One pot direct synthesis of amides or oxazolines from carboxylic acids using Deoxo-Fluor reagent

Article abstract of DOI:10.1016/j.tetlet.2005.10.068

A mild and highly efficient one pot-one step condensation and/or condensation-cyclization of various acids to amides and/or oxazolines using Deoxo-Fluor reagents is described. Parallel syntheses of various free fatty acids with 2-amino-2,2-dimethyl-1-propanol resulted with excellent yields.

Full text of DOI:10.1016/j.tetlet.2005.10.068

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8917–8920
One pot direct synthesis of amides or oxazolines
from carboxylic acids using Deoxo-Fluor reagent
Cyrous O. Kangani* and David E. Kelley
Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Received 21 September 2005;revised 12 October 2005;accepted 17 October 2005
Available online 2 November 2005
Abstract—A mild and highly efficient one pot–one step condensation and/or condensation–cyclization of various acids to amides
and/or oxazolines using Deoxo-Fluor reagents is described. Parallel syntheses of various free fatty acids with 2-amino-2,
2-dimethyl-1-propanol resulted with excellent yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Natural fatty acid amides have been detected in total
lipids of microorganisms,1,2 plants3 and animals.4 Very
recently, both fatty acid amides and ethanol-amides
have been found to be physiological signaling molecules
in the brain.5,6 GC–MS separation of fatty acid amides
has been studied, mainly picolinyl esters7 and 4,4-di-
methyl-2-oxazolines (DMOX)8 derivatives of fatty
acids, and their GC–MS properties have been reviewed
in detail9. DMOX derivatives exhibit good chromato-
graphic properties;indeed, only slight changes in
temperature programming are necessary to obtain,
retention times similar to those of their corresponding
fatty acid methyl esters (FAME). However, drastic
thermal conditions (150–190 ꢁC) and long reaction times
(6–12 h) are necessary to obtain sufficient derivatization
yield.9
(BOP)12,13 and N,N0-dicyclohexylcarbodiimide (DCC).14
More recently, new systems were developed using
carbon tetrabromide/triphenylphosphine,15 2-chloro-1-
methylpyridinium iodide (CMPI) and/or 2-bromide-1-
methylpyridinium iodide (BMPI),16 titanium and/or
divalent tin reagents,17 or a lanthanide chloride18 as
catalyst. Drawbacks of these methods include modest
yields, expensive coupling reagents and difficulty in
removal of excess reagent and reagent byproducts.
Comparative analysis of acyl fluorides and acyl chlo-
rides shows that acyl fluoride possess greater stability
than the corresponding acid chlorides towards neutral
oxygen nucleophiles (water and methanol), yet have
high reactivity toward anionic nucleophiles and
amines.19 Moreover acid fluorides react more like acti-
vated esters than acid halides (Cl, Br and I). Recently,
Lal and co-workers reported a fluorinating reagent bis
(2-methoxyethyl) aminosulfur trifluoride (Deoxo-Fluor)
as a thermally stable alternative to the diethylaminosul-
fur trifluoride (DAST).20,21 Studies by Tunoori et al.
have demonstrated that Deoxo-Fluor converts carbox-
ylic acids to acid fluorides and then into Weinreb amides
in one flask.22 In 2000, the WipfÕs and WilliamsÕs groups
reported the use of DAST as well as Deoxo-Fluor in
cyclodehydration reactions to convert b-hydroxy amides
to oxazolines under mild reaction conditions.23
There is considerable interest in the synthesis of amides
as well as oxazolines by direct combination of carboxylic
acids and amines and/or amino alcohols, as the methods
employed may be utilized in peptide and natural product
syntheses. Different methodologies have been reported
in the literature,10 the most common being conversion
of a carboxylic acid moiety to a more reactive functional
group, such as an acyl chloride, mixed anhydride, acyl
azide, N-acylbenzotriazoles11 or active esters, or via an
in situ activation of carboxylic group by some peptide
coupling reagents such as benzotriazol-1-yl-N-oxy-
tris(dimethylamino)phosphonium hexafluorophosphate
As part of our search for new methods to quantify free
fatty acids in human plasma, we sought a convenient
synthesis of their free fatty amides to provide stable
chromatographic behavior and high volatility. In the
present work, we report the use of Deoxo-Fluor for
*
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 ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.068

