiments revealed that, without CaO, the oxazoline yield
was extremely low (15%) and charred residues were obtained
(Table 1). It is thought that the solid residue is a polymeric by-
product formed by the action of boric acid on the oxazoline. This
was ascribed to the high susceptibility of oxazolines to acids yield-
ing polymeric products while decomposing the boron ester. The
polymerization of 2-oxazolines promoted by boric acid at elevated
* Corresponding authors. Tel.: +90 212 2953280; fax: +90 212 2856386 (O.S.).
E-mail address: sirkeci@itu.edu.tr (O. Sirkecioglu).
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.167

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B. Ilkgul et al. / Tetrahedron Letters 51 (2010) 5313–5315
Table 1
Effects of boric acid scavengers on the yield of 2-methyl 2-oxazoline
Entry
Base
Time (h)
Yield (%)
Remarks
1
2
3
4
None
Pyridine
Trioctylamine
CaO (solid)
1.5
2
2
15
34
39
84
Charred residue
Viscous residue
Viscous residue
None
2
Figure 1. Synthesis of 2-oxazolines in three steps starting from ethanolamine and
carboxylic acids or their esters.
These experiments showed that the use of an acid scavenger
such as solid CaO is essential to avoid side reactions including
polymerization and other thermal decompositions. Indeed, higher
yields of oxazoline were obtained in the presence of CaO. We also
studied pyridine and trioctylamine as bases for trapping the boric
acid. The yields of the 2-methyl-2-oxazoline in both cases were
higher in comparison to the yield of the reaction performed with-
out base under the same conditions. The highest yield of oxazoline
(84%) in the presence of solid CaO must be due to the formation of
insoluble calcium borate by the reaction with boric acid as it forms.
Therefore, CaO acts as trapping agent for the boric acid and sup-
presses side reactions at elevated temperatures. Removal of the
temperatures was proved by a separate experiment in which 2-
methyloxazoline (2 mL) was heated at 115 °C together with
0.05 g of H3BO3 for 3 h. The resulting dark residue was diluted with
a small amount of water (ꢀ5 mL) and precipitated from acetone.
The 1H NMR spectrum of the product in CDCl3 revealed a poly(N-
acetyl ethyleneimine) structure.
This result seems to contradict early reports describing the syn-
thesis of 2-oxazolines by acid-catalyzed cyclodehydration of N-(2-
hydroxyethyl) amides. Reasonable yields in those reports might be
due to low reaction temperatures.
Table 2
Synthesis of oxazolines from N-(2-hydroxyethyl) amides via boron esters
Entry
1
Precursor
Product
Yielda,b (%)
99a (94b)
Bpc/Mpd (°C)
Reference
21
110–112c
O
C
C2H5
2
3
99a (92b)
91a (86b)
128–130c
21
21
O
H
75–77c (0.1 Torr)
4
90a (82b)
80–85c (0.2 Torr)
21
5
6
89a (79b)
86a (75b)
51–52d
21
21
165–171c (0.4 Torr)
7
8
90a (85b)
96–97d
22
22
22a (17b)
Oild
a
b
c
Conversion estimated by 1H NMR spectroscopy.
Yield of isolated product.
Boiling point of isolated product.
Melting point of isolated product.
d

B. Ilkgul et al. / Tetrahedron Letters 51 (2010) 5313–5315
5315
boric acid from the liquid phase in this way results in considerable
rises in the oxazoline yields.
procedure attractive as an alternative protocol for mono-
oxazolines.
The 1H NMR spectrum of the product obtained by thermolysis
of the boron ester of N-(2-hydroxyethyl) acetamide indicated the
2-methyl-2-oxazoline structure. A methyl group signal was ob-
served as a singlet at 1.58 ppm. The protons of the methylene
group adjacent to an oxygen atom occurred as a triplet at
3.90 ppm. The other methylene group of the oxazoline was present
as a triplet at 3.46 ppm.
