Open vessel mode microwave-assisted synthesis of 2-oxazolines from carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2009.07.079

Microwave-assisted synthesis of 2-oxazolines from carboxylic acids using the open vessel technique is described. This efficient method involves direct condensation of carboxylic acids with excess 2-amino-2-methyl-1-propanol at 170 °C to give the corresponding 2-oxazolines in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.07.079

Tetrahedron Letters 50 (2009) 5780–5782
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Open vessel mode microwave-assisted synthesis of 2-oxazolines
from carboxylic acids
*
Rishi Sharma, Subramanian K. Vadivel, Richard I. Duclos Jr., Alexandros Makriyannis
Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, 116 Mugar Life Sciences Building, Boston, MA, 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-assisted synthesis of 2-oxazolines from carboxylic acids using the open vessel technique is
described. This efficient method involves direct condensation of carboxylic acids with excess 2-amino-
2-methyl-1-propanol at 170 °C to give the corresponding 2-oxazolines in moderate to excellent yields.
Ó 2009 Published by Elsevier Ltd.
Received 16 April 2009
Revised 13 July 2009
Accepted 15 July 2009
Available online 18 July 2009
Keywords:
Oxazoline
Open vessel mode
Microwave
Carboxylic acid
1. Introduction
2. Results and discussion
Oxazolines have been of great interest1 due to their versatility
as protecting groups,2 as chiral auxiliaries in asymmetric synthe-
sis,3 and as ligands for asymmetric catalysis.4 Various methods
have been developed for the preparation of 2-oxazolines from car-
boxylic acids. One early method (see Scheme 1) used conventional
heating of equimolar concentrations of carboxylic acids 1 and 2-
aminoethanol (2a, R1 = R2 = H) at 200 °C followed by dehydration
of N-acyl-2-aminoethanols 3a using phosphorous pentoxide to
generate oxazolines 4a;5 thionyl chloride and other reagents have
also been used.1 A recent method used 2-chloro-4,6-dimethoxy-
1,3,5-triazine and N-methylmorpholine to generate a complex
(1 equiv), which upon treatment with carboxylic acids 1 and
3 equiv of 2-amino-2-methyl-1-propanol (2b, R1 = R2 = CH3) at
room temperature, gave the corresponding oxazolines 4b.6 More
recently, Kangani and Kelley7 reported using bis(2-methoxy-
ethyl)aminosulfur trifluoride (Deoxo-Fluor, 2.2 equiv) with carbox-
ylic acids 1 in the one-pot synthesis of amides from secondary
amines or 2-oxazolines 4b from 1.8 equiv of 2-amino-2-methyl-
1-propanol (2b) at 0 °C. This method reportedly worked better
than the triazine complex6 coupling for aliphatic and benzoic acids.
We were unable to prepare the corresponding 2-oxazoline of 3,5-
dimethoxyphenylacetic acid by this method, however. We now
report a general and efficient method which is a variation of the
direct synthesis8–10 of 2-oxazolines from carboxylic acids.
The use of microwave heating in organic chemistry has be-
come a valuable tool in drug discovery to carry out reactions
more efficiently than the use of conventional heating by offering
improved reaction yields, decreased reaction times, and solvent-
free conditions.11,12 During the course of our work in the charac-
terization of the endocannabinoid metabolome, we recently con-
verted the carboxylic acid moieties of various fatty acids
associated with endocannabinoids to 4,4-bis(hydroxymethyl)-2-
oxazolines 4c (R1 = R2 = CH2OH) using tris(hydroxymethyl)amino-
methane 2c (R1 = R2 = CH2OH) with microwave heating.10 We
have now extended this methodology by transforming various
carboxylic acids into their corresponding 2-substituted 4,4-di-
methyl-2-oxazolines 4b (R1 = R2 = CH3) with microwave heating
using 2-amino-2-methyl-1-propanol 2b (see Table 1). Various car-
boxylic acids and microwave heating conditions were studied for
this transformation. Microwave heating in closed vessels led to
R1
MW
R2
O
O
R1 R2
R2 R1
170 °C
N
+
OH
OH
R
N
R
OH
H2N
O
R
H
4
1
2
3
a
-R1 = -R2 = -H
-R1 = -R2 = -CH3
-R1 = -R2 = -CH2OH
b
c
* Corresponding author. Tel.: +1 617 373 4200; fax: +1 617 373 7493.
E-mail address: a.makriyannis@neu.edu (A. Makriyannis).
Scheme 1. Reaction of carboxylic acids
2-oxazolines 4.
1
with 2-aminoalcohols
2
to give
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.07.079

R. Sharma et al. / Tetrahedron Letters 50 (2009) 5780–5782
5781
Table 1
Synthesis of 2-oxazolines 4b from carboxylic acids 1 using open vessel mode microwave heating
Entry
Acid
Oxazoline product
Reaction conditions
% Yield
85
COOH
COOH
N
O
1
170 °C, 15 min
Br
Br
N
2
3
170 °C, 15 min
170 °C, 15 min
78
79
O
COOH
N
O
Br
Br
COOH
N
O
4
5
170 °C, 15 min
170 °C, 15 min
83
81
N
COOH
O
OMe
OMe
OMe
OMe
6
7
8
9
N
170 °C, 15 min
170 °C, 15 min
170 °C, 15 min
170 °C, 25 min
73
71
80
78
COOH
O
MeO
MeO
MeO
MeO
N
COOH
O
N
COOH
O
O
O
N
O
OH
OH
N
O
O
O
HOOC
10
11
12
170 °C, 25 min
170 °C, 40 min
170 °C, 25 min
82
73
78
COOH
N
N
O
O
COOH
COOH
N
N