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C. O. Kangani, D. E. Kelley / Tetrahedron Letters 46 (2005) 8917–8920
Table 1. Deoxo-Fluor direct cyclization of carboxylic acids to oxazo-
lines
the one pot and direct conversion of carboxylic acids
into their corresponding amides and/or oxazolines
under mild conditions with excellent yields. We first
examined the reported procedure.22 The carboxylic acid
(1 equiv) was dissolved in CH2Cl2, cooled to 0 ꢁC and
treated with diisopropylethylamine (DIPEA) (1.5 equiv)
and Deoxo-Fluor (1.2 equiv). After 30 min (acid fluoride
formation), an amine (1.5 equiv) was added. After
15 min, the reaction was warmed to room temperature
and stirred for 3–8 h. While the yields of amides were
good to excellent, the duration of the reaction was long,
making it tedious for use with high sample volumes in
clinical studies. Based on previous reports23,24 of the effi-
ciency and mild nature of the Deoxo-Fluor reagent in
condensation and dehydration cyclization reactions,
we hypothesized that it could be used for the direct con-
version of carboxylic acid moiety to an oxazoline. We
explored the possibility of mixing the acids and amines
together before adding the Deoxo-Fluor reagent. After
a series of experimentation, it was established that the
oxazoline could be readily obtained by treatment of a
mixture palmitic acid and 2-amino-2-methyl-1-propanol
with Deoxo-Fluor at 0 ꢁC for 30 min. Encouraged by
this result, we incorporated various aliphatic (saturated
and unsaturated), and aromatic carboxylic acids with a
variety of amines using this methodology giving the
results shown in Tables 1 and 2.
O
O
Deoxo-Fluor
CH2Cl2, 0oC
OH
+
H2N
N
2
R
OH
R
1
Entry
Carboxylic acid
Product
(yield%)a,b
Reaction
time (min)
1
2
3
4
5
6
7
1a, palmitic acid
1b, stearic acid
1c, oleic acid
1d, linoleic acid
1e, benzoic acid
1f, p-toluic acid
1g, p-nitrobenzoic acid
2a, 98
2b, 99
2c, 96
2d, 96
2e, 97
2f, 97
2g, 96
30
30
30
30
30
30
30
a Yield of isolated pure product.
b Products were characterized by NMR, MS and by comparison with
authentic samples.
n-heptane. The combined organic layer was then dried
over MgSO4, filtered, and concentrated. The GC ana-
lysis showed the compound was P93% pure without
any purification. The excellent yields, ease of reaction
setup and mild reaction condition of this method,
encouraged us to utilize it for parallel synthesis of five
different amides as well as oxazoline of free fatty acids
(Fig. 1a–d).
In conclusion, we have developed a new, very mild and
efficient one pot/one step method to a range of amides
and oxazolines from various carboxylic acids (aliphatic,
unsaturated aliphatic and aromatic acids) with various
amines. The utility of this highly efficient method for
The carboxylic acid (1 equiv), amine (1.8 equiv) and
diisopropylethylamine (2.2 equiv) were dissolved in
CH2Cl2, cooled to 0 ꢁC, and treated with Deoxo-Fluor
(2.2 equiv). After 30 min, the reaction was quenched
with saturated sodium bicarbonate and extracted with
Table 2. Deoxo-Fluor direct condensation of carboxylic acids to amides
O
O
Deoxo-Fluor
CH2Cl2, 0oC
HNR1R2
R
NR1R2
R
OH
+
1
3-5
Entry
Carboxylic acid
Amine
Product (yield%)a,b
Reaction time (min)
1
2
3
4
5
6
7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a, palmitic acid
1b, stearic acid
1c, oleic acid
1d, linoleic acid
1e, benzoic acid
1f, p-toluic acid
1g, p-nitrobenzoic acid
1a, palmitic acid
1b, stearic acid
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Diethyl amine
Diethyl amine
Diethyl amine
Diethyl amine
Diethyl amine
Diethyl amine
Diethyl amine
Dimethyl amine
Dimethyl amine
Dimethyl amine
Dimethyl amine
Dimethyl amine
Dimethyl amine
Dimethyl amine
3a, 94
3b, 94
3c, 91
3d, 90
3e, 96
3f, 94
3g, 93
4a, 99
4b, 99
4c, 98
4d, 95
4e, 99
4f, 97
4g, 97
5a, 99
5b, 99
5c, 96
5d, 94
5e, 98
5f, 97
5g, 97
45
45
45
45
45
45
45
30
30
30
30
30
30
30
30
30
30
30
30
30
30
1c, oleic acid
1d, linoleic acid
1e, benzoic acid
1f, p-toluic acid
1g, p-nitrobenzoic acid
1a, palmitic acid
1b, stearic acid
1c, oleic acid
1d, linoleic acid
1e, benzoic acid
1f, p-toluic acid
1g, p-nitrobenzoic acid
a Yield of isolated pure product.
b Products were characterized by NMR, MS and by comparison with authentic samples.

C. O. Kangani, D. E. Kelley / Tetrahedron Letters 46 (2005) 8917–8920
8919
Figure 1. GC chromatograms of the reaction products of C16:0 (palmitic acid), C17:0 (heptadecanoic acid), C18:0 (stearic acid), C18:1 (oleic acid),
and C18:2 (linoleic acid) with 2-amino-3-methyl-1-propanol, pyrrolidine, dimethyl amine and diethylamine, respectively. Conditions: GC-FID
(Agilent GC-6890) the flow rate of carrier gas (He) was set at 5 mL/min. The oven temperature was programmed to initiate at 160 ꢁC and held for
2 min. The temperature was raised to 200 ꢁC at a rate of 20 ꢁC and held for 4 min, and finally increased to 270 ꢁC at a rate of 5 ꢁC and held for
23 min. Column: SPD-1 fused-silica capillary column (30 m · 0.53 mm I.D., 0.10 lm film thickness;Supelco, Bellefonte, CA, USA). (a) Oxazolines
derivatives;(b) pyrrolidine amide derivatives;(c) dimethyl amide derivatives;(d) diethyl amide derivatives.
combinatorial solution-phase synthesis was demon-
strated. The ease, efficiency, and mild conditions of this
reaction make it superior to the existing methods. We
are currently using this method for the estimation of free
fatty acids in plasma of patients.
Acknowledgements
This investigation was supported by
(DK046204) from National Institutes of Diabetes and
Digestive and Kidney Diseases. We thank Professor
a
Grant

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C. O. Kangani, D. E. Kelley / Tetrahedron Letters 46 (2005) 8917–8920
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