One pot direct synthesis of oxazolines, benzoxazoles, and oxadiazoles from carboxylic acids using the Deoxo-Fluor reagent

Article abstract of DOI:10.1016/j.tetlet.2006.07.032

A one-pot, high yield direct synthesis of various 2-substituted oxazolines, benzoxazoles, and 2-oxadiazoles from carboxylic acids using Deoxo-Fluor reagent is described.

Full text of DOI:10.1016/j.tetlet.2006.07.032

Tetrahedron Letters 47 (2006) 6497–6499
One pot direct synthesis of oxazolines, benzoxazoles, and
oxadiazoles from carboxylic acids using the Deoxo-Fluor reagent
Cyrous O. Kangani,a,* David E. Kelleya and Billy W. Dayb
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
bPharmaceutical Sciences and Chemistry, University of Pittsburgh, Pittsburgh, PA 15213, United States
Received 29 June 2006; revised 7 July 2006; accepted 11 July 2006
Available online 1 August 2006
Abstract—A one-pot, high yield direct synthesis of various 2-substituted oxazolines, benzoxazoles, and 2-oxadiazoles from carb-
oxylic acids using Deoxo-Fluor reagent is described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In recent years, considerable interest has been devoted
to finding a new methodology for the synthesis of oxaz-
oline and oxadiazole building blocks.1,2 These five-mem-
bered heterocycles belong to an important class of
compounds due to their biological activities.3,4 Oxazo-
line moieties have a wide variety of applications such
as chiral auxiliaries, synthetic intermediates, and pro-
tecting groups.5–7 On the other hand, oxadiazole rings
are important class of heterocycles with a wide range
of pharmaceutical and biological activities (anti-inflam-
matory, anticonvulsant, and analgesic activities).8
pling reagents and difficulty in removal of excess reagent
and by-products.
As part of our program to develop new analytical meth-
ods for location of double bonds in polyunsaturated
fatty acids, as well as new methods to quantify free fatty
acids in human plasma, we discovered a highly efficient
conversion of carboxylic acids to related oxazolines and
oxadiazoles, namely a one-pot synthesis using the
Deoxo-Fluor reagent.
Recently, we reported the use of the Deoxo-Fluor re-
agent for the one step synthesis of amides and oxazo-
lines.14 Here, we demonstrate that this reagent is very
efficient at promoting the coupling and/or coupling/
cyclodehydration of carboxylic acids with amines and/
or 2-amino alcohol, giving amides and/or oxazolines,
respectively, in high yields and purities (P93%). The
simplicity and mildness of this protocol compared to
the reported methods led us to examine the applicability
of the process in a number of other cases. Typically, the
reaction is run by addition of the Deoxo-Fluor reagent
into a mixture of the carboxylic acid and amino alcohol
in CH2Cl2 at 0 ꢁC. When other amino alcohols (chiral
and aromatic) were explored, we found that in all cases
we obtained the desired cyclized products (oxazolines
and benzoxazoles) in high yield, along with the
bis(methoxyethyl)amide (less than 10%) (Scheme 1).15
Numerous methods for the synthesis of oxazolines have
been reported. Widely used methods are (i) reaction of
amino alcohols with carboxylic acids9 or carboxylic acid
derivatives (ortho esters, nitriles, imino ether hydrochlo-
rides, and acyl benzotriazoles);10 and (ii) cyclodehydra-
tion of b-hydroxyamides with a number of reagents
including the Burgess reagent, diethylaminosulfur tri-
fluoride (DAST), PPh3/DEAD, and the Vilsmeier
reagent.11 Oxadiazoles have been prepared by (i)
cyclodehydration of diacylhydrazines with various
anhydrous reagents and oxidation of acylhydrazones
with different oxidizing agents;12 and (ii) direct reaction
of an acid chloride and/or a carboxylic acid with an acid
hydrazide and hydrazine.13 Drawbacks of these methods
include drastic thermal conditions (160–220 ꢁC), long
reaction times (12–18 h), modest yield, expensive cou-
To eliminate this impurity, we made a slight modifica-
tion to our procedure. The carboxylic acid (1 equiv),
2-aminophenol (2.2 equiv), diisopropylethylamine (DI-
PEA) (2.6 equiv) and potassium carbonate (K2CO3)
*
Corresponding author. Tel.: +1 412 647 6796; fax: +1 412 692
2165; e-mail: kanganic@msx.dept-med.pitt.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.032