It is important to note that Barton et al. described a related pro-
cedure based on direct heating of a carboxylic acid and 2-ethanol-
amine mixture in the presence of boric acid as the catalyst.19 Using
3 equiv of ethanolamine and 0.66 equiv of boric acid, this group
was able to attain high yields of 2-oxazolines, but after very long
reaction times (65–72 h). Apparently, the use of excess ethanol-
amine in this procedure deactivates the boric acid and prevents
polymerization. However, this procedure was reported to be
unsuccessful for preparing oxazolines derived from aromatic car-
boxylic acids, though why this procedure fails in these cases is
not clear.
2. General procedure for the preparation of 2-oxazolines
All the oxazolines were prepared by a one-pot, three-step pro-
cess. Thus, 2-hydroxyethyl amides were formed either by aminol-
ysis of carboxylic acid esters with ethanolamine or by dehydration
of the carboxylic acid salt of ethanolamine in the first step. These
were then heated with 0.33 equiv of boric acid to generate the cor-
responding boron esters at 130 °C in the second step. The water
was removed in 3–4 h by azeotropic removal with toluene
(50 mL per 0.1 mol) and collected in a Dean–Stark trap. In the final
step, solid CaO (0.3 mmol) was added to the flask and the temper-
ature of the oil-bath was adjusted to 280 °C and thermolysis was
conducted for 3 h.
The oxazolines (Table 2, entries 1–4) were isolated by distilla-
tion under vacuum (see Table 1) and redistillation gave pure prod-
ucts. Isolation of higher oxazolines (Table 2, entries 5–8) was
carried out by extraction with CH2Cl2 (3 Â 10 mL). The organic
solution was washed with aqueous Na2CO3 solution (50 mL, 5%)
and treated with activated charcoal (1 g per 50 mL). The filtered
solutions were dried over anhydrous Na2SO4 and the CH2Cl2 was
removed by evaporation. The products were recrystallized from
EtOH.
In a similar study, Wipf and Wang described the use of 3-nitro-
phenylboronic acid as a catalyst for dehydration of hydroxamides
and mercaptoamides for preparing oxazolines and thiazolines in
moderate to excellent yields.20 However, the yields of oxazoline
from phenyl hydroxethyl benzamides were reported to be low
(33–41%) even after 30–45 h reaction times.
By contrast, the procedure presented herein is also applicable
for the synthesis of 2-oxazolines derived from aromatic carboxylic
acids. Thermolysis of the boron esters of hydroxyamides derived
from monocarboxylic acids proceeded without significant coloriza-
tion and the crude thermolysis products were highly pure as in-
ferred from their 1H NMR spectra showing only the presence of
water as an impurity. Drying and redistillation yielded pure oxaz-
olines in very good to excellent yields (Table 2).
The hydroxyethyl amide of salicylic acid was an exception; the
oxazoline yield in this case did not exceed 17% using the same
reaction conditions. An attempt to increase the oxazoline yield
by using K2CO3 instead of CaO was not successful, but we did not
study this reaction any further.
This procedure also failed in preparing bis-oxazolines from the
corresponding bis-hydroxamides. The yields of bis-oxazoline from
dihydroxyethyl amides derived from malonic, terephthalic acids,
and pyridine 2,5-dicarboxylic acid were extremely low (8–12%)
under the same reaction conditions. This must be due to the forma-
tion of polymeric boron esters by reaction of the trivalent boric
acid with the bis-hydroxyamides. Owing to the heterogeneity of
the reaction medium in this case, the heat transfer was lowered
and CaO was unable to trap the boric acid formed in the polymer
matrix. To overcome this drawback, the reaction was performed
in silicon oil and liquid paraffin. Despite the difficulties in isolation
of the products from the reaction medium, no significant improve-
ments in the bis-oxazoline yields were observed.
Supplementary data
Supplementary data (materials, instrumentation and spectral
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.07.167.
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In conclusion, the present procedure based on the thermolysis
of boron esters of hydroxyamides represents a useful synthetic
pathway to 2-oxazolines possessing aromatic and aliphatic groups.
In contrast to the boric acid-catalyzed procedure reported by
Barton et al., the present method is also applicable for preparing
2-oxazolines with aromatic moieties. The easy access to the start-
ing materials and no requirement for a special catalyst make this