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R. Sharma et al. / Tetrahedron Letters 50 (2009) 5780–5782
intermediate amide 3b formation, but not to cyclization. How-
ever, by performing the reaction in an open vessel mode, which
allows for the dehydration of the amide 3b intermediates, the
2-oxazoline 4b products were prepared in moderate to high
yields.
4. Typical procedure
The 3,5-dimethoxyphenyl acetic acid (500 mg, 2.55 mmol) was
mixed with 2-methyl-2-aminopropanol 2b (1.36 g, 15.3 mmol,
6 equiv) in a CEM microwave vessel. The resulting mixture was
irradiated using the open vessel mode at 170 °C for 15 min. The
reaction mixture was quenched with water (4 mL) and extracted
with ethyl acetate (3 Â 10 mL). The combined organic extracts
were dried over magnesium sulfate, and concentrated by rotoeva-
poration under vacuum to give the crude product, which was then
chromatographed on silica gel using a Biotage SP2 eluting with
acetone/hexane (0–30% acetone gradient) to give the correspond-
ing 2-(3,5-dimethoxyphenylmethyl)-2-oxazoline 4b (464 mg,
1.86 mmol, 73% yield, entry 6) as a faint yellow liquid product that
was homogeneous by TLC (40:60 acetone/hexane, Rf 0.65).
Open vessel mode microwave heating of carboxylic acids in ex-
cess 2-amino-2-methyl-1-propanol 2b without solvent at 150 °C
for 5 min led to intermediate amides 3b with very little oxazoline
4b formation. The optimized reaction conditions required heating
at 170 °C for 15 min, except for entries 9, 10, and 12 which re-
quired 25 min and entry 11 that required 40 min for oxazoline for-
mation. Longer heating tends to result in more decomposition
byproducts. Yields of 2-phenyl (entry 1, 85%; lit.6 78%; lit.7 97%;
lit.9 90%) and aliphatic (entry 11, 73%; lit.6 82%; lit.7 99%; lit.9
84%) 2-oxazolines were comparable to those obtained through
the mild methods using coupling and dehydrating reagents or zinc
oxide-assisted microwave conditions for these thermally stable
carboxylic acids. In addition to aliphatic and aromatic carboxylic
acids, entries 3, 4, and 12 demonstrate the application of this open
vessel methodology to unsaturated carboxylic acids. The method
was also successfully applied to dicarboxylic acids as demon-
strated by entries 9 and 10. We were unable to prepare the corre-
sponding 2-oxazoline 4b of 3,5-dimethoxyphenylacetic acid using
Deoxo-Fluor, but obtained a 73% isolated yield (entry 6) using open
vessel microwave heating with 6 equiv of 2-amino-2-methyl-1-
propanol 2b at 170 °C for 15 min. A comparable 68% isolated yield
of this oxazoline 4b was obtained from 3,5-dimethoxyphenylacetic
acid using 2 equiv of 2-aminoalcohol 2b with longer heating
(40 min) conditions, and when using 1 equiv of 2-aminoalcohol
2b , a 60% isolated yield was obtained after 40 min. Thus, using
an excess of 2-aminoalcohol 2b, when possible, results in higher
conversion to 2-oxazoline, less amide intermediate and other
byproduct impurity, and less product decomposition.
Acknowledgments
This work was supported by Grants DA-7215, DA-3801, DA-152,
and DA-9158 from the National Institute on Drug Abuse. We thank
Lakshmipathi Pandarinathan for valuable discussions.
Supplementary data
Supplementary data (characterizations and 1H NMR spectra of
all 2-oxazoline 4b products) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.07.079.
References and notes
1. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
2. Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich, E. D. J. Org. Chem. 1974,
39, 2787.
3. Meyers, A. I. Acc. Chem. Res. 1978, 11, 375.
4. Hoarau, O.; Haddou-Ait, H.; Castro, M.; Balavoine, G. G. A. Tetrahedron:
Asymmetry 1997, 8, 3755.
5. Wenker, H. J. Am. Chem. Soc. 1935, 57, 1079.
6. Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2003, 44, 2331.
7. Kangani, C. O.; Kelly, D. E. Tetrahedron Lett. 2005, 46, 8917.
8. Zhang, J. Y.; Yu, Q. T.; Liu, B. N.; Huang, Z. H. Biomed. Environ. Mass Spectrom.
1988, 15, 33.
9. García-Tellado, F.; Loupy, A.; Petit, A.; Marrero-Terrero, A. L. Eur. J. Org. Chem.
2003, 22, 4387.
10. Williams, J.; Pandarinathan, L.; Wood, J.; Vouros, P.; Makriyannis, A. AAPS J.
2006, 8, E655.
3. Conclusions
The reported method proved to be simple and efficient for the
conversion of carboxylic acids into 2-oxazolines in good yields. Un-
like some of the previously reported methods, our microwave open
vessel technique requires only the reactants (solvent-free), rela-
tively short reaction times, and simple chromatographic
purifications.
11. Wathey, B.; Tierney, J.; Lidstrom, P.; Westmen, J. Drug Discovery Today 2002, 7,
373.
12. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.