6498
C. O. Kangani et al. / Tetrahedron Letters 47 (2006) 6497–6499
iPr2NEt, 0 oC
O
O
O
R2
R1
R1
O
Deoxo-Fluor,
CH2Cl2
R1
OH
R2
N
N
OH +
H2N
2
a > 90 %
b < 10 %
Scheme 1.
Table 1. Deoxo-Fluor mediated direct cyclization of carboxylic acids to oxazolines and benzoxazoles
(H or NO2)
(H or NO2)
iPr2NEt, 0 oC
Deoxo-Fluor,
CH2Cl2
RCO2H
or
+
O
O
H2N
or
OH
N
N
H2N
OH
R
R
1-6
7-18
(S)-Phenylglycinol
2-Aminophenol
5-Nitro-2-aminophenol
Palmitic acid
linoleic acid
Elaidic acid
Benzoic acid
p-Toluic acid
p-Nitrobenzoic acid
1 (95%)a,b
2 (95%)a,b
3 (97%)a,b
4 (97%)a,b
5 (94%)a,b
6 (98%)a,b
7 (99%)a,b
8 (98%)a,b
9 (97%)a,b
10 (99%)a,b
11 (98%)a,b
12 (95%)a,b
13 (98%)a,b
14 (97%)a,b
15 (98%)a,b
16 (98%)a,b
17 (98%)a,b
18 (98%)a,b
a Yield of isolated pure product.
b The purity of all products was determined to be >95% by 1H and 13C NMR spectroscopy and GC–MS analysis.
(excess) were dissolved in CH2Cl2, cooled to 0 ꢁC, trea-
ted with the Deoxo-Fluor reagent (2.2 equiv) and vor-
texed. The reaction took place rapidly and cleanly
within 30–120 min.16 To the best of our knowledge, this
is the first example of a one-pot method for the efficient
generation of benzoxazoles from carboxylic acids at
0 ꢁC. Table 1 shows the results we obtained for the di-
rect reaction of various carboxylic acids with various
amino alcohols. The products were generally obtained
in high purity and high yield. Aliphatic carboxylic acids
(entries 1–3 saturated and unsaturated (cis and trans)) as
well as aromatic acids (entries 4–6 electron-rich and elec-
tron poor) were all reacted with aromatic amino alco-
hols (2-aminophenol and 2-amino-5-nitrophenol) to
give equally excellent results. When a chiral amino alco-
hol (S)-phenylglycinol was employed, less than 2% race-
mization was observed.17 These results illustrate the
general applicability of this method to the preparation
of various oxazolines and benzoxazoles under very mild
condition and short reaction times.
The efficiency and the ease of the reaction setup led us to
speculate that a one pot process for the synthesis of
oxadiazoles might be possible. The same procedure was
in fact successfully applied to the preparation of oxadi-
azoles. The carboxylic acid (1 equiv), benzhydrazide
(2.2 equiv), diisopropylethylamine (DIPEA) (2.6 equiv)
and potassium carbonate (K2CO3) (excess) were dis-
solved in CH2Cl2, cooled to 0 ꢁC, and treated with
Deoxo-Fluor reagent (2.2 equiv) for 2 h to furnish the
desired products, 2,5-disubstituted 1,3,4-oxadiazoles in
excellent yields (Table 2). We would like to mention that
when the alkyl instead of aryl acid hydrazide was applied,
the yield of the reaction was low (less than 45%).18
Table 2. Deoxo-Fluor direct cyclization of carboxylic acids to oxadiazoles
O
O
iPr2NEt, 0 oC
H2N
O
N
+
N
H
R
OH
R
Deoxo-Fluor,
CH2Cl2
N
19-24
Entry
Carboxylic acid
Product (Yield)a,b
Reaction time (h)
1
2
3
4
5
6
Palmitic acid
Linoleic acid
Elaidic acid
Benzoic acid
p-Toluic acid
19 (82%)a,b
20 (80%)a,b
21 (79%)a,b
22 (95%)a,b
23 (94%)a,b
24 (90%)a,b
3
3
3
2
2
2
p-Nitrobenzoic acid
a Yield of pure isolated products.
b The purity of all products was determined to be >95% by 1H and 13C NMR spectroscopy and GC–MS analysis.

C. O. Kangani et al. / Tetrahedron Letters 47 (2006) 6497–6499
6499
Vorbruggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49,
9353–9372.
¨
In conclusion, we have developed an efficient, straight-
forward and common method for the synthesis of oxaz-
olines, benzoxazoles, and oxadiazoles from various
carboxylic acids using the Deoxo-Fluor reagent. The
reaction is carried out in one-pot and is operationally
simple, mild, and gives products with high yields and
purity. Moreover, short reaction times, ease of
work-up and high degree of chemoselectivity are other
noteworthy advantages of this new method.
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Acknowledgments
This investigation was supported by funding from
National Institutes of Health, NIDDK (DK046204),
and by the University of Pittsburgh Obesity and Nutri-
tion Research Center (DK46204).
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´